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Sample records for allogeneic mixed lymphocyte

  1. The immunosuppressive compound 2-acetyl-4-tetrahydroxybutyl imidazole inhibits the allogeneic mixed lymphocyte reaction by sequestration of a recirculating subpopulation of T cells.

    PubMed Central

    Bradbury, M G; Doherty, K V; Parish, C R; Lyons, A B

    1996-01-01

    2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) is an immunosuppressive component of caramel food colouring that causes lymphopenia in mice and rats by an unknown mechanism. In this study we investigated some of the affects of THI on the murine immune system. Initially we showed that splenic T lymphocytes from mice treated with 50 mg/l THI in their drinking water were unable to launch a mixed lymphocyte reaction (MLR) against allogeneic stimulator cells, and had decreased and delayed interleukin-2 (IL-2) production. However, these T cells exhibited a normal proliferative response to concanavalin A (Con A), immobilized anti-CD3 monoclonal antibody (mAb) and anti-CD3 plus anti-CD28 mAb. Furthermore, the MLR response could be restored by the addition of IL-2 to the MLR culture. Homing studies using intravenous injection of fluorescence-labelled splenocytes showed that THI treatment decreased absolute numbers of labelled T and B lymphocytes in the blood and the spleen. Furthermore, these labelled cells reappeared in the blood and the spleen when mice were taken off THI, indicating that lymphocyte recirculation and splenic homing were modified reversibly by THI treatment. Cessation of THI treatment also resulted in a rapid reappearance of MLR responsiveness in the spleen, indicating that THI treatment does not functionally impair recirculating T cells. Collectively these data are compatible with the concept that a rapidly recirculating population of T cells, which produce IL-2 in an allogeneic MLR, are lost from the blood and spleen following THI treatment, and are sequestered in other, yet to be identified, tissues. PMID:8666439

  2. Allogeneic Transplantation for Chronic Lymphocytic Leukemia

    PubMed Central

    Laurenti, Luca; Tarnani, Michela; Chiusolo, Patrizia; Sorà, Federica; Sica, Simona

    2010-01-01

    Even if Chronic lymphocytic leukemia (CLL) often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called “poor-risk” patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT) CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment. Allogeneic transplant has potential curative role in CLL, however burden with very high transplant related mortality (TRM) rates of 38–50%. A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT) has been the introduction of non-myeloablative or reduced intensity conditioning (RIC) regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL) activity. The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD) affecting quality of life, high graft rejection and infection rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients. Sensitive minimal residual disease (MRD) quantification has strong prognostic impact after transplant. PMID:21415973

  3. Mechanisms of suppression in mixed allogeneic chimeras

    SciTech Connect

    Sykes, M.; Sachs, D.H.

    1988-08-01

    Cells with the ability to suppress cytotoxic T lymphocyte generation are found in the spleens of whole-body-irradiated (WBI) mixed allogeneic and syngeneic bone marrow transplant recipients in the early weeks after BMT. Previous studies have indicated that suppression is mediated by null cells similar to natural suppressor (NS) cells (1), and have ruled out several possible trivial explanations for the suppressive effect. We report here the results of additional experiments designed to assess possible mechanisms of suppression. We compared the cell populations after 5 days' incubation of cultures containing normal responding splenocytes plus irradiated allogeneic stimulator cells, with or without a cocultured suppressive chimeric splenocyte population. The data indicate that total viable cell yields are only slightly reduced, if at all, in suppressed cultures, but that the proportion of T cells is markedly reduced as measured at the end of the incubation period. Splenocytes from early BMT recipients do not appear to proliferate during the suppression of a mixed lymphocyte culture, and such populations represent only 15% of cells at the end of the 5-day incubation period. Suppression is strongest when the suppressive population is added at the initiation of MLC, and is lost if addition is delayed beyond day 3. Suppression can be overcome by T cell growth factor (TCGF)--and, to a lesser extent, by recombinant IL-2 (rIL-2), although resting suppressive populations do not consume appreciable amounts of these lymphokines. These results therefore suggest that suppression in MLC may occur primarily during the induction of helper T lymphocytes.

  4. Ro/SSA inhibits the autologous mixed lymphocyte reaction.

    PubMed Central

    Karsh, J; Harley, J B; Goldstein, R; Lazarovits, A I

    1993-01-01

    To test the hypothesis that the Ro/SSA autoantigen can be recognized as antigenic by the human immune system, lymphocytes obtained from normal volunteers were used in in vitro assays evaluating the ability of Ro/SSA (mol. wt 60 kD) to induce B and/or T cell responses. Bovine Ro/SSA strongly inhibited the autologous mixed lymphocyte reaction in a dose-dependent manner without similar effects on concurrently performed allogeneic mixed lymphocyte reactions or T cell proliferation induced by phytohaemagglutinin. Using three colour FACS analysis, Ro/SSA was found to decrease the percentage of CD4+CD45+RA+ T cells in the proliferative, S+(G2+M), phase of the cell cycle. Associated with the decrease in the percentage of suppressor-inducer cells, was the finding that Ro/SSA was able to augment RF production in pokeweed mitogen stimulated cultures of peripheral blood lymphocytes. PMID:7678209

  5. Spinal fluid lymphocytes responsive to autologous and allogeneic cells in multiple sclerosis and control individuals.

    PubMed Central

    Birnbaum, G; Kotilinek, L; Schwartz, M; Sternad, M

    1984-01-01

    Spinal fluid lymphocytes from multiple sclerosis (MS) patients and controls were stimulated with either autologous non-T cells or with allogeneic non-T cells followed by stimulation with autologous non-T lymphocytes. Cells responding to these stimuli were cloned and their proliferative responses to autologous and allogeneic MS and normal non-T cells were measured. Large numbers of clones with specific patterns of reaction to both autologous and allogeneic cells were obtained from lymphocytes in MS cerebrospinal fluid (CSF), but only occasionally from cells in control CSF. Patterns of responses among clones from a particular CSF were similar and often identical, which suggested that cells in MS CSF were relatively restricted in their specificities. Surface antigen phenotyping of the clones showed them to be predominantly OKT4+, with 13% OKT8+ and 11% OKT4+8+. Peripheral T cells that were stimulated and cultured in parallel with CSF cells were different in that they usually did not give rise to as many clones nor were their patterns of response similar. Many CSF clones were heteroclitic, that is they responded to particular allogeneic cells but not autologous cells. Lymphocytes in MS CSF thus appear to represent a selected population of cells with a high frequency of responsiveness to autologous and allogeneic antigens. Such responses may be evidence for immune regulation within the central nervous system or could represent responses to altered-self antigens. PMID:6237121

  6. Defective autologous mixed lymphocyte reactivity in multiple sclerosis.

    PubMed Central

    Hirsch, R L

    1986-01-01

    T cells from patients with multiple sclerosis (MS) and normal controls were assessed for their ability to respond in the autologous mixed lymphocyte reaction (AMLR). Cells from stable MS patients demonstrated a significant defect in their proliferative response to non-T cells in comparison to normal controls. Despite the defective AMLR response, T cells from MS patients reacted as well as T cells from normal controls to allogeneic stimuli. Furthermore, MS non-T-cells were fully capable of stimulating allogeneic MLR responses by normal and MS T cells. Since the T4+ cell is the major subpopulation which proliferates in the AMLR, these studies suggest a functional defect in a subpopulation of T4+ cells in MS patients. Since the AMLR may represent an important mechanism by which immune responses are regulated, a defect in the ability of MS T cells to respond to autologous cells could account for several of the autoimmune features of the disease. PMID:2942317

  7. Rejection of the second allogeneic graft in a child with Fanconi anemia reversed by antilymphocyte globulin and donor lymphocyte infusion.

    PubMed

    Abdelkefi, Abderrahman; Ben Othman, T; Ladeb, S; Torjman, L; Ben Abdeladhim, A

    2003-01-01

    Rejection after allogeneic bone marrow transplantation for Fanconi anemia (FA) is a complication with a high risk of mortality. We describe a patient who, following a second episode of rejection after a second allogeneic stem cell transplantation, was successfully treated with antilymphocyte globulin, followed by donor lymphocyte infusion. At three and a half years after donor lymphocyte infusion, she is alive with a Karnofsky score of 90%. Her molecular chimerism is of donor origin. Thus, donor lymphocyte infusion can be considered as a therapy option for rejection after allogeneic bone marrow transplantation for FA. PMID:14671621

  8. Different stimulating capacity of B and T lymphocytes in primary and secondary allogeneic reactions: cellular detection of HLA-D products on T lymphocytes.

    PubMed

    Wollman, E E; Cohen, D; Fradelizi, D; Sasportes, M; Dausset, J

    1980-11-01

    The present study was undertaken to define the best way to produce and to test primed lymphocyte typing (PLT) cells using B- and T-enriched lymphocyte suspensions. Intrafamilial PLT cells were produced with primed unseparated and T purified lymphocytes against haplo-identical donors' T and B cells. These PLT cells were then restimulated with a panel of related or unrelated individuals' T and B cells and with allogeneic in vitro activated T cells. The best discrimination was obtained when PLT reagents, regardless of the production method, were restimulated by a B-enriched population of peripheral lymphocytes. Furthermore, the results have shown that enriched primed or unprimed T cell suspensions stimulated by enriched T lymphocytes did not give any proliferation. Experiments performed to explain the results led us to distinguish 2 different phenomena: in primary cultures, the addition of monocytes autologous to the responder cell restored the proliferation of enriched T cells stimulated by T lymphocytes. In secondary cultures, the addition of monocytes autologous to the PLT cell did not restore the proliferation of PLT lymphocytes stimulated by enriched T cells. This was shown to be due to the lack of Dr antigen on the stimulating cell: if allogeneically activated T cells were used as stimulating lymphocytes, a DR-specific proliferative response appeared. This correlates with serologic findings were DR determinants are found on activated T cells and not on unprimed T lymphocytes. However, this difference might be only quantitative, since peripheral lymphocytes could be primed by T cells and be DR specifically restimulated. PMID:6968771

  9. Mycoplasma-dependent activation of normal lymphocytes: induction of a lymphocyte-mediated cytotoxicity for allogeneic and syngeneic mouse target cells.

    PubMed Central

    Aldridge, K E; Cole, B C; Ward, J R

    1977-01-01

    Mycoplasma arthritidis, M. hominis, and M. arginini were tested for their ability to induce a cytotoxic response from normal CBA mouse lymphocytes against 51Cr-labeled allogeneic target cells. In most cases, the mycoplasmas alone were not toxic for the target cells. Furthermore, the mycoplasmas did not result in decreased lymphocyte viability but, in fact, contributed to enhanced lymphocyte survival. In the absence of normal CBA lymphocytes, mycoplasmas alone did not induce a significant amount of cell damage in either the allogeneic or the syngeneic target cells. Strains of M. arthritidis and M. hominis, when added to the lymphocyte-target cell mixtures, induced statistically significant increases in 51Cr release from both target cell types at each assay period after 6 h. The release of 51Cr was taken as a measure of cell death. M. arginini induced only low levels of cytotoxicity or none at all. Both arthritogenic and non-arthritogenic strains of M. arthritidis induced the cytotoxic response. The degree of cytotoxicity produced was directly related to the size of the initial inoculum. The presence or absence of serum in the culture medium did not contribute significantly to the cytotoxicity response. PMID:562853

  10. Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10. D2----B10)

    SciTech Connect

    Ildstad, S.T.; Wren, S.M.; Bluestone, J.A.; Barbieri, S.A.; Stephany, D.; Sachs, D.H.

    1986-01-01

    Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. Experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it.

  11. Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation

    PubMed Central

    Fellowes, Vicki; Rose, Jeremy J.; Odom, Jeanne; Pittaluga, Stefania; Steinberg, Seth M.; Blacklock-Schuver, Bazetta; Avila, Daniele N.; Memon, Sarfraz; Kurlander, Roger J.; Khuu, Hahn M.; Stetler-Stevenson, Maryalice; Mena, Esther; Dwyer, Andrew J.; Levine, Bruce L.; June, Carl H.; Reshef, Ran; Vonderheide, Robert H.; Gress, Ronald E.; Fowler, Daniel H.; Hakim, Frances T.; Bishop, Michael R.

    2012-01-01

    Donor lymphocyte infusion (DLI), a standard relapse treatment after allogeneic stem cell transplantation (AlloSCT), has limited efficacy and often triggers GVHD. We hypothesized that after AlloSCT tumor-infiltrating donor lymphocytes could be costimulated ex vivo to preferentially activate/expand antitumor effectors. We tested the feasibility and safety of costimulated, tumor-derived donor lymphocyte (TDL) infusion in a phase 1 trial. Tumor was resected from 8 patients with B-cell malignancy progression post-AlloSCT; tumor cell suspensions were costimulated with anti-CD3/anti-CD28 Ab-coated magnetic beads and cultured to generate TDL products for each patient. Costimulation yielded increased proportions of T-bet+FoxP3− type 1 effector donor T cells. A median of 2.04 × 107 TDL/kg was infused; TDLs were well tolerated, notably without GVHD. Two transient positron emission tomography (PET) responses and 2 mixed responses were observed in these refractory tumors. TDL are a feasible, tolerable, and novel donor cell therapy alternative for relapse after AlloSCT. This trial is registered at clinicaltrials.gov as no. NCT00445666. PMID:22289893

  12. Nonspecific suppressor T cells cause decreased mixed lymphocyte culture reactivity in bone marrow transplant patients

    SciTech Connect

    Harada, M.; Ueda, M.; Nakao, S.; Kondo, K.; Odaka, K.; Shiobara, S.; Matsue, K.; Mori, T.; Matsuda, T.

    1986-07-15

    Decreased reactivity in mixed lymphocyte culture (MLC) was observed in patients within 1 yr after allogeneic and autologous bone marrow transplantation. Suppressor activity of peripheral blood mononuclear cells (PBMC) from transplant patients was studied by adding these cells as modulator cells to a bidirectional MLC with cells from normal individuals. PBMC from transplant patients markedly suppressed MLC reactivity in a dose-dependent manner. Suppressor activity was present in cells forming rosettes with sheep erythrocytes. Treatment of modulator cells with monoclonal antibodies against T cell differentiation antigens (OKT8, OKIa1) and complement completely abolished suppression of MLC. Suppressor activity was unaffected by 30 Gy irradiation. Suppressor activity declined gradually after transplantation and was inversely correlated with MLC reactivity of each patient at a significant level (p less than 0.01). These observations suggest that OKT8+ Ia+ radioresistant suppressor T cells play a role in the development of decreased MLC reactivity observed during the early post-transplant period.

  13. Long-term survival of murine allogeneic bone marrow chimeras: effect of anti-lymphocyte serum and bone marrow dose

    SciTech Connect

    Norin, A.J.; Emeson, E.E.; Veith, F.J.

    1981-02-01

    Graft-vs-host disease (GVHD) and failure of donor stem cells to engraft permanently are two major obstacles to successful bone marrow transplantation. The effect of a single large dose of anti-lymphocyte serum (ALS) on mice receiving various numbers of H-2 incompatible bone marrow cells was evaluated. Most animals receiving lethal total body irradiation (TBI) and allogeneic marrow died within 45 days due to GVHD. Mice that were given ALS 6 to 24 h before TBI and bone marrow 24 h after irradiation survived in good health for more than 200 days. These cell preparations caused lethal GVHD in third party mice indicating that the lack of alloreactivity was specific to the strain in which the unresponsiveness was originally induced.

  14. Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes.

    PubMed Central

    Baxevanis, C. N.; Tsiatas, M. L.; Cacoullos, N. T.; Spanakos, G.; Liacos, C.; Missitzis, I.; Papadhimitriou, S. I.; Papamichail, M.

    1997-01-01

    The present study investigated the ability of supernatants collected from cultures of healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) to induce, upon brief exposure, tumour-reactive cytotoxic lymphocytes in cancer patients' PBMCs. ACD3S enhanced natural killer (NK) and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. ACD3S contained increased levels of interleukins (IL) 1, 2, 6, 7 and 12, as well as of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). MAbs against these cytokines significantly reduced the ACD3S-induced cytotoxicity. ACD3S-induced cytotoxicity was not inhibited by anti-CD4, CD8 and MHC class I MAbs, but was markedly reduced in the presence of MAb against CD18. In contrast to HD-PBMC, ACD3S derived from cancer patients' lymphocytes exhibited lower levels of the above-mentioned cytokines and exerted reduced biological activity. In conclusion, ACD3S are able to activate, upon short-term incubation, tumour-reactive lymphocytes from cancer patients' PBMCs that lyse a variety of tumour targets, including autologous tumours. ACD3S contain high levels of certain cytokines that positively influence the induction of autologous tumour-reactive lymphocytes. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer. They may also be indicated in the construction of cytokine cocktails that have the ability to induce anti-tumour cytotoxicity. PMID:9376269

  15. Phase I Trial of Adoptive Cell Transfer with Mixed-Profile Type-I/Type-II Allogeneic T Cells for Metastatic Breast Cancer

    PubMed Central

    Hardy, Nancy M.; Mossoba, Miriam E.; Steinberg, Seth M.; Fellowes, Vicki; Yan, Xiao-Yi; Hakim, Frances T.; Babb, Rebecca R.; Avila, Daniele; Gea-Banacloche, Juan; Sportès, Claude; Levine, Bruce L.; June, Carl H.; Khuu, Hahn M.; Carpenter, Ashley E.; Krumlauf, Michael C.; Dwyer, Andrew J.; Gress, Ronald E.; Fowler, Daniel H.; Bishop, Michael R.

    2011-01-01

    PURPOSE Metastatic breast cancer (MBC) response to allogeneic lymphocytes requires donor T-cell engraftment and is limited by graft-versus-host disease (GVHD). In mice, Type-II-polarized T cells promote engraftment and modulate GVHD whereas Type-I-polarized T cells mediate more potent graft-versus-tumor (GVT) effects. This Phase-I translational study evaluated adoptive transfer of ex-vivo-costimulated Type-I/Type-II (T1/T2) donor T cells with T-cell-depleted (TCD) allogeneic stem-cell transplantation (AlloSCT) for MBC. EXPERIMENTAL DESIGN Patients had received anthracycline, taxane and antibody therapies, been treated for metastatic disease and an HLA-identical-sibling donor. Donor lymphocytes were costimulated ex vivo with anti-CD3/anti-CD28 antibody-coated magnetic beads in IL-2/IL-4-supplemented media. Patients received reduced-intensity conditioning, donor stem cells and T1/T2 cells, and monitoring for toxicity, engraftment, GVHD and tumor response; results were compared with historical controls, identically treated except for T1/T2-product infusions. RESULTS Mixed Type-I/Type-II CD4+-T cells predominated in T1/T2 products. Nine patients received T1/T2 cells at Dose-Level 1 (5×106 cells/kg). T-cell donor chimerism reached 100% by a median of 28 days. Seven (78%) developed acute GVHD. At Day +28, five patients had partial responses (56%) and none had MBC progression; thereafter, two patients had continued responses. Donor-T-cell engraftment and tumor responses appeared faster than in historical controls, but GVHD rates were similar and responders progressed early, often following treatment of acute GVHD. CONCLUSION Allogeneic T1/T2 cells were safely infused with TCD-AlloSCT, appeared to promote donor engraftment, and may have contributed to transient early tumor responses. PMID:21948234

  16. Functional characteristics of intraepithelial lymphocytes from mouse small intestine. II. In vivo and in vitro responses of intraepithelial lymphocytes to mitogenic and allogeneic stimuli.

    PubMed Central

    Mowat, A M; MacKenzie, S; Baca, M E; Felstein, M V; Parrott, D M

    1986-01-01

    Although isolated intraepithelial lymphocytes (IEL) have been shown to have specific and non-specific cytolytic functions, their ability to proliferate in response to T-cell mitogens or alloantigens is controversial. Here we show that IEL from mouse small intestine do not respond to mitogens such as concanavalin A and phytohaemagglutinin A or in mixed lymphocyte reactions unless an accessory spleen cell is also present. Adherent spleen cells possess the most potent helper function, but a dividing accessory cell may also be required. Supernatants from stimulated lymphocytes also assist IEL to proliferate in vitro, particularly in the presence of adherent accessory cells. IEL could not mediate lethal graft-versus-host disease in irradiated hosts, but could produce popliteal lymph node hypertrophy or splenomegaly in unirradiated hosts. Thus, IEL have the potential for proliferative activities characteristic of T cells, but they require accessory cells and/or factors such as interleukin-2 for their function in vitro and in vivo. PMID:2942464

  17. Transferrin receptor expression by stimulated cells in mixed lymphocyte culture.

    PubMed Central

    Salmon, M; Bacon, P A; Symmons, D P; Walton, K W

    1985-01-01

    Transferrin receptor (TRFr) expression by cells in mixed lymphocyte culture increases steadily for the first 5 days, but then reaches a plateau. By the sixth day in culture, about 20% of viable cells express TRFr in two-way mixed lymphocyte reactions. This subpopulation of TRFr-positive cells represents the proliferating population; it is heterogeneous, containing T-cell blasts and smaller cells which are a mixture of T and non-T cells. A small group of non-T cells have phenotypic similarity to natural killer (NK) cells. T cells appear to divide earlier in the course of the response than non-T cells. The biphasic nature of this response and the slower non-T reactivity may be due to a secondary stimulation of non-T cells by factors released from activated T cells (such as interleukin-2). PMID:2982734

  18. Effects of xenogeneic, allogeneic and isogeneic thymus grafts on lymphocyte populations in peripheral lymphoid organs of the nude rat.

    PubMed

    Hougen, H P; Klausen, B; Stenvang, J P; Kraemmer, J; Rygaard, J

    1987-04-01

    In order to gain information about the effect of xenografted, allografted and isografted thymic tissue on peripheral lymphoid organs of immune-deficient rats, athymic nude LEW rats of ninth backcross-intercross were grafted with fetal calf and neonatal BDIX and LEW thymus. Adrenalectomy was also performed in some animals in order to obtain a possible enhancement of the immunological reconstitution. Both groups of isogeneic-thymus-grafted animals had more T helper cells than the nude controls. Furthermore, they had more densely populated paracortical areas in the inguinal lymph nodes and higher lymphocyte counts in the thoracic duct lymph. Finally, the inguinal lymph nodes contained germinal centres. Xenogeneic and allogeneic thymus transplants did not induce constant changes in the parameters observed compared with the untreated nudes. No clear difference was observed between the adrenalectomized and non-adrenalectomized thymic-isografted animals. We therefore conclude that of all the experimental animals examined the isografted nude rats show by far the best response and that adrenalectomy seems unnecessary for the success of neonatal isogeneic thymus grafts. We also conclude that the isogeneic-thymus-grafted nude rat is a suitable tool for immunological reconstitution studies. PMID:3496487

  19. Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT.

    PubMed

    Marsh, Rebecca A; Lane, Adam; Mehta, Parinda A; Neumeier, Lisa; Jodele, Sonata; Davies, Stella M; Filipovich, Alexandra H

    2016-01-28

    Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels ≤0.15 vs ≥0.16 μg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P = .0002), and 32% vs 8%, respectively (P = .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level ≤0.15 μg/mL was 21%, vs 42% with levels of 0.16 to 4.35 μg/mL, and 100% with levels >4.35 μg/mL (P = .003). Patients with alemtuzumab levels ≤0.15 or 0.16 to 0.56 μg/mL had higher lymphocyte counts at day +30 and higher T-cell counts at day +100 compared with patients with levels ≥0.57 μg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 μg/mL. PMID:26644451

  20. Prevention of hepatitis C virus infection by adoptive allogeneic immunotherapy using suicide gene-modified lymphocytes: an in vitro proof-of-concept.

    PubMed

    Leboeuf, C; Roser-Schilder, J; Lambotin, M; Durand, S; Wu, T; Fauvelle, C; Su, B; Bôle-Richard, E; Deschamps, M; Ferrand, C; Tiberghien, P; Pessaux, P; Baumert, T F; Robinet, E

    2015-02-01

    Hepatitis C virus (HCV)-induced, end-stage liver disease is a major indication for liver transplantation, but systematic graft reinfection accelerates liver disease recurrence. Transplantation recipients may be ineligible for direct-acting antivirals, owing to toxicity, resistance or advanced liver disease. Adoptive immunotherapy with liver graft-derived, ex vivo-activated lymphocytes was previously shown to prevent HCV-induced graft reinfections. Alternatively, the applicability and therapeutic efficacy of adoptive immunotherapy may be enhanced by 'ready for use' suicide gene-modified lymphocytes from healthy blood donors; moreover, conditional, prodrug-induced cell suicide may prevent potential side effects. Here, we demonstrate that allogeneic suicide gene-modified lymphocytes (SGMLs) could potently, dose- and time-dependently, inhibit viral replication. The effect occurs at effector:target cell ratios that exhibits no concomitant cytotoxicity toward virus-infected target cells. The effect, mediated mostly by CD56+ lymphocytes, is interleukin-2-dependent, IFN-γ-mediated and, importantly, resistant to calcineurin inhibitors. Thus, post-transplant immunosuppression may not interfere with this adoptive cell immunotherapy approach. Furthermore, these cells are indeed amenable to conditional cell suicide; in particular, the inducible caspase 9 suicide gene is superior to the herpes simplex virus thymidine kinase suicide gene. Our data provide in vitro proof-of-concept that allogeneic, third-party, SGMLs may prevent HCV-induced liver graft reinfection. PMID:25394253

  1. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice.

    PubMed

    Verda, Larissa; Kim, Duck An; Ikehara, Susumu; Statkute, Laisvyde; Bronesky, Delphine; Petrenko, Yevgeniya; Oyama, Yu; He, Xiang; Link, Charles; Vahanian, Nicholas N; Burt, Richard K

    2008-02-01

    Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant complication, graft-versus-host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with >5% donor chimerism remained free of diabetes and insulitis, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model. PMID:17975228

  2. Peripheral blood late mixed chimerism in leucocyte subpopulations following allogeneic stem cell transplantation for childhood malignancies: does it matter?

    PubMed

    Pichler, Herbert; Fritsch, Gerhard; König, Margit; Daxberger, Helga; Glogova, Evgenia; Pötschger, Ulrike; Breuer, Sabine; Lawitschka, Anita; Güclü, Ece D; Karlhuber, Susanne; Holter, Wolfgang; Haas, Oskar A; Lion, Thomas; Matthes-Martin, Susanne

    2016-06-01

    The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 ± 7% for MC, and 18 ± 4% for CC patients (P = 0·734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 ± 4% for CC patients vs. 22 ± 8% for MC patients (day +50; P = 0·935) and 21 ± 4% vs. 20 ± 7% (day +100; P = 0·907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 ± 7% vs. 19 ± 4%; P = 0·960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4·7; P = 0·008), for AML (HR 3·0; P = 0·02) and from mismatched donors (HR 3·1; P = 0·03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse. PMID:26996395

  3. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Maury, Sébastien; Lemoine, François M; Hicheri, Yosr; Rosenzwajg, Michelle; Badoual, Cécile; Cheraï, Mustapha; Beaumont, Jean-Louis; Azar, Nabih; Dhedin, Nathalie; Sirvent, Anne; Buzyn, Agnès; Rubio, Marie-Thérèse; Vigouroux, Stéphane; Montagne, Olivier; Bories, Dominique; Roudot-Thoraval, Françoise; Vernant, Jean-Paul; Cordonnier, Catherine; Klatzmann, David; Cohen, José L

    2010-07-21

    Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T(reg)s) may reduce alloreactivity, the major component of the graft-versus-tumor effect. In the setting of donor lymphocyte infusion after hematopoietic stem cell transplantation, we postulated that T(reg) depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of T(reg)-depleted donor lymphocyte infusion was studied in 17 adult patients with malignancy relapse after hematopoietic stem cell transplantation. All but one had previously failed to respond to at least one standard donor lymphocyte infusion, and none had experienced graft-versus-host disease. Two of the 17 patients developed graft-versus-host disease after their first T(reg)-depleted donor lymphocyte infusion and experienced a long-term remission of their malignancy. Four of the 15 patients who did not respond after a first T(reg)-depleted donor lymphocyte infusion received a second T(reg)-depleted donor lymphocyte infusion combined with lymphodepleting chemotherapy aimed to also eliminate recipient T(reg)s. All four developed acute-like graft-versus-host disease that was associated with a partial or complete and durable remission. In the whole cohort, graft-versus-host disease induction through T(reg) depletion was associated with improved survival. These results suggest that T(reg)-depleted donor lymphocyte infusion is a safe, feasible approach that induces graft-versus-host or graft-versus-tumor effects in alloreactivity-resistant patients. In patients not responding to this approach, the combination of chemotherapy-induced lymphodepletion of the recipient synergizes with the effect of T(reg)-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy. PMID:20650872

  4. Allogeneic Hematopoietic Cell Transplantation for Patients with Mixed Phenotype Acute Leukemia.

    PubMed

    Munker, Reinhold; Brazauskas, Ruta; Wang, Hai Lin; de Lima, Marcos; Khoury, Hanna J; Gale, Robert Peter; Maziarz, Richard T; Sandmaier, Brenda M; Weisdorf, Daniel; Saber, Wael

    2016-06-01

    Acute biphenotypic leukemias or mixed phenotype acute leukemias (MPAL) are rare and considered high risk. The optimal treatment and the role of allogeneic hematopoietic stem cell transplantation (alloHCT) are unclear. Most prior case series include only modest numbers of patients who underwent transplantation. We analyzed the outcome of 95 carefully characterized alloHCT patients with MPAL reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2012. The median age was 20 years (range, 1 to 68). Among the 95 patients, 78 were in first complete remission (CR1) and 17 were in second complete remission (CR2). Three-year overall survival (OS) of 67% (95% confidence interval [CI], 57 to 76), leukemia-free survival of 56% (95% CI, 46 to 66), relapse incidence of 29% (95% CI, 20 to 38), and nonrelapse mortality of 15% (95% CI, 9 to 23) were encouraging. OS was best in younger patients (<20 years), but no significant differences were observed between those 20 to 40 years of age and those who were 40 years or older. A matched-pair analysis showed similar outcomes comparing MPAL cases to 375 acute myelogenous leukemia or 359 acute lymphoblastic leukemia cases. MPAL patients had more acute and a trend for more chronic graft-versus-host disease. No difference was observed between patients who underwent transplantation in CR1 versus those who underwent transplantation in CR2. AlloHCT is a promising treatment option for pediatric and adult patients with MPAL with encouraging long-term survival. PMID:26903380

  5. Transplantation tolerance in primates after total lymphoid irradiation and allogeneic bone marrow injection

    SciTech Connect

    Smit, J.A.; Hill, R.R.H.; Myburgh, J.A.; Browde, S.

    1980-08-01

    After total lymphoid irradiation (TLI), allogeneic bone marrow (BM) injection, and organ transplantation in baboons, there is a prolonged period of reduced lymphocyte proliferative responsiveness to polyclonal mitogens and allogeneic lymphocytes. The effect observed is greater with the use of fractionated TLI than after single doses of irradiation. Suppressor cell activity can be demonstrated in vitro in most animals by inhibition of mixed lymphocyte reactivity (MLR) by mitomycin-treated recipient lymphocytes harvested after TLI, with or without allogeneic BM injection, and organ transplantation. Preliminary data suggest the presence of both donor-specific and nondonor-specific suppression, although other interpretations are possible, and suppressor phenomena may not be responsible for the transplantation tolerance observed.

  6. T cells recognizing leukemic CD34+ progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation

    PubMed Central

    Smit, Willem M.; Rijnbeek, Marion; van Bergen, Cornelis A. M.; Fibbe, Willem E.; Willemze, Roel; Falkenburg, J. H. Frederik

    1998-01-01

    Adoptive immunotherapy with donor lymphocyte infusions (DLI) is an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. To identify the effector and target cell populations responsible for the elimination of the leukemic cells in vivo we developed an assay to measure the frequency of T lymphocyte precursor cells capable of suppressing leukemic progenitor cells. Target cells in this assay were CML cells that were cultured in the presence of stem cell factor, interleukin 3, granulocyte–macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [3H]thymidine incorporation at day 7 represented the proliferation of the progeny of the CD34+ CML progenitor cells, and not of the more mature CD34− CML cells. Effector cells were mononuclear cells, which were used in a limiting dilution analysis to measure the frequencies of CML progenitor cell-inhibitory lymphocyte precursors (PCILp) in peripheral blood of seven patients before and after DLI for relapsed CML. In the six patients who entered complete remission, a 5- to 100-fold increase of PCILp was found during the clinical response. In the patient with resistant relapse the frequency of PCILp was <10 per ml before and after DLI. Leukemia-reactive helper T lymphocyte precursor frequencies remained unchanged after DLI. A significant increase in cytotoxic T lymphocyte precursor frequency against more mature leukemic cells was found in only two responding patients. These results indicate that T cells specifically directed against CD34+ CML progenitor cells mediate the antileukemic effect of DLI. PMID:9707616

  7. Effects of T cell depletion in radiation bone marrow chimeras. III. Characterization of allogeneic bone marrow cell populations that increase allogeneic chimerism independently of graft-vs-host disease in mixed marrow recipients

    SciTech Connect

    Sykes, M.; Chester, C.H.; Sundt, T.M.; Romick, M.L.; Hoyles, K.A.; Sachs, D.H. )

    1989-12-01

    The opposing problems of graft-vs-host disease vs failure of alloengraftment severely limit the success of allogeneic bone marrow transplantation as a therapeutic modality. We have recently used a murine bone marrow transplantation model involving reconstitution of lethally irradiated mice with mixtures of allogeneic and syngeneic marrow to demonstrate that an allogeneic bone marrow subpopulation, removed by T cell depletion with rabbit anti-mouse brain serum and complement (RAMB/C), is capable of increasing levels of allogeneic chimerism. This effect was observed in an F1 into parent genetic combination lacking the potential for graft-vs-host disease, and radiation protection studies suggested that it was not due to depletion of stem cells by RAMB/C. We have now attempted to characterize the cell population responsible for increasing allogeneic chimerism in this model. The results indicate that neither mature T cells nor NK cells are responsible for this activity. However, an assay involving mixed marrow reconstitution in an Ly-5 congenic strain combination was found to be more sensitive to small degrees of stem cell depletion than radiation protection assays using three-fold titrations of bone marrow cells. Using this assay, we were able to detect some degree of stem cell depletion by treatment with RAMB/C, but not with anti-T cell mAb. Nevertheless, if the effects of alloresistance observed in this model are considered, the degree of stem cell depletion detected by such mixing studies in insufficient to account for the effects of RAMB/C depletion on levels of allogeneic chimerism, suggesting that another cell population with this property remains to be identified.

  8. The biological effect of three thymosin fraction 5 polypeptides in the murine mixed lymphocyte reaction.

    PubMed Central

    Baxevanis, C N; Perez, S; Kokkinopoulos, D; Papamichail, M

    1985-01-01

    The biological effects of three thymosin fraction 5 polypeptides, designated as beta 10, beta 4, and alpha 1 were tested in the MLR of mouse splenocytes, lymph node cells and thymocytes against syngeneic or allogeneic stimulators. It was found that all three polypeptides, after in vivo and in vitro treatment of the responder cell population, could enhance the allogeneic MLR. These polypeptides were also able to induce significant syngeneic MLR in systems where responder cells were used against irradiated syngeneic splenocytes. In addition, while beta 4 was shown to have a weak stimulatory effect on allogeneic MLR utilizing thymocytes as the responder cell type, alpha 1 could strongly induce such responses when syngeneic splenocytes were included into the culture system. Preincubation of purified mature T cells or thymocytes with alpha 1 has shown these cells to be the target of this polypeptide action. Thus, it appears that thymosin fraction 5 polypeptides not only initiate differentiation processes of immature T cells, but also exert their effects on mature T lymphocytes. PMID:3156810

  9. A comprehensive flow-cytometric analysis of graft infiltrating lymphocytes, draining lymph nodes and serum during the rejection phase in a fully allogeneic rat cornea transplant model

    PubMed Central

    Maenz, Martin; Morcos, Mourice

    2011-01-01

    Purpose To establish a cornea transplant model in a pigmented rat strain and to define the immunologic reaction toward corneal allografts, by studying the cellular and humoral immune response after keratoplasty. Methods Full thickness penetrating keratoplasty was performed on Brown Norway (RT1n) recipients using fully major histocompatibility complex (MHC)-mismatched Piebald-Viral-Glaxo (PVG; RT1c) donors. Using multicolor flow cytometry (FACS) we quantified and compared the cellular composition of draining versus non-draining lymph nodes (LN). Furthermore, we developed an isolation method to release viable graft infiltrating lymphocytes (GIL) and subjected them to phenotypic analysis and screened serum from transplanted animals for allo-antibodies. Results Assessing ipsi-lateral submandibular LN we find ample evidence for post surgical inflammation such as elevated absolute numbers of cluster of differentiation (CD)4+, CD8+, B-cells, and differential expression of CD134. However, we could not unequivocally identify an allo-antigen-specific immune response. FACS analysis of lymphocytes isolated from collagenase digested rejected corneas revealed the following six distinct subpopulations: MHC-2+ cells, CD4+ T-cells, CD8+ T-cells, CD161dull large granular lymphocytes, CD3+ CD8+ CD161dull natural killer (NK)-T-cells and CD161high CD3- NK cells. At post-operation day (POD)-07 only CD161dull MHC-2neg large granular lymphocytes (LGLs) were detected in syngeneic and allo-grafts. In concordance with an increase in B-cell numbers we often detected copious amounts of allo-antibodies in serum of rejecting animals, in particular immunoglobulin (Ig) M (IgM), immunoglobulin (Ig) G1 (IgG1), and IgG2a. Conclusions Our results demonstrate that despite its immune privileged status and low-responder characteristics of the strain combination, allogeneic corneal grafts mount a full fledged T helper1 (Th1) and Th2 response. The presence of NK-T-cells and NK-cells in rejecting corneas

  10. Durable Remission of Renal Cell Carcinoma in Conjuncture with Graft versus Host Disease following Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion: Rule or Exception?

    PubMed Central

    van Bergen, Cornelis A. M.; Verdegaal, Elisabeth M. E.; Honders, M. Wilhelmina; Hoogstraten, Conny; Steijn-van Tol, A. Q. M. Jeanne; de Quartel, Linda; de Jong, Joan; Meyering, Maaike; Falkenburg, J. H. Frederik; Griffioen, Marieke; Osanto, Susanne

    2014-01-01

    Allogeneic stem cell transplantation (alloSCT) followed by donor lymphocyte infusion (DLI) can be applied as immunotherapeutic intervention to treat malignant diseases. Here, we describe a patient with progressive metastatic clear cell renal cell carcinoma (RCC) who was treated with T cell depleted non-myeloablative alloSCT and DLI resulting in disease regression accompanied by extensive graft versus host disease (GVHD). We characterized the specificity of this immune response, and detected a dominant T cell population recognizing a novel minor histocompatibility antigen (MiHA) designated LB-FUCA2-1V. T cells specific for LB-FUCA2-1V were shown to recognize RCC cell lines, supporting a dominant role in the graft versus tumor (GVT) reaction. However, coinciding with the gradual disappearance of chronic GVHD, the anti-tumor effect declined and 3 years after alloSCT the metastases became progressive again. To re-initiate the GVT reaction, escalating doses of DLI were given, but no immune response could be induced and the patient died of progressive disease 8.5 years after alloSCT. Gene expression studies illustrated that only a minimal number of genes shared expression between RCC and professional antigen presenting cells but were not expressed by non-malignant healthy tissues, indicating that in patients suffering from RCC, GVT reactivity after alloSCT may be unavoidably linked to GVHD. PMID:24454818

  11. Expression Profiles of Cloned Channel Catfish (Ictalurus punctatus) Lymphoid Cell Lines and Mixed Lymphocyte Cultures

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Clonal channel catfish lymphoid cell lines and mixed lymphocyte cultures (MLC) have proven extremely useful in examining immune responses at the cellular and molecular levels. To date clonal catfish cell lines and MLC have been biologically and phenotypically characterized using a variety of techniq...

  12. Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

    PubMed Central

    Sorror, Mohamed L.; Storer, Barry E.; Sandmaier, Brenda M.; Maris, Michael; Shizuru, Judith; Maziarz, Richard; Agura, Edward; Chauncey, Thomas R.; Pulsipher, Michael A.; McSweeney, Peter A.; Wade, James C.; Bruno, Benedetto; Langston, Amelia; Radich, Jerald; Niederwieser, Dietger; Blume, Karl G.; Storb, Rainer; Maloney, David G.

    2008-01-01

    Purpose We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. Patients and Methods Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. Results Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy ≥ 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. Conclusion Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients. PMID:18794548

  13. Poor Mixed Lymphocyte Reaction Stimulatory Capacity of Leukemic B Cells of Chronic Lymphocytic Leukemia Patients Despite the Presence of Ia Antigens

    PubMed Central

    Halper, James P.; Fu, Shu Man; Gottlieb, Alice B.; Winchester, Robert J.; Kunkel, Henry G.

    1979-01-01

    The human Ia-like antigens, selectively expressed on B lymphocytes, are now recognized to be closely associated with, or identical to, the gene products of the major histocompatibility complex responsible for stimulation in the mixed lymphocyte reaction. The leukemic B lymphocytes of patients with chronic lymphocytic leukemia express these antigens very well. In the present study they were readily detected by several techniques utilizing both allo- and heteroantisera. However, the leukemic B cells from most patients were found to be extremely poor stimulating cells in the mixed lymphocyte reaction. This was particularly apparent when comparisons were made on a B-cell basis with isolated normal B lymphocytes. Leukemic cell death, abnormal kinetics of leukemic cell-mediated stimulation, and serum or cellular suppressor factors do not appear to explain these findings. Studies comparing cells from a leukemic patient with those of her HLA identical sibling and results of mixed lymphocyte reactions between normal and leukemic subjects discordant for D-region-associated Ia antigens ruled out genetic explanations for the differences observed. Experiments with normal peripheral blood mononuclear cells depleted of T cells and monocytes exclude the quantitative deficiency of monocytes which is found in the peripheral blood of most leukemic patients as an explanation. The present results with chronic lymphocytic leukemia cells indicate that the mere expression of the Ia-like antigens by cell populations does not render them effective stimulators. The accumulated evidence obtained indicate that abnormalities, particularly of membrane function and metabolism, known to occur in chronic lymphocytic leukemia lymphocytes may be involved in the poor stimulatory capacity of the leukemic B cells. PMID:159311

  14. [Detection of mixed lymphoid chimerism after allogeneic bone marrow transplantation: demonstration by interphase cytogenetics in paraffin-embedded tissue].

    PubMed

    Friedrich, T; Ott, G; Kalla, J; Helbig, W; Schwenke, H; Kubel, M; Pönisch, W; Feyer, P; Friedrich, A

    1994-01-01

    In bone marrow transplantation (BMT) the detection of residual host lymphoid or haematopoietic cells surviving conditioning therapy is because of its association to graft-versus-host disease, graft-versus-leukemia reaction, and relapse of leukemia a matter of great interest. We studied the occurrence of this mixed lymphoid chimerism (MC) in the formol-fixed lymphatic tissue of lymph nodes and spleen from 21 autopsies after allogeneic sex-mismatched BMT (5 females, 16 males, survival 5 to 1140 days after BMT). In situ hybridisation with biotinylated centromer-specific anti-X- and anti-Y-chromosome probes was performed on pepsin-digested paraffin sections. The number of double X-, single X-, and Y-chromosome bearing cells was analysed microscopically. Because of artefacts only 14 cases remained for valid investigation. MC was detected in 6 cases (5 out of 11 males 5 days to 840 days and 1 out of 3 females 76 days after BMT). MC occurred after whole body irradiation with 10 Gy (n = 5) and 7 Gy (n = 1). In 1 autopsy relapse of leukemia caused host cell infiltration. Cases with MC did not express histological signs of acute or chronic graft-versus-host disease, but 5 out of 8 with complete lymphoid chimerism did. The sensitivity of interphase cytogenetics on paraffin embedded tissue is low. PMID:7534002

  15. Skewed T cell receptor repertoire of Vδ1+ γδ T lymphocytes after human allogeneic haematopoietic stem cell transplantation and the potential role for Epstein–Barr virus-infected B cells in clonal restriction

    PubMed Central

    Fujishima, N; Hirokawa, M; Fujishima, M; Yamashita, J; Saitoh, H; Ichikawa, Y; Horiuchi, T; Kawabata, Y; Sawada, K-I

    2007-01-01

    The proliferation of Vδ1+ γδ T lymphocytes has been described in various infections including human immunodeficiency virus (HIV), cytomegalovirus (CMV) and malaria. However, the antigen specificity and functions of the human Vδ1+ T cells remain obscure. We sought to explore the biological role for this T cell subset by investigating the reconstitution of T cell receptor (TCR) repertoires of Vδ1+ γδ T lymphocytes after human allogeneic haematopoietic stem cell transplantation (HSCT). We observed skewed TCR repertoires of the Vδ1+ T cells in 27 of 44 post-transplant patients. Only one patient developed EBV-associated post-transplant lymphoproliferative disorder in the present patient cohort. The -WGI- amino acid motif was observed in CDR3 of clonally expanded Vδ1+ T cells in half the patients. A skew was also detected in certain healthy donors, and the Vδ1+ T cell clone derived from the donor mature T cell pool persisted in the recipient's blood even 10 years after transplant. This T cell clone expanded in vitro against stimulation with autologous EBV–lymphoblastoid cell lines (LCL), and the Vδ1+ T cell line expanded in vitro from the same patient showed cytotoxicity against autologous EBV–LCL. EBV-infected cells could also induce in vitro oligoclonal expansions of autologous Vδ1+ T cells from healthy EBV-seropositive individuals. These results suggest that human Vδ1+ T cells have a TCR repertoire against EBV-infected B cells and may play a role in protecting recipients of allogeneic HSCT from EBV-associated disease. PMID:17425654

  16. Chimerism-based pre-emptive immunotherapy with fast withdrawal of immunosuppression and donor lymphocyte infusions after allogeneic stem cell transplantation for pediatric hematologic malignancies.

    PubMed

    Horn, Biljana; Petrovic, Aleksandra; Wahlstrom, Justin; Dvorak, Christopher C; Kong, Denice; Hwang, Jimmy; Expose-Spencer, Jueleah; Gates, Michael; Cowan, Morton J

    2015-04-01

    The presence of increasing host chimerism or persistent mixed chimerism (MC) after hematopoietic stem cell transplantation for leukemia in children is a predictor of relapse. To reduce the risk of relapse, we prospectively studied post-transplantation chimerism-based immunotherapy (IT) using fast withdrawal of immunosuppression (FWI) and donor lymphocyte infusions (DLI) in children with early post-transplantation MC. Forty-three children with hematologic malignancies at 2 institutions were enrolled prospectively in this study from 2009 until 2012 and were followed for a mean of 42 (SD, 10) months. Twelve patients (28%) were assigned to the observation arm based on the presence of graft-versus-host disease (GVHD) or full donor chimerism (FDC), and 5 (12%) sustained early events and could not undergo intervention. Twenty-six (60%) patients with MC were assigned to IT with FWI, which started at a median of 49 days (range, 35 to 85 days) after transplantation. Fourteen patients proceeded to DLI after FWI. Toxicities of treatment included GVHD, which developed in 19% of patients undergoing intervention, with 1 of 26 (4%) dying from GVHD and 1 (4%) still requiring therapy for chronic GVHD 21 months after DLI. Patients with MC undergoing IT had similar 2-year event-free survival (EFS) (73%; 95% confidence interval (CI), 55% to 91%) compared with patients who achieved FDC spontaneously (83%; 95% CI, 62% to 100%); however, because 50% of all relapses in the IT occurred later than 2 years after transplantation, the EFS declined to 55% (95% CI, 34% to 76%) at 42 (SD, 11) months. There were no late relapses in the observation group. EFS in the entire cohort was 58% (95% CI, 42% to 73%) at 42 (SD, 11) months after transplantation. Evidence of disease before transplantation remained a significant predictor of relapse, whereas development of chronic GVHD was protective against relapse. PMID:25644958

  17. Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults.

    PubMed

    Le Bourgeois, Amandine; Peterlin, Pierre; Guillaume, Thierry; Delaunay, Jacques; Duquesne, Alix; Le Gouill, Steven; Moreau, Philippe; Mohty, Mohamad; Campion, Loïc; Chevallier, Patrice

    2016-08-01

    This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (≥615/mm(3); hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (≥395/mm(3); HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony-stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure. PMID:27118570

  18. Staphylococcal protein A primed leukocytes enhance the autologous mixed lymphocyte reaction

    SciTech Connect

    Berk, G.I.; Lederman, M.M.; Liebman, M.L.; Ellner, J.J.

    1986-04-01

    Human peripheral blood mononuclear cells (PBMC) were preincubated for 3 days in medium alone or with various mitogens then washed and irradiated. The preincubated cells then were cultured with autologous T-cells in an autologous mixed lymphocyte reaction (AMLR). Staphylococcal protein A (SPA) pretreatment of PBMC enhanced autologous T-lymphocyte proliferation from 1375 +/- 321 cpm (mean +/- SEM untreated PBMC) to 42,467 +/- 7985 cpm (SPA primed PBMC) (p less than 0.01). The ability of SPA treated PBMC to enhance the AMLR was not simply a reflection of their proliferation in preculture, as PBMC precultured with phytohemagglutinin and concanavalin A showed greater proliferation than SPA-treated PBMC yet only minimally enhanced the AMLR. Kinetic studies and pre-exposure of PBMC to graded doses of gamma radiation showed that SPA augmentation of the AMLR was mediated by 2 components which differed in kinetics and radiosensitivity. Although incubation of PBMC with SPA did not increase the percentage of cells with detectable surface Ia antigen, SPA did increase the density of Ia in the preincubated cells. Cell separation studies revealed that SPA enhancement of the AMLR was not mediated by T-cells, but was mediated by a non-adherent non-E-rosetting fraction of cells. SPA enhancement of the AMLR was associated with an increased Ia density in the stimulator population but not with an increase in Ia positive cells and was mediated by proliferation-dependent and proliferation-independent mechanisms.

  19. Suppressor cell hyperactivity relative to allogeneic lymphocyte proliferation as a manifestation of defective T-T-cell interactions in systemic lupus erythematosus

    SciTech Connect

    Stenina, M.A.; Potapova, A.A.; Biryukov, A.V.; Skripnik, A.Yu.; Cheredeev, A.N.

    1987-01-01

    The authors study the state of immunoregulatory process in patients with systemic lupus erythematosus at the T-T-cell interaction level and seek to test the possibility of the pharmacological modulation of this process. The proliferative activity of mononuclear lymphocytes, extracted from the blood of ten lupus patients, was assessed by measuring the incorporation of tritiated thymidine into cultures stimulated by phytohemagglutinin, concanavalin, and theophylline. The comparative effects of each of these agents on the immunoregulatory and proliferative activity of the lymphocytes are reported.

  20. In vitro characteristics on human lymphocyte functions of a new immunomodulatory agent, a cyclic peptide, cyclomunine.

    PubMed Central

    Niaudet, P; Beaurain, G; Leibowitch, J; Bach, J F

    1980-01-01

    Cyclomunine, a cyclic peptide extracted from Fusarium equisiti, inhibits responses of human lymphocytes to mitogens, soluble antigens and allogeneic cells and the proliferation of lymphoblastoid cell lines. Cyclomunine has little effect on small lymphocytes but acts rather on lymphoblasts. It has no effect on fibroblasts and myeloid cells. Cyclomunine partially inhibits the generation of suppressor cells induced by Con A and the generation of cytotoxic T cells in a mixed lymphocyte culture and totally inhibits the in vitro synthesis of Ig by PBL. Cyclomunine merits consideration as a new in vitro anti-lymphoblastic agent. PMID:6451339

  1. [Effect of synthetic beta-carotene on the formation of cytolytic T-lymphocytes].

    PubMed

    Efimov, S A; Vakulova, L A; Rytenko, A N; Samokhvalov, G I; Sergeev, I M

    1984-06-01

    The effect of intraperitoneal injection of beta-carotene in different doses on the formation of cytolytic T lymphocytes (CTL) in a one-way mixed lymphocyte culture (MLC) of allogeneic mice was studied. The maximal cytotoxic activity of lymphocytes was attained in the MLC with splenocytes of mice which received 10 mg/kg beta-carotene 6 days before experimentation. The correlation was studied between the beta-carotene ability to stimulate CTL formation and antineoplastic activity. It was discovered that injection of beta-carotene in doses and times provoking maximal CTL induction had no effect on the animals' lifespan and the size of transplanted sarcoma 180. PMID:6234949

  2. CT60 single-nucleotide polymorphism as a surrogate marker for donor lymphocyte infusion outcome after allogeneic cell transplantation for acute leukemia.

    PubMed

    Metaxas, Y; Bertz, H; Spyridonidis, A; Spyroupoulou-Vlachou, M; Porzelius, C; Finke, J

    2012-03-01

    The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. PMID:21552305

  3. Characterization of a cellular inhibitory activity affecting the human autologous mixed lymphocyte reaction

    SciTech Connect

    Haynes, M.K.

    1987-01-01

    The human autologous mixed lymphocyte reaction, peripheral blood T cells are stimulated to proliferate when co-cultured with irradiated, autologous, non-T cells was studied. ({sup 3}H)-thymidine uptake was maximal on day 7 and observable on day 9. Non-adherent and adherent fractions of non-T population and lectin-activated T cell blasts contributed. Unseparated non-T stimulator cells were used. Autologous T cells, when added as irradiated third party cells, reduced AMLR proliferative responses. Depletion of Fc IgG receptor-bearing cells (T{gamma}) from T cell population by (a) IgG-sensitized ox erythrocyte rosetting (EA-rosettes) or (b) adsorption of the T{gamma} cells onto a Sepharose 6MB {approximately} BSA/anti-BSA immune complex column resulted in enhanced AMLR proliferation not attributed solely to an increase in CD8+ AMLR responder cell phenotype. Isolated T{gamma} populations exhibited a reversed helper/suppressor phenotype containing HLA DR+ and CD8+ cells. Dual labeling studies demonstrated 7-24% of CD8+ cells expressed DR antigens. After separation, AMLR proliferative capacity was localized in T-depleted population.

  4. Disseminated Bacillus Calmette-Guérin (BCG) infection following allogeneic hematopoietic stem cell transplant in a patient with Bare Lymphocyte Syndrome type II

    PubMed Central

    Abu-Arja, R.F.; Gonzalez, B.E.; Jacobs, M.R.; Cabral, L.; Egler, R.; Auletta, J.; Arnold, J.; Cooke, K.R.

    2016-01-01

    We describe the first case, to our knowledge, of disseminated Mycobacterium bovis Bacillus Calmette-Guérin infection in a child with Bare Lymphocyte Syndrome type II after undergoing hematopoietic stem cell transplantation (HSCT). The patient presented 30 days post HSCT with fever and lymphadenitis. Lymph node, blood, and gastric aspirates were positive for M. bovis. The patient received a prolonged treatment course with a combination of isoniazid, levofloxacin, and ethambutol. Her course was further complicated by granulomatous lymphadenitis and otitis media associated with M. bovis that developed during immune suppression taper and immune reconstitution. Ultimately, the patient recovered fully, in association with restoration of immune function, and has completed 12 months of therapy. PMID:24995715

  5. The role of HLA-DR antigens in PPD-stimulated lymphocyte-monocyte interactions.

    PubMed

    Haar, D; Heron, I

    1982-11-01

    Autologous monocytes are required for an optimal lymphocyte proliferative response to purified protein derivate of tuberculin (PPD) in vitro and for a mixed lymphocyte culture induced by alloantigens. In the proliferative response to PPD we found that autologous monocytes could be replaced with HLA-DR-compatible monocytes and partly with HLA-DR semi-identical. In spite of a statistically significant difference between autologous and HLA-DR disparate monocytes in their cooperative capacity with PPD-stimulated lymphocytes, replacement in nearly one third of the cases was possible. These findings were supported by more detailed studies in which increasing numbers of allogenic and autologous monocytes were added to the isolated lymphocytes in the presence of PPD. It is concluded that the serologically defined HLA-DR antigens alone give insufficient information of the restriction elements controlling the PPD-stimulated lymphocyte-monocyte interactions. PMID:6184773

  6. Idarubicin-intensified BUCY2 conditioning regimen improved survival in high-risk acute myeloid, but not lymphocytic leukemia patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective comparative study.

    PubMed

    Fang, Jun; Zhang, Ran; Wang, Huafang; Hong, Mei; Wu, Qiuling; Nie, Dimin; You, Yong; Zhong, Zhaodong; Li, Weiming; Hu, Yu; Xia, Linghui

    2016-07-01

    The intensity of conditioning regimen is highly correlated with outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported that idarubicin (IDA) intensified BUCY2 regimen could reduce relapse and improve survival for high-risk hematological malignancies undergoing allo-HSCT. However, there is no published study comparing the efficacy of IDA-BUCY2 regimen for high-risk acute myeloid leukemia (AML) versus acute lymphocytic leukemia (ALL). We further retrospectively compared therapeutic outcomes of intensified conditioning regimen on 140 high-risk AML and ALL patients in the data analyses. IDA 15mg/m(2)/d was administered by continuous infusion from day -11 to -9, followed by intravenous injection of busulfan (BU) (3.2mg/kg/d) from day -6 to -4, and intravenous injection of cyclophosphamide (CY) (1.8g/m(2)/d) from day -3 to -2 in IDA-BUCY2 regimen. For high-risk AML, cumulative probabilities of 3-year relapse rates in IDA-BUCY2 and traditional BUCY2 regimens were 16.9%, 43.3% (P=0.016). Cumulative probabilities of 3-year overall survival (OS) and disease-free survival (DFS) were 69.2% vs 44.0% (P=0.024), and 66.9% vs 38.2% (P=0.01). However, two regimens showed no significant differences for high-risk ALL. Multivariate analysis also indicated that IDA intensified BUCY2 conditioning was the favorable variable to reduce relapse and elevate survival for high-risk AML patients. In conclusion, IDA-BUCY2 regimen reduces relapse and improves survival for high-risk AML undergoing allo-HSCT, but not presenting uniform therapeutic effects for high-risk ALL. PMID:27131062

  7. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.

    PubMed

    Yanagisawa, Ryu; Nakazawa, Yozo; Sakashita, Kazuo; Saito, Shoji; Tanaka, Miyuki; Shiohara, Masaaki; Shimodaira, Shigetaka; Koike, Kenichi

    2016-01-01

    An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy. PMID:26586462

  8. 90Yttrium Ibritumomab Tiuxetan Therapy in Allogeneic Transplantation in B-cell Lymphoma with Extensive Marrow involvement and Chronic Lymphocytic Leukemia: Utility of Pre-transplantation Biodistribution

    PubMed Central

    Matesan, Manuela; Rajendran, Joseph; Press, Oliver W.; Maloney, David G.; Storb, Rainer F.; Cassaday, Ryan D.; Pagel, John M.; Oliveira, George; Gopal, Ajay K.

    2014-01-01

    Biodistribution data to-date using 111In- ibritumomab tiuxetan has been initially obtained in patients with <25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL). Thirty nine patients with diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis, however only 38 of these completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest (ROI) over the liver, lungs, kidneys, spleen and sacrum. The observed interpatient variability including higher liver uptake in 4 patients is discussed. No severe solid organs toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) 90Yibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 hour images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment. These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of 90Y- ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by 111Inibritumomab tiuxetan, indicating potential efficacy in this patient population. PMID:25076159

  9. Fetal pancreas transplantation in miniature swine. IV. Suppression of DTH and MLR responses by treatment with ultraviolet light-irradiated peripheral blood lymphocytes

    SciTech Connect

    Taura, Y.; Stein, E.; Miyazawa, K.; Mullen, Y. )

    1990-07-01

    Irradiation of peripheral blood lymphocytes of miniature swine with ultraviolet light prevented them from initiating proliferative responses in allogeneic mixed lymphocyte reactions and also reduced IL-2 production in these MLRs. When pigs were injected in a series of 4-5 weekly transfusions with UV-irradiated allogeneic PBL differing at the MHC, PBL of recipient pigs progressively responded less strongly to donor PBL in MLRs over the treatment period. These pigs also gave negligible delayed-type hypersensitivity responses to donor PBL at the end of the treatment period. Of the seven UV-irradiated PBL-treated pigs, four produced no antidonor PBL antibody and three produced antibody. Serum from the three antibody-producing pigs also suppressed MLRs of unrelated PBL. By contrast, pigs that received a series of injections of untreated allogeneic PBL gave strong DTH responses to donor PBL and heightened proliferation in MLRs with donor PBL, and all produced antidonor PBL antibody.

  10. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements

    PubMed Central

    Yang, Hua; Huang, Sai; Zhu, Cheng-Ying; Gao, Li; Zhu, Hai-Yan; Lv, Na; Jing, Yu; Yu, Li

    2016-01-01

    Background Acute myeloid leukemia (AML) patients with mixed lineage leukemia (MLL) gene rearrangements always had a very poor prognosis. In this study, we report the incidence of MLL rearrangements in AML patients using gene analysis, as well as the clinical significance and prognostic features of these rearrangements. Material/Methods This retrospective study took place from April 2008 to November 2011 in the People’s Liberation Army General Hospital. A total 433 AML patients were screened by multiple nested reverse transcription polymerase chain reaction (RT-PCR) to determine the incidence of the 11 MLL gene rearrangements. There were 68 cases of MLL gene rearrangements, for a positive rate of 15.7%. A total of 24 patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and 34 patients received at least 4 cycles of chemotherapy. Ten patients were lost to follow-up. Results The median follow-up was 29 months. The complete remission (CR) rate was 85.4%. The overall survival (OS) was 57.4±5.9 months for the Allo-HSCT group and 21.0±2.1 months for the chemotherapy group. The Allo-HSCT group had superior survival compared with the chemotherapy group (5-year OS: 59±17% vs. 13±8%, P<0.01; 5-year disease-free survival [DFS]: 65±10% vs. 40±16%, P>0.05). Multivariate analysis showed that transplantation, platelets >50×109/L at onset, and CR are associated with a better OS in MLL rearranged AML patients. Patients with thrombocytopenia and extramedullary involvement were prone to relapse. Conclusions Our results suggest that Allo-HSCT is superior to chemotherapy alone for treating MLL rearranged AML patients. Patients treated with Allo-HSCT have a better prognosis and a longer survival. CR is an independent prognostic factor for OS, and extramedullary involvement is an independent prognostic factor for DFS. MLL rearranged AML patients with thrombocytopenia at onset <50×109 had very bad OS and DFS. PMID:27373985

  11. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements.

    PubMed

    Yang, Hua; Huang, Sai; Zhu, Cheng-Ying; Gao, Li; Zhu, Hai-Yan; Lv, Na; Jing, Yu; Yu, Li

    2016-01-01

    BACKGROUND Acute myeloid leukemia (AML) patients with mixed lineage leukemia (MLL) gene rearrangements always had a very poor prognosis. In this study, we report the incidence of MLL rearrangements in AML patients using gene analysis, as well as the clinical significance and prognostic features of these rearrangements. MATERIAL AND METHODS This retrospective study took place from April 2008 to November 2011 in the People's Liberation Army General Hospital. A total 433 AML patients were screened by multiple nested reverse transcription polymerase chain reaction (RT-PCR) to determine the incidence of the 11 MLL gene rearrangements. There were 68 cases of MLL gene rearrangements, for a positive rate of 15.7%. A total of 24 patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and 34 patients received at least 4 cycles of chemotherapy. Ten patients were lost to follow-up. RESULTS The median follow-up was 29 months. The complete remission (CR) rate was 85.4%. The overall survival (OS) was 57.4±5.9 months for the Allo-HSCT group and 21.0±2.1 months for the chemotherapy group. The Allo-HSCT group had superior survival compared with the chemotherapy group (5-year OS: 59±17% vs. 13±8%, P<0.01; 5-year disease-free survival [DFS]: 65±10% vs. 40±16%, P>0.05). Multivariate analysis showed that transplantation, platelets >50×10^9/L at onset, and CR are associated with a better OS in MLL rearranged AML patients. Patients with thrombocytopenia and extramedullary involvement were prone to relapse. CONCLUSIONS Our results suggest that Allo-HSCT is superior to chemotherapy alone for treating MLL rearranged AML patients. Patients treated with Allo-HSCT have a better prognosis and a longer survival. CR is an independent prognostic factor for OS, and extramedullary involvement is an independent prognostic factor for DFS. MLL rearranged AML patients with thrombocytopenia at onset <50×10^9 had very bad OS and DFS. PMID:27373985

  12. Mechanism of protection from graft-vs-host disease in murine mixed allogeneic chimeras. I. Development of a null cell population suppressive of cell-mediated lympholysis responses and derived from the syngeneic bone marrow component

    SciTech Connect

    Sykes, M.; Eisenthal, A.; Sachs, D.H.

    1988-05-01

    Splenocyte populations from whole body-irradiated recipients of mixed T cell-depleted (TCD) syngeneic and allogeneic (complete H-2 disparity) bone marrow, or of TCD syngeneic marrow alone, contain cells with the ability to suppress the generation of cell-mediated lympholysis responses in vitro. This activity, which is present by 8 days after bone marrow transplantation and persists for several weeks, has been analyzed for possible veto-like or other specificity. Although reproducible patterns of suppression were observed, depending both on host strain and on the genetic combination of the response examined, the overall suppression in vitro most closely resembles that which has been ascribed to natural suppressor cells in other systems. The suppression appears to be mediated by a non-T cell, non-B cell, nonadherent, asialo GM1-negative population. Cold target inhibition and CTL activity of chimeric cells have been ruled out as factors contributing to the observed suppression. Significantly, in mixed chimeras, suppression was found to be mediated exclusively by cells which were syngeneic to the recipient in both recipient strains tested. The rapid development of this suppressive activity may explain the resistance to graft-vs-host disease conferred on whole body-irradiated mice by the addition of TCD syngeneic marrow to an allogeneic graft-vs-host disease-producing inoculum.

  13. Traffic and proliferative responses of recirculating lymphocytes in fetal calves.

    PubMed Central

    Hein, W R; Shelton, J N; Simpson-Morgan, M W; Morris, B

    1988-01-01

    The thoracic duct or efferent prescapular duct was cannulated in four fetal calves aged 121-259 days post-conception. The duration of lymph flow ranged from 2 to 20 days and the mean flow rates sustained over these collection periods varied from 5.4 to 48.8 ml/hr. Lymphocyte output ranged from 4.4 x 10(6) cells/hr in thoracic duct lymph from a 121-day fetus to 3.9 x 10(8) cells/hr in efferent prescapular lymph from a 259-day fetus. The circulating lymphocyte pool in fetal calves of about 120 and 190 days gestational age was calculated to contain, respectively, 4 x 10(8) cells and 2 x 10(10) cells. The proportion of lymphocytes bearing surface immunoglobulin detected in fetal lymph ranged from 2.1% to 8.7%. Recirculating lymphocytes from fetal calves produced strong proliferative responses when stimulated by T-cell mitogens but responded poorly to B-cell mitogens. Fetal lymphocytes also responded to stimulation by allogeneic cells and stimulated other cells to proliferate during mixed lymphocyte culture. When stimulated with Con A, fetal lymphocytes secreted IL-2 to a degree that was indistinguishable from the secretory behaviour of lymphocytes from adult animals. The results presented in this paper show that chronic lymphatic fistulae can be established successfully in fetal calves to give access to recirculating lymphocytes. This provides a new experimental approach for studying the development of the bovine immune system. PMID:2971606

  14. Facilitation of allogeneic bone marrow transplantation by a T cell-specific immunotoxin containing daunomycin

    SciTech Connect

    Xie, S.S.; Inazawa, M.; Sinha, N.; Sawada, S.; Vergidis, R.; Diener, E.

    1987-12-01

    Daunomycin coupled via an acid-sensitive spacer to monoclonal Thy-1.2-specific antibody was used to purge T lymphocytes from a 1:1 mixture of murine C57BL/6J bone marrow and spleen cells prior to engraftment in fully allogeneic, irradiated BALB/c recipients. Treatment of bone marrow with the immunotoxin at a concentration used for purging had no effect on the viability of committed hematopoietic progenitor or multipotent stem cells. All of the recipients of purged bone marrow were at least 80% chimeric for donor peripheral blood cells and none developed graft-versus-host disease. Out of 50 chimeras, 49 were still alive more than 200 days posttransplantation. The chimeras were shown to be tolerant to donor tissue as tested by mixed lymphocyte reactivity, cell-mediated cytotoxicity, and skin grafting. The same tests revealed full immunocompetence of chimeras to third-party alloantigens. In vivo IgM and IgG antibody responses to sheep red blood cells were similar in magnitude in allogeneically and syngeneically reconstituted mice.

  15. Monitoring mixed lineage leukemia expression may help identify patients with mixed lineage leukemia--rearranged acute leukemia who are at high risk of relapse after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Liu, Jing; Wang, Yu; Xu, Lan-Ping; Liu, Dai-Hong; Qin, Ya-Zhen; Chang, Ying-Jun; Liu, Kai-Yan; Huang, Xiao-Jun

    2014-07-01

    To evaluate the prognostic value of the expression of the mixed lineage leukemia (MLL) gene for predicting the relapse of patients with MLL-rearranged acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the levels of MLL transcripts in bone marrow (BM) specimens were monitored serially by real-time quantitative polymerase chain reaction (RQ-PCR) at predetermined time points in 40 patients with MLL-rearranged AL who were treated with allo-HSCT. These patients were followed for a median of 24.5 months (range, 8 to 60 months). A total of 236 BM samples were collected and analyzed. Of these, 230 were monitored concurrently for minimal residual disease (MRD) by flow cytometry (FCM) for leukemia-associated aberrant immune phenotypes and by RQ-PCR for the expression of the Wilms tumor (WT1) gene. The 3-year cumulative incidence of relapse in patients who experienced MLL-positive patients (MLL > .0000%) (n = 9) after HSCT was 93.5% (95% confidence interval [CI], 87% to 100%) compared with 12.5% (95% CI, 5.6% to 19.4%) for MLL-negative patients (n = 31) (P < .001). For these 2 patient groups, the 3-year overall survival (OS) was 12.5% (95% CI, .8% to 24.2%) and 77.8% (95% CI, 68.4% to 87.2%) (P < .001), respectively, and the 3-year leukemia-free survival (LFS) was 0% and 72.2% (95% CI, 61.1% to 83.3%), respectively (P < .001). MLL positivity was associated with a higher rate of relapse (hazard ratio [HR], 18.643; 95% CI, 3.449 to 57.025; P = .001), lower LFS (HR, 7.267; 95% CI, 2.038 to 25.916; P = .002), and lower OS (HR, 8.259; 95% CI, 2.109 to 32.336; P = .002), as determined by Cox multivariate analysis. The expression of the MLL gene had a higher specificity and sensitivity than WT1 or MRD monitored by FCM for predicting the relapse of the patients with MLL + AL. Our results suggest that monitoring the expression of the MLL gene may help to identify patients with MLL + AL who are at high risk of relapse after allo-HSCT and may

  16. Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD

    SciTech Connect

    Sykes, M.; Sheard, M.; Sachs, D.H.

    1988-10-01

    The opposing problems of graft-vs-host disease (GVHD) and failure of alloengraftment present major obstacles to the application of bone marrow transplantation (BMT) across complete MHC barriers. The addition of syngeneic T-cell-depleted (TCD) bone marrow (BM) to untreated fully allogeneic marrow inocula in lethally irradiated mice has been previously shown to provide protection from GVHD. We have used this model to study the effects of allogeneic T cells on levels of chimerism in recipients of mixed marrow inocula. The results indicate that T cells in allogeneic BM inocula eliminate both coadministered recipient-strain and radioresistant host hematopoietic elements to produce complete allogeneic chimerism without clinical GVHD. To determine the role of GVH reactivity in this phenomenon, we performed similar studies in an F1 into parent combination, in which the genetic potential for GVHD is lacking. The presence of T cells in F1 marrow inocula led to predominant repopulation with F1 lymphocytes in such chimeras, even when coadministered with TCD-recipient-strain BM. These results imply that the ability of allogeneic BM cells removed by T cell depletion to increase levels of allochimerism may be mediated by a population which is distinct from that which produces GVHD. These results may have implications for clinical BM transplantation.

  17. Present and Future of Allogeneic Natural Killer Cell Therapy

    PubMed Central

    Lim, Okjae; Jung, Mi Young; Hwang, Yu Kyeong; Shin, Eui-Cheol

    2015-01-01

    Natural killer (NK) cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation revealed the antitumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions. PMID:26089823

  18. Induction of transplantation tolerance in mice across major histocompatibility barrier by using allogeneic thymus transplantation and total lymphoid irradiation

    SciTech Connect

    Waer, M.; Palathumpat, V.; Sobis, H.; Vandeputte, M. )

    1990-07-15

    The use of allogeneic thymus transplantation as a means of inducing tolerance across MHC barriers was investigated in thymectomized, total lymphoid irradiated BALB/c mice. In 90% of the animals long term outgrowth of histologically normal C57BL thymus grafts was observed. None of the latter animals was chimeric. All thymus graft-bearing mice showed specific nonresponsiveness for C57BL MHC Ag in mixed lymphocyte reaction and cell-mediated lympholysis. Spleen cells of the C57BL thymus-bearing mice were unable to induce lethal graft-vs-host disease in neonatal (BALB/c X C57BL) F1 mice but provoked a vigorous graft-vs-host disease reaction in (BALB/c x C3H) F1 neonates. Tolerant mice permanently accepted C57BL heart and pancreas grafts, but all rejected C3H grafts. Induction of tolerance of BALB/c pre-T cells through allogeneic thymus graft and/or specific suppressor cells seems to be involved. The present model offers new opportunities to study thymocyte maturation in a fully allogeneic environment and may yield applications for clinical organ transplantation.

  19. Generation of chronic myelogenous leukemia-specific T cells in cytokine-modified autologous mixed lymphocyte/tumor cell cultures.

    PubMed

    Müller, L; Provenzani, C; Pawelec, G

    2001-01-01

    Chronic myelogenous leukemia (CML) may be amenable to cell-based adoptive immunotherapy, as suggested by the graft-versus-leukemia effect of bone marrow transplantation and the therapeutic benefit of donor leukocyte infusions. Specific adoptive immunotherapy without bone marrow transplantation might be more effective and less cost-intensive. Professional antigen-presenting cells, the dendritic cells, from patients with CML are derived from the malignant clone and may stimulate antileukemia T-cell responses. Autologous T cells may also be able to recognize tumor antigens on CML cells directly. Here, the authors show that CD4 and CD8 T-cell responses to autologous CML cells can be generated in vitro rapidly and effectively by performing modified autologous mixed lymphocyte/tumor cell cultures (MLTC) in serum-free medium in the presence of cytokines known to support dendritic cell differentiation. MLTC-sensitized T cells secreted large amounts of the type 1 cytokine interferon-gamma, as well as interleukin (IL)-2. However, they also secreted a variety of other cytokines, including the type 2-subtype cytokine IL-13 but not the classic type 2 cytokines IL-4, IL-5, and IL-10. Monoclonal populations of CML-specific CD4 cells could be derived from these lines in limited numbers but showed markedly enhanced reactivity. This suggests that CML-specific T cells are relatively rare in these autologous MTLC-derived sensitized populations, but that their isolation and propagation would yield much more potent antitumor effector cells for use in adoptive immunotherapy without the need for bone marrow transplantation. PMID:11759071

  20. Functional inactivation of lymphocytes by methylene blue with visible light.

    PubMed

    Zhang, Bo; Cheng, Zhenzhen; Mo, Qin; Wang, Li; Wang, Xun; Wu, Xiaofei; Jia, Yao; Huang, Yuwen

    2015-10-01

    Transfusion of allogeneic white blood cells (WBCs) may cause adverse reactions in immunocompromised recipients, including transfusion-associated graft-versus-host disease (TA-GVHD), which is often fatal and incurable. In this study, the in vitro effect of methylene blue with visible light (MB + L) treatment on lymphocyte proliferation and cytokine production was measured to investigate whether MB + L can be used to prevent immune reactions that result from transfused lymphocytes. WBCs and 3 μM of MB were mixed and transferred into medical PVC bags, which were then exposed to visible light. Gamma irradiation was conducted as a parallel positive control. The cells without treatment were used as untreated group. All the groups were tested for the ability of cell proliferation and cytokine production upon stimulation. After incubation with mitogen phytohemagglutinin (PHA) or plate-bound anti-CD3 plus anti-CD28, the proliferation of MB + L/gamma-irradiation treated lymphocytes was significantly inhibited (P < 0.01) as compared to the untreated ones; the proliferation inhibitive rate of the MB + L group was even higher than that of gamma-irradiated cells (73.77% ± 28.75% vs. 44.72% ± 38.20%). MB + L treated cells incubated up to 7 days with PHA also showed no significant proliferation. The levels of TNF-α, IFN-γ, IL-6, IL-8, IL-10 and IL-1β present in the supernatant of MB + L treated lymphocytes upon stimulation were significantly lower than those of untreated lymphocytes. These results demonstrated that MB + L treatment functionally and irreversibly inactivated lymphocytes by inhibiting lymphocyte proliferation and the production of cytokines. MB + L treatment might be a promising method for the prevention of adverse immune responses caused by WBCs. PMID:26295729

  1. Cellular therapy following allogeneic stem-cell transplantation

    PubMed Central

    Rager, Alison

    2011-01-01

    Allogeneic hematopoietic stem-cell transplantation (HSCT) is the most effective approach for many patients with hematologic malignancies. Unfortunately, relapse remains the most common cause of death after allogeneic HSCT, and the prognosis of relapsed disease is poor for most patients. Induction of a graft-versus-leukemia (GVL), or graft-versus-tumor, effect through the use of donor leukocyte infusion (DLI), or donor lymphocyte infusion, has been remarkably successful for relapsed chronic myelogenous leukemia. Unfortunately, response to DLI in other hematologic malignancies is much less common and depends on many factors including histology, pace and extent of relapse, and time from HSCT to relapse. Furthermore, graft-versus-host disease (GVHD) is common after DLI and often limits successful immunotherapy. Ultimately, manipulations to minimize GVHD while preserving or enhancing GVL are necessary to improve outcomes for relapse after allogeneic HSCT. PMID:23556106

  2. T-lymphocyte induction of human monocyte angiotensin converting enzyme (ACE) is not dependent upon T-lymphocyte proliferation

    SciTech Connect

    Vuk-Pavlovic, Z.; Rohrbach, M.S.

    1986-03-05

    Human peripheral blood monocytes cultured in serum free media for seven days show a basal activity of the ectoenzyme ACE which is augmented 2-3 times by the presence of autologous peripheral blood T-lymphocytes. Since these two cell types are also involved in autologous mixed lymphocyte reaction if serum is present, the authors compared the ability of T-cells to stimulate ACE activity in the presence or absence of proliferation (measured by /sup 3/H-thymidine incorporation). By the seventh day, cultures with 5% AB/sup +/ serum showed significant increase in proliferation but no increase in ACE activity compared to the serum free cultures. Even higher proliferation rate achieved by co-culturing T-lymphocytes with allogeneic monocytes did not increase ACE production; on the contrary, ACE activity remained at the basal level. Monocyte-T-cell co-cultures stimulated with increasing concentrations of ConA or PHA showed dose dependent increases in proliferation but parallel decreases in ACE activity. Addition of soluble antigen (Candida albicans) also enhanced proliferation but not ACE synthesis. They conclude that T-lymphocyte induction of monocyte ACE is a result of cooperation between autologous cells which is not dependent upon T-cell proliferation.

  3. Nonmyeloablative Allogeneic Transplant

    ClinicalTrials.gov

    2013-12-05

    Aplastic Anemia; Paroxysmal Nocturnal Hemoglobinuria; Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Myelodysplastic Syndrome; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma; Mantle Cell Lymphoma; Multiple Myeloma; Waldenstrom Macroglobulinemia; Breast Cancer; Renal Cell Carcinoma; Melanoma; Sarcoma; Ovarian Cancer; Thymoma

  4. Locomotor responses of human CD45 lymphocyte subsets: preferential locomotion of CD45RO+ lymphocytes in response to attractants and mitogens.

    PubMed Central

    Newman, I; Wilkinson, P C

    1993-01-01

    The CD45RO+ population of lymphocytes from human blood contains a higher proportion of locomotor cells than the CD45RA+ population. Direct from blood there were few locomotor lymphocytes (< 15%), but, among these, a higher proportion of CD45RO+ than of CD45RA+ cells responded to the chemotactic stimuli, foetal calf serum (FCS) and interleukin-2 (IL-2) in polarization assays. Likewise, after overnight culture, a higher proportion of CD45RO+ cells responded to IL-8. Culture for 24-72 hr in activators such as anti-CD3, purified protein derivative (PPD), phytohaemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM) or in an allogeneic mixed leucocyte reaction (AMLR) increased the proportion of locomotor lymphocytes to 20-60%, and the CD45RO+ subset showed proportionately more polarized cells than the CD45RA+ subset after culture with all the above activators. Preferential migration of CD45RO+ cells into collagen gels was also seen after culture in antigenic stimuli (PPD or AMLR) but not with polyclonal activators (alpha CD3 or Con A). Double labelling showed that, within the CD4+ and CD8+ subsets, antigen-stimulated CD45RO+ T cells invaded collagen gels in higher proportions than CD45RA+ T cells. Clustering of lymphocytes with accessory cells is an essential prerequisite for locomotion and, after culture in alpha CD3, CD45RO+ lymphocytes were found preferentially in clusters with monocytes. In all of the above populations, CD45RO+ lymphocytes were larger in size. These findings suggest that, not only selective adhesion to vascular endothelium as reported earlier, but also selective locomotion recruits CD45RO+ lymphocytes into sites of inflammation. PMID:8436407

  5. Thymic influence on the T-lymphocyte self MHC repertoire. II. Cytotoxic T-lymphocyte precursors.

    PubMed

    Jenski, L J; Miller, B A

    1988-01-01

    We measured the frequency and specificity of thymic alloantigen-reactive cytotoxic T-lymphocyte precursors in spleens of allogeneic thymus-grafted nude mice tolerant to thymic alloantigens. Under our conditions of limiting dilution analysis we found no selective loss of cytotoxic T-lymphocyte precursors in allogeneic thymus-grafted mice. Upon analysis of individual cytotoxic T-lymphocyte clones, we found that lysis of specific and third party targets was mediated by distinct clones specific for H-2 antigens. Precursors from allogeneic thymus-grafted nudes stimulated at limiting dilutions with thymic alloantigens tended to lyse fewer targets than were lysed by normal cytotoxic T-lymphocytes or allogeneic thymus-grafted nude precursors stimulated with third party alloantigens, but the reduction in lytic activity was not statistically significant. Specific suppression was not demonstrated, but could not be ruled out unequivocally. We conclude that intrathymic deletion of thymic alloantigen-reactive pCTL is not necessary to achieve specific tolerance to thymic alloantigens. PMID:3259029

  6. Detection of cardiac transplant rejection with radiolabeled lymphocytes. [Rats

    SciTech Connect

    Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-03-01

    To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy.

  7. Nodular sclerosing, mixed cellularity and lymphocyte-depleted variants of Hodgkin's disease are probable dendritic cell malignancies.

    PubMed Central

    Kennedy, I C; Hart, D N; Colls, B M; Nimmo, J C; Willis, D A; Angus, H B

    1989-01-01

    The normal counterpart of the Reed-Sternberg cell and its mononuclear variant, collectively referred to as Hodgkin's cells (HC), remains controversial. The possibility that HC are malignant dendritic cells was tested by using a panel of 38 monoclonal antibodies to phenotype the cells from 16 cases of Hodgkin's disease (HD), excluding lymphocyte-predominant HD, and the Hodgkin's cell line L428. The results were then compared with the known phenotype of human dendritic cells. HC stained strongly for HLA Class I and Class II antigens. The leucocyte common antigen was weakly expressed in most cases. Expression of T and B cell markers was unusual, with the exception of the CD40 antigen which was found on a majority of HC. HC commonly expressed the CD11a, CR4 (CD11c), CD15, CD18 and a number of activation antigens but did not stain with a variety of macrophage-specific antibodies. The antigenic phenotype of L428 and the HC of case material were similar. This immunocytological analysis failed to support a lymphocyte or macrophage origin for HC. Instead the antigenic phenotype of the Reed-Sternberg cell and its mononuclear variant more closely resembles that of dendritic cells than of any other haemopoietic cell normally resident in lymph nodes. PMID:2787713

  8. Effects of 8-aminoguanosine and 2'-deoxyguanosine on the human mixed lymphocyte reaction (MLR). I. Description of the inhibition

    SciTech Connect

    Scott, M.E.; Gilbertsen, R.B.

    1986-03-05

    Patients deficient in purine nucleoside phosphorylase (PNP) generally have a pronounced deficiency in T cell function with no deleterious effect on B cell function. It has been demonstrated that high concentrations of 8-amino-guanosine (8-AG), an inhibitor of PNP, in combination with the PNP substrate 2'-deoxyguanosine (dGuo) can inhibit mitogen and antigen responsiveness of human lymphocytes in culture. The studies described here evaluated the effects of 8-AG and dGuo on the human MLR. Normal human lymphocytes were isolated from venous blood using Ficoll-Hypaque gradients. Stimulator cells, pretreated with mitomycin C (50 ..mu..g/ml), were added with an equal number of responder cells (2 x 10/sup 5/) to the wells of flat-bottomed microtiter plates. Cell proliferation was quantitated by the uptake of /sup 3/H-thymidine (TdR) during the final 4 hrs of six-day cultures. dGuo at 10-50 ..mu..M had no effect or stimulated proliferation, while dGuo at > 75 ..mu..M was markedly inhibitory. 8-AG alone at 100 ..mu..M had essentially no effect on TdR uptake. 8-AG (10-100 ..mu..M) plus dGuo (50 ..mu..M) produced a concentration-dependent inhibition of the MLR resulting in 8-AG IC/sub 50/s generally < 60 ..mu..M. Coaddition of 50 ..mu..M 2'-deoxycytidine, hypoxanthine or adenine partially prevented inhibition of the MLR.

  9. Inhibition of protein phosphorylation by synthetic peptides from the Fc region of human IgG during the mixed lymphocyte response

    SciTech Connect

    McClurg, M.R.; Hahn, G.S.; Plummer, J.M.

    1986-03-01

    Certain synthetic peptides derived from the Fc region of human IgG suppressed protein, RNA, and DNA synthesis during mixed lymphocyte reactions. Responder mononuclear cells were incubated with medium or agents that alter phosphorylation of cellular proteins before immunomodulatory Fc peptides and stimulator cells were added. Incubating cells with trifluoperazine which inhibits calcium binding to calmodulin and inhibits protein kinase C (PKC) increased inhibition of the MLR induced by Fc peptides. Conversely, incubating cells with dubutyryl cyclic AMP (DBcAMP), calmodulin, 1,2-diolein, or phorbol myristate acetate (PMA) abolished inhibition of the MLR induced by Fc peptides. Inhibition of the MLR by Fc ..gamma.. peptides was not affected when DBcAMP or PMA was added after peptide addition. The PKC activity of cell homogenates was decreased by 69% when Fc..gamma.. peptides were present during the MLR. The in vitro phosphorylation of histone Hl by partially purified PKC from lymphocytes was inhibited 74% in the presence of Fc..gamma.. peptides. These results indicate that suppression of the MLR induced by Fc..gamma.. peptides is dependent on inhibition of protein phosphorylation by kinases including protein kinase C. The inhibition of phosphorylation may be related to the ability of Fc..gamma.. peptides to reverse animal models of autoimmune disease.

  10. Outcomes of donor lymphocyte infusion for treatment of mixed donor chimerism after a reduced-intensity preparative regimen for pediatric patients with nonmalignant diseases.

    PubMed

    Haines, Hilary L; Bleesing, Jack J; Davies, Stella M; Hornung, Lindsey; Jordan, Michael B; Marsh, Rebecca A; Filipovich, Alexandra H

    2015-02-01

    Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen. PMID:25464116

  11. Purine nucleoside modulation of functions of human lymphocytes.

    PubMed

    Priebe, T; Platsoucas, C D; Seki, H; Fox, F E; Nelson, J A

    1990-09-01

    The accumulation of endogenous substrates in patients with adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency is believed to be responsible for the immunodeficiency observed in these patients. To identify the lymphocyte populations that are most susceptible to these substrates, we investigated the effect of their nucleoside analogs on a number of T and B cell functions of human lymphocytes. We found that tubercidin (Tub), 2-chloro 2'deoxyadenosine (2CldA), 2-fluoro adenine arabinoside-5'phosphate (FaraAMP), and 9-beta-D-arabinosyl guanine (AraGua) inhibited the proliferative responses of human peripheral blood mononuclear cells (PBMC) to polyclonal activators (PHA, OKT3 mab) or to allogeneic PBMC in mixed lymphocyte cultures (MLC). Addition of recombinant IL-2 from the beginning of the culture did not alter the inhibition by Tub of the proliferative responses of PBMC. These purine nucleoside analogs also inhibited the proliferative responses of purified human peripheral blood CD4+ and CD8+ T cells to PHA and of purified B cells to SAC. The concentrations of these nucleosides required to achieve a given degree of inhibition of proliferative responses of T lymphocyte subpopulations or B cells was similar, suggesting that these analogs do not exhibit any selectivity for these purified lymphocyte populations. Tub and FaraAMP, respectively, inhibited and enhanced, at the effector phase, both NK cytotoxicity and specific T cell-mediated cytotoxicity. In contrast to these findings, LAK cytotoxicity at the effector phase was not significantly inhibited by Tub, and was not enhanced by FaraAMP. Both analogs inhibited rIL-2-induced proliferative responses of PBMC, but did not affect the generation of LAK cytotoxicity (induction phase) against the K562 targets when added at the beginning of the culture. This suggests that DNA synthesis is not required for LAK cell induction. Both Tub and FaraAMP inhibited immunoglobulin production (IgG and IgM) by

  12. Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia.

    PubMed

    Marks, David I; Alonso, Laura; Radia, Rohini

    2014-12-01

    This review discusses the use of prognostic factors, patient and donor selection, choice of conditioning regimens, and timing of transplant. It also describes the management of Philadelphia-positive acute lymphocytic leukemia (ALL) and central nervous system disease. All aggressively treated adults with ALL should be considered for allogeneic transplantation and tissue typed at diagnosis. We further suggest that eligible patients be entered into clinical trials (that incorporate transplantation); these unselected prospective outcome data are essential to evaluate the true value of allogeneic transplantation in adults with ALL. PMID:25459175

  13. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  14. Favorable Outcomes in Patients with High Donor-Derived T Cell Count Following in vivo T Cell Depleted Reduced Intensity Allogeneic Stem Cell Transplantation

    PubMed Central

    Toor, Amir A.; Sabo, Roy T.; Chung, Harold M.; Roberts, Catherine; Manjili, Rose H.; Song, Shiyu; Williams, David C.; Edmiston, Wendy; Gatesman, Mandy L.; Edwards, Richard W.; Ferreira-Gonzalez, Andrea; Clark, William B.; Neale, Michael C.; McCarty, John M.; Manjili, Masoud H.

    2016-01-01

    Patients with hematological malignancies were conditioned using a rabbit anti-thymocyte globulin based reduced intensity conditioning regimen for allogeneic stem cell transplantation (SCT). Donor-derived CD3+ cell count (ddCD3), a product of CD3+ cell chimerism and absolute CD3+ cell count, when less than 110/μL, eight weeks post-transplant, predicted a high risk of sustained mixed chimerism and relapse. Alternatively, patients with a higher ddCD3 developed GVHD more frequently, and when partially chimeric, had higher rates of conversion to full donor chimerism upon withdrawal of immunosuppression. In conclusion, early data from a small cohort of patients indicates that ddCD3+ cell count at 8 weeks may be used to guide the decision-making process regarding withdrawal of immunosuppression and administration of donor lymphocyte infusion in partially T cell depleted reduced intensity regimens. PMID:22005648

  15. Dendritic cells transduced with Rsf-1/HBXAP gene generate specific cytotoxic T lymphocytes against ovarian cancer in vitro

    SciTech Connect

    Sun, Li; Kong, Beihua; Sheng, Xiugui; Sheu, Jim Jinn-Chyuan; Shih, Ie-Ming

    2010-04-09

    Recently, some studies have indicated that Rsf-1/HBXAP plays a role in chromatin remodeling and transcriptional regulation that may contribute to tumorigenesis in ovarian cancer. The present study demonstrates that using dendritic cells (DCs) from human cord blood CD34{sup +} cells transduced with Rsf-1/HBXAP DNA plasmids by nucleofection generate specific cytotoxic T lymphocytes (CTL) against ovarian cancer in vitro. After transfection, DCs were analyzed for Rsf-1/HBXAP mRNA expression by RT-PCR and protein expression by Western blot. Then the DC phenotypes, T-cell stimulatory capacity, endocytic activity and migration capacity were explored by flow cytometry analysis, allogeneic mixed lymphocyte reaction, endocytosis and transwell chemotaxis assay, respectively. After transfection, Rsf-1/HBXAP expression was detected at mRNA and protein levels. Allogeneic T-cell proliferation induced by transfected DCs was obviously higher than non-transfected DCs, but the endocytosis capacity and migratory ability were not different. Rsf-1/HBXAP gene-transduced DCs could induce antigen-specific CTL and generate a very potent cytotoxicity to OVCAR3 cells. These data suggest that Rsf-1/HBXAP gene-transduced DCs may be a potential adjuvant immunotherapy for ovarian cancer in clinical applications.

  16. 5-Azacytidine as Salvage Treatment in Relapsed Myeloid Tumors after Allogeneic Bone Marrow Transplantation

    PubMed Central

    Bolaños-Meade, Javier; Smith, B. Douglas; Gore, Steven D.; McDevitt, Michael A.; Luznik, Leo; Fuchs, Ephraim J.; Jones, Richard J.

    2011-01-01

    Relapse after allogeneic blood or marrow transplantation carries a very poor prognosis. Current strategies for management that include donor lymphocyte infusions (DLIs) and salvage chemotherapies are usually toxic and ineffective. Here we report the outcome of 10 patients with myeloid malignancies that received 5-azacytidine after a failed allogeneic bone marrow transplant. Of the 10 patients, 6 achieved a complete remission, 1 had stable disease, and 3 progressed after a median of 6 cycles administered. Only 1 patient has died (of disease progression), and no flares of graft-versus-host disease (GVHD) were observed with 5-azacytidine. As of latest follow-up, the median overall survival (OS) for the group was 422.5 days (127–1411). These results further suggest that 5-azacytidine is an active agent after failing an allogeneic bone marrow transplant, and prospective studies are warranted. PMID:20951817

  17. Dental pulp stem cells suppress the proliferation of lymphocytes via transforming growth factor-β1.

    PubMed

    Ding, Gang; Niu, Jianyi; Liu, Yi

    2015-04-01

    Dental pulp stem cells (DPSCs) possess self-renewal capability, multi-lineage differentiation potential, and can generate a dentin-pulp-like tissue in vivo, which is promising for tooth regeneration. To enlarge the cells resource of DPSCs and explore the feasibility of DPSCs-mediated immune therapy, it is prerequisite to investigate the immunological properties of DPSCs and the underlying mechanisms. Human DPSCs and peripheral blood mononuclear cells were isolated and cultured. Then we used lymphocytes proliferation assays, cytokines detection, Transwell cultures, neutralization experiments, and flow cytometry to examine the in vitro immune characteristics of DPSCs. We found that DPSCs failed to stimulate allogeneic T cells proliferation and suppressed T cells proliferation, B cells proliferation, and mixed lymphocyte reaction. In addition, DPSCs could up-regulate IL-10, down-regulate the production of IL-2, IL-17, and IFN-γ, and did not affect the production of IL-6. Monoclonal antibody against transforming growth factor-β1 restored the T cells proliferation inhibited by DPSCs. Moreover, the population of regulatory T cells increased significantly and T-helper 17 cells decreased significantly in peripheral blood mononuclear cells co-cultured with DPSCs. These data confirmed that DPSCs are low immunogenic, could inhibit the proliferation of lymphocytes, regulate the production of cytokines in vitro, and the secretion of transforming growth factor-β1 may be involved in this event. PMID:25605036

  18. Allogeneic adipose-derived stem cells promote survival of fat grafts in immunocompetent diabetic rats.

    PubMed

    Zhang, Jun; Bai, Xiaozhi; Zhao, Bin; Wang, Yunchuan; Su, Linlin; Chang, Peng; Wang, Xujie; Han, Shichao; Gao, Jianxin; Hu, Xiaolong; Hu, Dahai; Liu, Xiaoyan

    2016-05-01

    Autologous adipose-derived stem cells (ADSCs) can protect fat grafts in cell-assisted lipotransfer (CAL). However, diabetes alters the intrinsic properties of ADSCs and impairs their function so that they lack these protective effects. We investigate whether allogeneic ADSCs from healthy donors could protect fat grafts in immunocompetent diabetic rats. Syngeniec adipose tissues and ADSCs were derived from diabetic Lewis (LEW) rats, whereas allogeneic ADSCs were from healthy brown-Norway rats. A grafted mixture containing 0.7 ml granule fat and 0.3 ml 6 × 10(6) allogeneic/syngeneic ADSCs was injected subcutaneously on the skulls of diabetic LEW rats. Fat samples were harvested to evaluate the levels of injury and vascularization as shown by perilipin A, CD34 and VEGF at 14 days. The immune response was evaluated with a lymphocytotoxicity test and the CD4/CD8 ratio in peripheral blood at 14 days. The volume retention of fat grafts was measured at 3 months. Healthy allogeneic ADSCs increased the expression levels of perilipin A, CD34 and VEGF at 14 days. The volume retention of fat grafts was improved by allogeneic ADSCs at 3 months. ADSCs were demonstrated to have low immunogenicity by the lymphocyte proliferation test and immunophenotype including MHC and co-stimulatory markers. The lymphocytotoxicity test and CD4/CD8 ratio indicated no obvious immune response elicited by allogeneic ADSCs. Thus, healthy allogeneic ADSCs can promote the survival of fat grafts in this immunocompetent diabetic rat model, with little or no obvious immune rejection. PMID:26662284

  19. Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study.

    PubMed

    Or, R; Ackerstein, A; Nagler, A; Kapelushnik, J; Naparstek, E; Samuel, S; Amar, A; Bruatbar, C; Slavin, S

    1998-03-01

    Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for patients relapsing after allogeneic bone marrow transplantation (BMT), indicating that tumor cells resisting chemoradiotherapy may still respond to immunocompetent allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects in six patients with metastatic breast cancer that would be comparable to the graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in hematologic malignancies. The patients were cytoreduced with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and were treated ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor peripheral blood lymphocytes (PBL) activated in vivo with human recombinant interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT was augmented with infusion of donor PBL, preactivated in vitro with rIL-2. Treatment was well tolerated, with low therapy-related toxicity in all patients. Two patients developed signs and symptoms compatible with GVHD grade I-II, one of whom shows no evidence of disease at more than 34 months out. In the remaining patients, progression-free survival following allo-CT ranged between 7 and 13 months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be utilized for induction of GVT in metastatic breast cancer. A search for techniques to boost chimerism without severe GVHD is indicated. PMID:9557210

  20. Allogeneic bone marrow transplantation in models of experimental autoimmune encephalomyelitis: evidence for a graft-versus-autoimmunity effect.

    PubMed

    Van Wijmeersch, Bart; Sprangers, Ben; Rutgeerts, Omer; Lenaerts, Caroline; Landuyt, Willy; Waer, Mark; Billiau, An D; Dubois, Bénédicte

    2007-06-01

    Autologous hematopoietic stem cell transplantation (HSCT) is being explored in the treatment of severe multiple sclerosis (MS), and is based on the concept of "resetting" the immune system. The use of allogeneic HSCT may offer additional advantages, such as the replacement of the autoreactive immune compartment by healthy allogeneic cells and development of a graft-versus-autoimmunity (GVA) effect. However, in clinical practice, the genetic susceptibility to MS of allogeneic stem cell donors is generally unknown, and GVA may therefore be an important mechanism of action. Experimental autoimmune encephalomyelitis (EAE)-susceptible and -resistant mouse strains were used to determine the roles of genetic susceptibility, level of donor-chimerism, and alloreactivity in the therapeutic potential of syngeneic versus allogeneic bone marrow transplant (BMT) for EAE. After transplantation and EAE induction, animals were evaluated for clinical EAE and ex vivo myelin oligodendrocyte glycoprotein-specific proliferation. Early after BMT, both syngeneic and allogeneic chimeras were protected from EAE development. On the longer term, allogeneic but not syngeneic BMT conferred protection, but this required high-level donor-chimerism from EAE-resistant donors. Importantly, when EAE-susceptible donors were used, robust protection from EAE was obtained when active alloreactivity, induced by donor lymphocyte infusions, was provided. Our findings indicate the requirement of a sufficient level of donor-chimerism from a nonsusceptible donor in the therapeutic effect of allogeneic BMT. Importantly, the data indicate that, independently of genetic susceptibility, active alloreactivity is associated with a GVA effect, thereby providing new evidence to support the potential role of allogeneic BMT in the treatment of MS. PMID:17531772

  1. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.

    PubMed

    Jacoby, Elad; Yang, Yinmeng; Qin, Haiying; Chien, Christopher D; Kochenderfer, James N; Fry, Terry J

    2016-03-10

    Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD. PMID:26660684

  2. Differential sensitivity of T lymphocytes and hematopoietic precursor cells to photochemotherapy with 8-methoxypsoralen and ultraviolet A light.

    PubMed

    Mabed, Mohamed; Coffe, Christian; Racadot, Evelyne; Angonin, Regis; Pavey, Jean-Jaques; Tiberghien, Pierre; Herve, Patrick

    2006-01-01

    The combination of 8-methoxypsoralen (8-MOP) and long wave ultraviolet radiation (UV-A) has immunomodulatory effects and might abolish both graft-vs-host and host-vs-graft reactions after allogeneic hematopoietic stem cell transplantation. In the present study, we have confirmed the sensitivity of T lymphocytes to 8-MOP treatment plus UV-A exposure as evidenced by the abrogation of the alloreactivity in mixed lymphocyte cultures as well as the inhibition of the response to phytohemagglutinin A. However, the clonogenic capacity of the bone marrow hematopoietic progenitors was inhibited with UV-A doses lower than the doses needed to inhibit T-lymphocytes alloreactivity. Moreover, long-term bone marrow cultures showed that 8-MOP plus UV-A treatment had detrimental effects on the more immature bone marrow stem cells. These data were confirmed when murine bone marrow graft was treated with 8-MOP, exposed to UV-A, then transplanted into semiallogeneic recipient mice. The treated cells could not maintain their clonogenic capacity in vivo resulting in death of all animals. Taken together, these data show that ex vivo 8-MOP plus UV-A treatment of the marrow graft cannot be used to prevent post-bone marrow transplantation alloreactivity. PMID:16208471

  3. An ATP-activated channel is involved in mitogenic stimulation of human T lymphocytes.

    PubMed

    Baricordi, O R; Ferrari, D; Melchiorri, L; Chiozzi, P; Hanau, S; Chiari, E; Rubini, M; Di Virgilio, F

    1996-01-15

    We investigated the effect of pharmacologic modulation of the ATP receptor on intracellular ion changes and proliferative response of human peripheral blood lymphocytes (PBLs) and purified T lymphocytes. Extracellular ATP (ATPe) triggered in these cells an increase in the cytoplasmic Ca2+ concentration ([Ca2+]i) and plasma membrane depolarization. Whereas both Ca2+ release from intracellular stores and influx across the plasma membrane were detected in the whole PBL population, only Ca2+ influx was observed in T cells. In the presence of near physiologic extracellular Na+ concentrations (125 mmol/L), Ca2+ permeability through the ATPe-gated channel was very low, suggesting a higher selectivity for monovalent over divalent cations. The selective P2Z agonist benzoylbenzoic ATP (BzATP) increased [Ca2+]i in the presence but not the absence of extracellular Ca2+ and also caused plasma membrane depolarization. The covalent blocker oxidized ATP (oATP), an inhibitor of P2X and P2Z receptors, prevented Ca2+ influx and plasma membrane depolarization, but had no effect on Ca2+ release from stores. Stimulation with ATPe alone had no significant effects on PBL 3H-thymidine incorporation. On the contrary, ATPe or BzATP had a synergistic effect on DNA synthesis stimulated by selective T-cell mitogens such as phytohemagglutinin, anti-CD3 monoclonal antibody, or allogenic PBLs (mixed lymphocyte cultures). Treatment with oATP inhibited mitogenic stimulation by these receptor-directed agents but not by the combined application of the Ca2+ ionophore ionomycin and phorbol myristate acetate. Interleukin-2 partially relieved inhibition by oATP. These results suggest that human T lymphocytes express a plasma membrane channel gated by ATPe that is involved in mitogenic stimulation. PMID:8555491

  4. [Alternatives to allogenous blood transfusion].

    PubMed

    Cernea, Daniela; Vlădoianu, Alice; Stoica, Maria; Novac, M; Berteanu, Cristina

    2009-01-01

    Blood transfusion is usually meant to lower morbidity and mortality rates. Allogenous blood transfusion implies certain risks that can be avoided by autologous blood transfusions techniques including: preoperatory autologous blood donation, acute normovolemic hemodilution, intraoperatory and postoperatory blood salvage. Preoperatory blood donation and acute normovolemic hemodilution are used for planned interventions with an estimated blood loss higher than 20% of blood volume. These methods imply Erythropoietin and iron treatment. Intraoperatory and postoperatory blood salvage is performed by personnel trained in blood donation, handling and storage. Autologous blood transfusions are used for certain surgical procedures that commonly require transfusions: orthopedic surgery, radical prostatectomy, cardiovascular surgery, organ transplantation. An alternative to allogenous blood transfusion is the use of artificial oxygen transporters: human or animal hemoglobin solutions or pefluorocarbonate solutions. These solutions do not require cross reactions, do not carry diseases and are generally well tolerated and easily stored in the operating room, ambulance and other transport means. They have however a slight degree of toxicity. PMID:21495338

  5. Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE.

    PubMed

    Hirano, M; Martí, R; Casali, C; Tadesse, S; Uldrick, T; Fine, B; Escolar, D M; Valentino, M L; Nishino, I; Hesdorffer, C; Schwartz, J; Hawks, R G; Martone, D L; Cairo, M S; DiMauro, S; Stanzani, M; Garvin, J H; Savage, D G

    2006-10-24

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystemic autosomal recessive disease due to primary thymidine phosphorylase (TP) deficiency. To restore TP activity, we performed reduced intensity allogeneic stem cell transplantations (alloSCTs) in two patients. In the first, alloSCT failed to engraft, but the second achieved mixed donor chimerism, which partially restored buffy coat TP activity and lowered plasma nucleosides. Thus, alloSCT can correct biochemical abnormalities in the blood of patients with MNGIE, but clinical efficacy remains unproven. PMID:16971696

  6. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation

    PubMed Central

    Fowler, Daniel H.; Mossoba, Miriam E.; Steinberg, Seth M.; Halverson, David C.; Stroncek, David; Khuu, Hahn M.; Hakim, Frances T.; Castiello, Luciano; Sabatino, Marianna; Leitman, Susan F.; Mariotti, Jacopo; Gea-Banacloche, Juan C.; Sportes, Claude; Hardy, Nancy M.; Hickstein, Dennis D.; Pavletic, Steven Z.; Rowley, Scott; Goy, Andre; Donato, Michele; Korngold, Robert; Pecora, Andrew; Levine, Bruce L.; June, Carl H.; Gress, Ronald E.; Bishop, Michael R.

    2013-01-01

    In experimental models, ex vivo induced T-cell rapamycin resistance occurred independent of T helper 1 (Th1)/T helper 2 (Th2) differentiation and yielded allogeneic CD4+ T cells of increased in vivo efficacy that facilitated engraftment and permitted graft-versus-tumor effects while minimizing graft-versus-host disease (GVHD). To translate these findings, we performed a phase 2 multicenter clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after allogeneic-matched sibling donor hematopoietic cell transplantation (HCT) for therapy of refractory hematologic malignancy. T-Rapa cell products, which expressed a balanced Th2/Th1 phenotype, were administered as a preemptive donor lymphocyte infusion at day 14 post-HCT. After T-Rapa cell infusion, mixed donor/host chimerism rapidly converted, and there was preferential immune reconstitution with donor CD4+ Th2 and Th1 cells relative to regulatory T cells and CD8+ T cells. The cumulative incidence probability of acute GVHD was 20% and 40% at days 100 and 180 post-HCT, respectively. There was no transplant-related mortality. Eighteen of 40 patients (45%) remain in sustained complete remission (range of follow-up: 42-84 months). These results demonstrate the safety of this low-intensity transplant approach and the feasibility of subsequent randomized studies to compare T-Rapa cell-based therapy with standard transplantation regimens. This trial was registered at www.cancer.gov/clinicaltrials as #NCT 00077480. PMID:23426943

  7. Thymic influence on the T-lymphocyte self MHC repertoire. I. Helper T-lymphocyte precursors.

    PubMed

    Jenski, L J; Belloni, M L; Miller, B A

    1988-01-01

    We measured the frequencies of helper T-cell precursors in spleens of allogeneic thymus-grafted nude mice to determine whether allogeneic thymus engraftment resulted in clonal deletion of helper T-cells reactive to thymic major histocompatibility complex alloantigens, thereby producing tolerance to the thymic alloantigens. C3H thymus-grafted nudes had nearly normal numbers of C3H-reactive helper T-cell precursors, whereas C57BL/6 thymus-grafted nudes had significantly reduced numbers of C57BL/6-reactive helper T-cell precursors. Additional evidence suggested that tolerance was not due to a paucity of helper T-cell precursors: a) there was no correlation between the helper T-cell precursor frequency and the ability to mount cytotoxic responses against the thymic alloantigens, and b) exogenous helper factors did not break cytotoxic T-lymphocyte tolerance to thymic alloantigens. Thus, we conclude that immune tolerance resulting from engraftment of allogeneic thymic tissue is not necessarily due to clonal deletion of specific helper T-cell precursors. PMID:2966463

  8. IFN-γ mediates graft-versus-breast cancer effects via enhancing cytotoxic T lymphocyte activity.

    PubMed

    Zhao, Qianjie; Tong, Lingling; He, Ningning; Feng, Guowei; Leng, Liang; Sun, Weijun; Xu, Yang; Wang, Yuebing; Xiang, Rong; Li, Zongjin

    2014-08-01

    Previous studies have demonstrated the beneficial effect of graft-versus-tumor (GVT) following hematopoietic stem cell transplantation (HSCT) on the incidence of leukemia relapse and the overall survival rate of patients with leukemia; however, detailed mechanisms underlying the effects GVT exhibits on solid tumors following allogeneic HSCT are yet to be elucidated. The aim of the present study was to investigate the immune mechanism underlying the effect of interferon (IFN)-γ on GVT following allogeneic HSCT in breast cancer therapy. An in situ breast cancer mouse model was established by injecting 5×10(4) 4T1 cells into the mammary fat pads of BALB/c mice. The 4T1 cells were transfected with the firefly luciferase reporter gene in order to monitor the tumor progression in real time. An allogeneic HSCT model was then established by transplanting bone marrow mononuclear cells from C57BL/6 mice to the BALB/c mice. To investigate the influence of T lymphocyte proliferation following allogeneic bone marrow transplantation, the levels of CD3(+)CD8(+) cytotoxic T lymphocytes (CTLs) and CD4(+)CD25(+) regulatory T cells were determined. In addition, IFN-γ and granzyme B expression levels in splenic lymphocytes were analyzed using flow cytometry. Allogeneic HSCT was found to significantly promote the proliferation and cytotoxicity of CTLs and suppress the growth of breast cancer. Furthermore, the secretory levels of IFN-γ and granzyme B by T cells were elevated following allogeneic HSCT. These results indicated that alloreactive T cells increased the secretion of IFN-γ, which promoted the alloresponse of donor CTLs. In addition, the CTLs produced granzyme B, which exerted a tumor suppressive effect. PMID:25009582

  9. Functional Reconstitution of Natural Killer Cells in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ullah, Md Ashik; Hill, Geoffrey R.; Tey, Siok-Keen

    2016-01-01

    Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are important in mediating immunity against both leukemia and pathogens. Although NK cell numbers generally reconstitute within a month, the acquisition of mature NK cell phenotype and full functional competency can take 6 months or more, and is influenced by graft composition, concurrent pharmacologic immunosuppression, graft-versus-host disease, and other clinical factors. In addition, cytomegalovirus infection and reactivation have a dominant effect on NK cell memory imprinting following allogeneic HSCT just as it does in healthy individuals. Our understanding of NK cell education and licensing has evolved in the years since the “missing self” hypothesis for NK-mediated graft-versus-leukemia effect was first put forward. For example, we now know that NK cell “re-education” can occur, and that unlicensed NK cells can be more protective than licensed NK cells in certain settings, thus raising new questions about how best to harness graft-versus-leukemia effect. Here, we review current understanding of the functional reconstitution of NK cells and NK cell education following allogeneic HSCT, highlighting a conceptual framework for future research. PMID:27148263

  10. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

    PubMed Central

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G.

    2016-01-01

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. PMID:27103745

  11. TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses.

    PubMed

    Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G; Davies, Jeffrey K

    2016-07-01

    Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. PMID:27103745

  12. Origin and Biology of the Allogeneic Response

    PubMed Central

    Lakkis, Fadi G.; Lechler, Robert I.

    2013-01-01

    The recognition by the immune system of nonself determinants on cells, tissues, or organs transplanted between genetically disparate members of the same species can lead to a potent allogeneic response that is responsible for rejection. We review here fundamental concepts that underlie the origins and biology of allorecognition in the mammalian immune system. We examine why and how T cells are alloreactive and discuss emerging evidence of allorecognition by innate immune cells. The nature of T cells (naïve vs. memory) and the alloantigen presentation pathways (direct, indirect, and semidirect) that initiate the allogeneic response are outlined. PMID:23906882

  13. In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.

    PubMed

    Leboeuf, Céline; Mailly, Laurent; Wu, Tao; Bour, Gaetan; Durand, Sarah; Brignon, Nicolas; Ferrand, Christophe; Borg, Christophe; Tiberghien, Pierre; Thimme, Robert; Pessaux, Patrick; Marescaux, Jacques; Baumert, Thomas F; Robinet, Eric

    2014-03-01

    Cell therapy based on alloreactivity has completed clinical proof of concept against hematological malignancies. However, the efficacy of alloreactivity as a therapeutic approach to treat solid tumors is unknown. Using cell culture and animal models, we aimed to investigate the efficacy and safety of allogeneic suicide gene-modified killer cells as a cell-based therapy for hepatocellular carcinoma (HCC), for which treatment options are limited. Allogeneic killer cells from healthy donors were isolated, expanded, and phenotypically characterized. Antitumor cytotoxic activity and safety were studied using a panel of human or murine HCC cell lines engrafted in immunodeficient or immunocompetent mouse models. Human allogeneic suicide gene-modified killer cells (aSGMKCs) exhibit a high, rapid, interleukin-2-dependent, and non-major histocompatibility complex class I-restricted in vitro cytotoxicity toward human hepatoma cells, mainly mediated by natural killer (NK) and NK-like T cells. In vivo evaluation of this cell therapy product demonstrates a marked, rapid, and sustained regression of HCC. Preferential liver homing of effector cells contributed to its marked efficacy. Calcineurin inhibitors allowed preventing rejection of allogeneic lymphocytes by the host immune system without impairing their antitumor activity. Our results demonstrate proof of concept for aSGMKCs as immunotherapy for HCC and open perspectives for the clinical development of this approach. PMID:24445938

  14. High proportions of regulatory T cells in PBSC grafts predict improved survival after allogeneic haematopoietic SCT

    PubMed Central

    Danby, R D; Zhang, W; Medd, P; Littlewood, T J; Peniket, A; Rocha, V; Roberts, D J

    2016-01-01

    Regulatory T cells (Tregs) modulate immune responses and improve survival in murine transplant models. However, whether the Treg content of allogeneic cell grafts influences the outcome in human haematopoietic stem cell (HSC) transplantation is not well established. In a prospective study of 94 adult allogeneic PBSC transplants (60% unrelated; 85% reduced intensity conditioning), the median Treg (CD3+CD4+CD25+FOXP3+CD127dim/−) dose transplanted was 4.7 × 106/kg, with Tregs accounting for a median of 2.96% of CD4+ T cells. Patients transplanted with grafts containing a Treg/CD4+ T-cell ratio above the median had a 3-year overall survival of 75%, compared with 49% in those receiving grafts with a Treg/CD4+ T-cell ratio below the median (P=0.02), with a 3-year non-relapse mortality of 13% and 35%, respectively (P=0.02). In multivariate analysis, a high graft Treg/CD4+ T-cell ratio was an independent predictor of lower non-relapse mortality (hazard ratio (HR), 0.30; P=0.02), improved overall survival (HR, 0.45; P=0.03) and improved sustained neutrophil (HR, 0.52; P=0.002), platelet (HR, 0.51; P<0.001) and lymphocyte (HR, 0.54; P=0.009) recovery. These data support the hypothesis that the proportion of Tregs in allogeneic HSC grafts influences clinical outcome and suggest that Treg therapies could improve allogeneic HSC transplantation. PMID:26389831

  15. Reconstitution of the CD45RO(+) and CD20(+) lymphoid marrow population following allogeneic bone marrow transplantation for Ph(+) CML.

    PubMed

    Thiele, J; Kvasnicka, H M; Beelen, D W; Welter, A; Schneider, S; Leder, L D; Schaefer, U W

    2001-02-01

    Following bone marrow transplantation (BMT) investigations on the recovery of the B and T lymphocyte populations have focused on the peripheral blood and only marginally regard the bone marrow. An immunohistochemical and morphometric study was performed on 352 trephine biopsies derived from 123 patients with chronic myelogenous leukemia (CML) at standardized endpoints before and after allogeneic BMT and compared to a control group. The purpose of this investigation was to quantify the B-CD20(+) and T-CD45RO(+) lymphocyte subsets and to determine possible relationships with the occurrence of acute and chronic GVHD. Moreover, we studied the dynamics of lymphocyte repopulation in the post-transplant period, correlations with the total peripheral lymphocyte count and differences associated with sibling vs alternate HLA-compatible (unmanipulated) marrow grafts. Morphometric analysis revealed a very fast regeneration of CD45RO(+) and CD20(+) marrow lymphocytes in the first 2 weeks following BMT. In less than 2 months, in most patients, the post-transplant quantity of lymphocytes was comparable to that of the normal bone marrow. This finding was opposed to the profound depression of the absolute lymphocyte count in the peripheral blood. No relevant relationships could be calculated between engraftment status and the lymphocyte repopulation in the bone marrow. On the other hand, significant correlations were calculable between the development of (chronic and acute) GVHD including severity with the number of CD45RO(+) lymphocytes. In non-related graft constellations a more frequent evolution of acute grade III + IV GVHD was detectable. This complication was accompanied by an increased quantity of CD45RO(+) lymphocytes in the marrow. PMID:11313672

  16. Clinical characteristics and outcome of isolated extramedullary relapse in acute leukemia after allogeneic stem cell transplantation: a single-center analysis.

    PubMed

    Shi, Ji-Min; Meng, Xiao-Jian; Luo, Yi; Tan, Ya-Min; Zhu, Xiao-Li; Zheng, Gao-Feng; He, Jing-Song; Zheng, Wei-Yan; Xie, Wan-Zhuo; Li, Li; Ye, Xiu-Jin; Zhang, Jie; Cai, Zhen; Lin, Mao-Fang; Huang, He

    2013-04-01

    Isolated extramedullary relapse (EMR) of acute leukemia (AL) is a rare occurrence. However, it appears to be more common after allogeneic stem cell transplantation (allo-SCT). To characterize what has been observed in isolated EMR, we investigated 287 consecutive AL patients (144 acute myeloid leukemia; 138 acute lymphocytic leukemia; 5 acute mixed-lineage leukemia) who underwent allo-SCT. Twelve cases experienced relapse at extramedullary sites without concomitant involvement of the bone marrow (BM). The onset to relapse after allo-SCT was longer in extramedullary sites than in the BM (median, 10 months versus 5.5 months). EMR sites varied widely and included the central nervous system, skin, bone, pelvis and breasts. Univariate analysis demonstrated that cytogenetic abnormalities were correlated significantly with the onset of isolated EMR (P=0.001). The prognosis for patients who develop EMR remained poor but was relatively better than that after BM relapse (overall survival, 10 versus 18 months). Compared with local or single therapy, patients treated with systemic treatment in combination with local treatment could yield a favorable prognosis. In conclusion, we observed a significant number of isolated cases of EMR in AL patients after allo-SCT, cytogenetic abnormalities were correlated significantly with the onset of isolated EMR. We found that intensive approaches combining local and systemic therapy could produce favorable responses which may cure a proportion of these patients. PMID:23347901

  17. Tolerance Associated Gene Expression following Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Pidala, Joseph; Bloom, Gregory C.; Eschrich, Steven; Sarwal, Minnie; Enkemann, Steve; Betts, Brian C.; Beato, Francisca; Yoder, Sean; Anasetti, Claudio

    2015-01-01

    Biologic markers of immune tolerance may facilitate tailoring of immune suppression duration after allogeneic hematopoietic cell transplantation (HCT). In a cross-sectional study, peripheral blood samples were obtained from tolerant (n = 15, median 38.5 months post-HCT) and non-tolerant (n = 17, median 39.5 post-HCT) HCT recipients and healthy control subjects (n = 10) for analysis of immune cell subsets and differential gene expression. There were no significant differences in immune subsets across groups. We identified 281 probe sets unique to the tolerant (TOL) group and 122 for non-tolerant (non-TOL). These were enriched for process networks including NK cell cytotoxicity, antigen presentation, lymphocyte proliferation, and cell cycle and apoptosis. Differential gene expression was enriched for CD56, CD66, and CD14 human lineage-specific gene expression. Differential expression of 20 probe sets between groups was sufficient to develop a classifier with > 90% accuracy, correctly classifying 14/15 TOL cases and 15/17 non-TOL cases. These data suggest that differential gene expression can be utilized to accurately classify tolerant patients following HCT. Prospective investigation of immune tolerance biologic markers is warranted. PMID:25774806

  18. ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Worel, Nina

    2016-01-01

    Summary Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for a variety of malignant and non-malignant hematological and congenital diseases. Due to the fact that the human leukocyte antigen system is inherited independently of the blood group system, approximately 40-50% of all HSCTs are performed across the ABO blood group barrier. The expected immune-hematological consequences after transplantation of an ABO-mismatched stem cell graft are immediate and delayed hemolytic complications due to presence of isohemagglutinins or passenger lymphocyte syndrome. The risks of these complications can partially be prevented by graft manipulation and appropriate transfusion support. Dependent on the kind of ABO mismatch, different effects on engraftment have been observed, e.g. delayed red blood cell recovery and pure red cell aplasia. Data on incidence of acute graft-versus-host disease (GVHD), non-relapse mortality, relapse, and overall survival are inconsistent as most studies include limited patient numbers, various graft sources, and different conditioning and GVHD prophylaxis regimens. This makes it difficult to detect a consistent effect of ABO-mismatched transplantation in the literature. However, knowledge of expectable complications and close monitoring of patients helps to detect problems early and to treat patients efficiently, thus reducing the number of fatal or life-threatening events caused by ABO-mismatched HSCT. PMID:27022317

  19. Recurrent abortions and lymphocyte transfusions.

    PubMed

    Bjercke, S

    1994-05-01

    Normal pregnancies depend on successful implantation of the placenta in the uterus. The trophoblast which forms the ultimate interface between the fetal and maternal tissue seems to lack the foreign (allo) antigens (namely HLA/TLX) required to induce immunological rejection reactions in the mother. It was previously believed that the trophoblast expressed paternal allo antigens and that successful pregnancies were dependent on so called 'kind' (non-cytotoxic or non-complement binding) blocking antibodies in order to protect the fetal unit from maternal cytotoxic T-cells and -antibodies. Blocking antibodies attached to paternal antigens on the trophoblast were assumed to prevent maternal cytotoxic T cell and cytotoxic antibodies from recognising the trophoblast as foreign tissue. On this assumption it was reasoned that transfusions of paternal HLA-expressing lymphocytes would increase maternal antipaternal HLA (TLX) blocking antibodies and thus be beneficial to women who experienced multiple miscarriages. There is, however, no scientific evidence for a specific immune response after lymphocyte transfusions that fulfil this function. Immunological tests, as for example mixed lymphocyte culture (MLC), on peripheral blood lymphocytes do not seem to reflect the local immune state in the uterus, either in the pregnant or the non-pregnant state. Since the trophoblast forms the ultimate interface between fetal and maternal tissue, its structure, secretions, and interaction with the decidua must be of definite importance for implantation of the blastocyst and growth of the embryo. PMID:8009967

  20. Chronic lymphocytic leukemia (CLL)

    MedlinePlus

    CLL; Leukemia - chronic lymphocytic (CLL) ... Byrd JC, Flynn JM. Chronic lymphocytic leukemia. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff's Clinical Oncology. 5th ed. Philadelphia, PA: Elsevier ...

  1. Acute Lymphocytic Leukemia

    MedlinePlus

    ... hard for blood to do its work. In acute lymphocytic leukemia (ALL), also called acute lymphoblastic leukemia, there are too ... of white blood cells called lymphocytes or lymphoblasts. ALL is the most common type of cancer in ...

  2. Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo

    SciTech Connect

    Lee, Miyoung; Jeong, Sang Young; Ha, Jueun; Kim, Miyeon; Jin, Hye Jin; Kwon, Soon-Jae; Chang, Jong Wook; Choi, Soo Jin; Oh, Wonil; Yang, Yoon Sun; Kim, Jae-Sung; Jeon, Hong Bae

    2014-04-18

    Highlights: • hUCB-MSCs maintained low immunogenicity even after immune challenge in vitro. • Humanized NSG mice were established using human UCB CD34+ cells. • Repeated intravenous hUCB-MSC injection into mice did not lead to immune responses and adverse events. • Allogeneic hUCB-MSCs maintained low immunogenicity in vitro and in vivo. - Abstract: Evaluation of the immunogenicity of human mesenchymal stem cells (MSCs) in an allogeneic setting during therapy has been hampered by lack of suitable models due to technical and ethical limitations. Here, we show that allogeneic human umbilical cord blood derived-MSCs (hUCB-MSCs) maintained low immunogenicity even after immune challenge in vitro. To confirm these properties in vivo, a humanized mouse model was established by injecting isolated hUCB-derived CD34+ cells intravenously into immunocompromised NOD/SCID IL2γnull (NSG) mice. After repeated intravenous injection of human peripheral blood mononuclear cells (hPBMCs) or MRC5 cells into these mice, immunological alterations including T cell proliferation and increased IFN-γ, TNF-α, and human IgG levels, were observed. In contrast, hUCB-MSC injection did not elicit these responses. While lymphocyte infiltration in the lung and small intestine and reduced survival rates were observed after hPBMC or MRC5 transplantation, no adverse events were observed following hUCB-MSC introduction. In conclusion, our data suggest that allogeneic hUCB-MSCs have low immunogenicity in vitro and in vivo, and are therefore “immunologically safe” for use in allogeneic clinical applications.

  3. Allogeneic hematopoietic stem cell transplantation in Tunisia.

    PubMed

    Ben Othman, T; Torjemane, L; Abdelkefi, A; Lakhal, A; Ladeb, S; Ben Hamed, L; Slama, H; Ben Abdeladhim, A

    2008-08-01

    In 1998, the Tunisian team of the 'Centre National de Greffe de Moelle Osseuse' initiated allogeneic hematopoietic SCT (AHSCT) in Tunisia. As of June 2007, information was collected about 299 patients with a first AHSCT and 12 additional retransplants. The median age was 19 years (range 2-49 years). The main indications were aplastic anemia (n=106, 36%), leukemia and nonmalignant disorders (n=153, 51%), Fanconi anemia (n=26, 9%) and other nonmalignant disorders (n=14, 4%). Preparative regimens depended on indication. All donors were HLA geno-identical. The stem cell sources were BM (87%) and PBSCs (13%). At the time of analysis, 200 patients (67%) were alive after a median follow-up of 42 months (range 3-112 months). The overall TRM rate was 17%. Outcome depended on indication. According to our results, allogeneic HSCT is potentially curative for hematological diseases, but it is a toxic approach for malignant disorders. PMID:18724288

  4. The Biology of Allogeneic Hematopoietic Cell Resistance

    PubMed Central

    Shizuru, Judith A.; Bhattacharya, Deepta; Cavazzana-Calvo, Marina

    2016-01-01

    At the most basic level, success of an allogeneic hematopoietic cell transplantation (HCT) procedure relies upon the engraftment of recipients with donor hematopoietic stem cells (HSCs) that will generate blood formation for the life of that individual. The formula to achieve durable HSC engraftment involves multiple factors including the recipient conditioning regimen, the nature of the genetic disparity between donor and recipient, and the content of the hematopoietic graft. Animal and clinical studies have shown that the biology of host resistance is complex, involving both immune and nonimmune elements. In this article, we review the factors that contribute to host resistance, describe emerging concepts on the basic biology of resistance, and discuss hematopoietic resistance as it relates specifically to patients with severe combined immunodeficiencies (SCID)— disorders that bring unique insights into the dynamics of cell replacement by allogeneic HSCs and progenitor cells. PMID:19913629

  5. Analysis of the in vitro effect of exogenous nitric oxide on human lymphocytes.

    PubMed

    Shoker, A S; Yang, H; Murabit, M A; Jamil, H; al-Ghoul, A; Okasha, K

    1997-06-01

    We investigated the role of endogenous or exogenous nitric oxide (NO) on human lymphocyte function. We used sodium nitroprusside, nitroglycerine, S-nitroso-N-acetylpenicillamine, sodium nitrite and S-nitroso-L-glutathione as NO-generating compounds. All agents were used at doses that do not produce direct cytotoxicity as measured by trypan blue exclusion as well as chromium-51 release assay. The immune responses examined were peripheral blood lymphocytes (PBL) proliferation and IL-2 production after activation with OKT3 and PHA; allogeneic mediated proliferation and cell mediated cytotoxicity (CML) in MLR; IgG and IgM production after PBL activation with Con-A; proliferation and expression of IFN-gamma and IL-4 mRNA after activation of allogeneic CD4+T cell clones. Cytokine mRNA expression was measured by reverse transcriptase PCR. Our results show that proliferating lymphocytes do not produce a detectable amount of NO as measured by the Griess reaction. In separate experiments, the addition of NG-monomethyl-L-arginine (L-NMMA) did not affect lymphocyte proliferation. Sodium nitroprusside and nitroglycerine exerted a dose dependent antimitogenic effect, inhibited cytokine production and expression, CML generation and antibody production. DNA gel electrophoresis showed no evidence for enhanced programmed cell death. The antimitogenic effect could not be blocked by the NO scavengers, hemoglobin or methylene blue. In contrast, the other nitric oxide generating compounds did not inhibit lymphocyte mitogenesis. The results suggest that human lymphocytes do not produce appreciable amounts of NO to affect lymphocyte mitogenesis. Sodium nitroprusside and nitroglycerine have a potent but nonspecific immunoinhibitory effect on human lymphocyte function by a mechanism other than NO production. In addition, pharmacological levels of NO do not inhibit human lymphocyte mitogenesis. PMID:9201699

  6. Apolizumab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-15

    Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Small Lymphocytic Lymphoma

  7. Ofatumumab, Pentostatin, and Cyclophosphamide in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2014-10-30

    Hematopoietic/Lymphoid Cancer; B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  8. Histocompatible chicken inbred lines: homogeneities in the major histocompatibility complex antigens of the GSP, GSN/1, PNP/DO and BM-C inbred lines assessed by hemagglutination, mixed lymphocyte reaction and skin transplantation.

    PubMed

    Valdez, Marcos B; Mizutani, Makoto; Fujiwara, Akira; Yazawa, Hajime; Yamagata, Takahiro; Shimada, Kiyoshi; Namikawa, Takao

    2007-10-01

    Chicken inbred lines of the GSP, GSN/1, PNP/DO and BM-C have been established by selection of a specific allele at the B blood group locus (MHC B-G region) and other polymorphic loci through pedigree mating. To extend the potential of these inbred lines as experimental animals in Aves, we assessed the antigenic homogeneities of the MHC antigens by three immunological methods. Antigenic variations of red blood cells (RBCs) were surveyed in the inbred lines and a random-bred line (NG) derived from the Nagoya breed by using ten kinds of intact antisera produced in the inbred line of chickens against RBCs of a red junglefowl and hybrids. In the hemagglutination test, no individual variations were found within the inbred line at all, while all the ten antisera detected highly heterogeneous reactions in individuals of the NG. The reciprocal one-way mixed lymphocyte reactions gave constantly higher stimulation responses (P<0.01) between individual pairs from the inbred lines having different B alleles compared to pairs within the inbred line, while lower stimulation was observed between pairs of the GSP and GSN/1 inbred lines both having the B(21) allele. In reciprocal skin transplantation, the transplanted skingrafts within the inbred line and between individuals from the GSP and GSN/1 inbred lines survived more than 100 days, while all the skingrafts showed signs of rejection within 7 days among the inbred lines having different B alleles. The results obtained by the three practical methods coincidentally indicated that the individuals in the respective four inbred lines were histocompatible, and further, that the GSP and GSN/1 individuals were histocompatible. PMID:18075192

  9. Lymphocyte Functions in Microgravity

    NASA Technical Reports Server (NTRS)

    Pellis, Neal R.; Risin, Diane; Sundaresan, A.; Cooper, D.; Dawson, David L. (Technical Monitor)

    1999-01-01

    To understand the mechanism of immunity impairment in space it is important to analyze the direct effects of space-related conditions on different lymphocytes functions. Since 1992, we are investigating the effect of modeled and true microgravity (MG) on numerous lymphocyte functions. We had shown that modeled (MMG) and true microgravity inhibit lymphocyte locomotion through type I collagen. Modeled microgravity also suppresses polyclonal and antigen-specific lymphocyte activation. Polyclonal activation of lymphocytes prior to exposure to MMG abrogates the MG-induced inhibition of lymphocyte locomotion. The relationship between activation deficits and the loss of locomotion in MG was investigated using PKC activation by phorbol ester (PMA) and calcium ionophore (ionomycin). Direct activation of PKC by PMA substantially restored the MMG-inhibited lymphocyte locomotion and PHA-induced lymphocyte activation lonomycin by itself did not restore either locomotion or activation of the lymphocytes, indicating that these changes are not related to the impairment in the calcium flux in MMG. Treatment of lymphocytes with PMA before exposure to MMG prevented the loss of locomotion. It was observed that DNA synthesis is not necessary for restoration of locomotion since mitomicin C treated and untreated cells recovered their locomotion to the same level after PKC activation. Our recent data indicate that microgravity may selectively effect the expression of novel Ca2+ independent isoforms of PKC, in particularly PKC sigma and delta. This provides a new insight in understanding of the mechanisms of MG-sensitive cellular functions.

  10. Prospective phase II trial to evaluate the complications and kinetics of chimerism induction following allogeneic hematopoietic stem cell transplantation with fludarabine and busulfan.

    PubMed

    Saito, Akiko M; Kami, Masahiro; Mori, Shin-Ichiro; Kanda, Yoshinobu; Suzuki, Ritsuro; Mineishi, Shin; Takami, Akiyoshi; Taniguchi, Shuichi; Takemoto, Yoshinobu; Hara, Masamichi; Yamaguchi, Masaki; Hino, Masayuki; Yoshida, Takashi; Kim, Sung-Won; Hori, Akiko; Ohashi, Yasuo; Takaue, Yoichi

    2007-10-01

    This prospective trial assessed the safety and efficacy of allogeneic hematopoietic stem cell transplantation from a HLA-matched donor with a reduced-intensity regimen (RIST) consisting of iv fludarabine 30 mg/m(2) for 6 days and oral busulfan 4 mg/kg/day for 2 days in patients older than 50 years with hematological malignancies. Cyclosporine alone or cyclosporine with short-term methotrexate was randomized for graft-versus-host disease prophylaxis. After 30 patients had been enrolled, an interim analysis was performed, and this report focuses on a precise evaluation of the toxicity profile and chimerism kinetics. Sustained engraftment in all patients, no severe regimen-related toxicity (RRT) within 20 days, and no transplant-related mortality through Day 100 were observed. T-cell (CD3+) full-donor (over 90%) chimerism was observed in 22 of the 30 patients, while the remaining eight had mixed-donor chimerism over 77% on Day 90. Thereafter, five subsequently converted to full-donor chimerism without donor lymphocyte infusion by day 120 (n = 4) or Day 180 (n = 1). Two showed persistent mixed chimerism without relapse through Day 180. Grade III-IV acute graft-versus-host disease and extensive chronic graft-versus-host disease occurred in 10% and 73%, respectively. With a median follow-up of 1.5 years, overall survival and disease-free survival at 1 year was 83% and 62%, respectively. Seven patients hematologically relapsed overall, and five of them had myelodysplastic syndrome with poor prognostic factors. In older patients, RIST with fludarabine and busulfan was associated with acceptable toxicities and a satisfactory antileukemia effect, regardless of the early chimerism status. PMID:17570513

  11. IL-10 inhibits alloreactive cytotoxic T lymphocyte generation in vivo.

    PubMed

    Wang, L; Goillot, E; Tepper, R I

    1994-12-01

    In this report, we present evidence that the CTL response directed against MHC Class I allo-determinants can be inhibited as a result of IL-10 expression in vivo. The presence of localized IL-10 secretion at the site of allogeneic tumor cell challenge resulted in marked inhibition of the CTL response and allowed growth of the tumor in the allogeneic host. Using purified CD4+ T cells from mice immunized in the presence or absence of IL-10, we have shown that the loss of alloreactivity as a consequence of IL-10 expression results from the inhibition of CD4+ T cell function. The expression of either IL-2 or IFN-gamma with IL-10 locally at the time of allogeneic cell challenge completely restored CTL alloreactivity, suggesting that the action of IL-10 could be bypassed by providing helper T lymphocyte-derived cytokines of the Th1 type at the site of immunization. Inhibition of alloreactivity by IL-10 was observed using either purified macrophages or dendritic cells as APC in an in vitro assay. Thus, the expression of IL-10 following antigenic challenge (such as that observed in Th2-like immune responses) may profoundly limit the ability for generating functional CTL in vivo. PMID:7994751

  12. Human thymocytes bind to autologous and allogeneic thymic epithelial cells in vitro.

    PubMed Central

    Singer, K H; Wolf, L S; Lobach, D F; Denning, S M; Tuck, D T; Robertson, A L; Haynes, B F

    1986-01-01

    The thymus plays a critical role in the generation of immunocompetent T lymphocytes. In the thymus, lymphocytes are in close contact with epithelial cells, and this contact is necessary for T-cell maturation. Using cultured human thymic epithelial (TE) cells, we have found that human thymocytes bind to human TE cells in vitro. Thymocytes bound to both allogeneic and autologous TE cells and to the epidermoid carcinoma cell line A431 but did not bind to epidermal keratinocytes or to thymic fibroblasts. Thymocyte binding to TE cells was trypsin- and cytochalasin B-sensitive. Indirect immunofluorescence assays showed that both mature (T6-, T3+) and immature (T6+, T3-) thymocytes bound TE cells. In our system, TE-thymocyte binding was not inhibited by antibodies to class I or class II major histocompatibility antigens. In vitro binding of thymocytes to TE cells may represent a correlate of in vivo TE-thymocyte interactions and provides a model system for the study of human intrathymic T-lymphocyte maturation and activation. Images PMID:3092215

  13. Membrane receptors for very low density lipoprotein (VLDL) inhibitor of lymphocyte proliferation

    SciTech Connect

    Yi, P.I.; Beck, G.; Zucker, S.

    1981-06-01

    Physiologic concentrations of human plasma very low density lipoproteins inhibit the DNA synthesis of lymphocytes stimulated by allogeneic cells or lectins. In this report reachers have compared the effects of isolated lipoproteins (very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL)) and lipoprotein-depleted plasma (LDP) on DNA synthesis by phytohemagglutinin-stimulated human lymphocytes. The relative potency for the inhibition of lymphocyte proliferation was VLDL greater than LDL greater than HDL greater than LDP. Fifty percent inhibition of DNA synthesis was observed at a VLDL protein concentration of 1.5--2.0 microgram/ml. Researchers have further demonstrated the presence of specific receptors for VLDL on human lymphocytes. Native VLDL was more effective than LDL in competing for 125I-VLDL binding sites. Subsequent to binding to lymphocytes, 125I-VLDL was internalized and degraded to acid-soluble products. Based on a Scatchard analysis of VLDL binding at 4 degrees C, the number of VLDL receptors per lymphocyte was estimated at 28,000 +/- 1300. Based on an estimated mean binding affinity for the VLDL receptor complex at half saturation of approximately 8.8 X 10(7) liter/mole, it is estimated that 91% of lymphocyte VLDL receptors are occupied at physiologic VLDL concentrations in blood. Although the immune regulatory role of plasma lipoproteins is uncertain, researchers suggest tha VLDL and LDL-In may maintain circulating blood lymphocytes in a nonproliferative state via their respective cell receptor mechanisms.

  14. Bendamustine Plus Alemtuzumab for Refractory Chronic Lymphocytic Leukemia (CLL)

    ClinicalTrials.gov

    2013-08-20

    Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  15. Relationship between age of allogeneic thymus donor and immunological restoration of athymic ('nude") mice.

    PubMed

    Radov, L A; Sussdorf, D H; McCann, R L

    1975-12-01

    In nude mice back-crossed a minimum of five times to BALB/c, solid thymus grafts from C57Bl donors 3 days of age or younger restored both the humoral immune response against sheep erythrocytes and cellular immunity as tested by rejection of CBA skin grafts. Donor thymus placed under the renal capsule at a dose of 0-5 mg/g of recipient resulted in normal humoral immunity, while a minimum dose of 1-5 mg/g was required to reconstitute cellular competence. None of the various amounts of allogeneic thymus tissue transplanted affected the immunological status of nude recipients when grafts were obtained from donors 4 days of age or older. Histological findings correlated with the humoral and cellular responses observed. In nudes grafted with neonatal tissue, the thymus implant proliferated and developed normal architecture. The density of lymphocytes in thymus-dependent regions of peripheral lymphoid organs was near normal. On the other hand, most grafts from older (3-week-old) donors were resorbed by 90 days after implantation. In a number of cases, however, Russell bodies and numerous blast and plasma cells were seen in the graft site. Our observations suggest a possible cytotoxic rejection of implants from older allogeneic donors, while the survival and restorative capacity of transplants from 3-day-old or younger donors may have been due to a tolerogenic effect of the graft on the nude recipient. PMID:1193689

  16. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update.

    PubMed

    Seggewiss, Ruth; Einsele, Hermann

    2010-05-13

    Allogeneic hematopoietic stem cell transplantation (HSCT) has advanced to a common procedure for treating also older patients with malignancies and immunodeficiency disorders by redirecting the immune system. Unfortunately, cure is often hampered by relapse of the underlying disease, graft-versus-host disease, or severe opportunistic infections, which account for the majority of deaths after HSCT. Enhancing immune reconstitution is therefore an area of intensive research. An increasing variety of approaches has been explored preclinically and clinically: the application of cytokines, keratinocyte growth factor, growth hormone, cytotoxic lymphocytes, and mesenchymal stem cells or the blockade of sex hormones. New developments of allogeneic HSCT, for example, umbilical cord blood or haploidentical graft preparations leading to prolonged immunodeficiency, have further increased the need to improve immune reconstitution. Although a slow T-cell reconstitution is regarded as primarily responsible for deleterious infections with viruses and fungi, graft-versus-host disease, and relapse, the importance of innate immune cells for disease and infection control is currently being reevaluated. The groundwork has been prepared for the creation of individualized therapy partially based on genetic features of the underlying disease. We provide an update on selected issues of development in this fast evolving field; however, we do not claim completeness. PMID:20215642

  17. Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow

    SciTech Connect

    Nakamura, H.; Gress, R.E. )

    1990-02-01

    Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

  18. Stem cell transplantation for indolent lymphoma and chronic lymphocytic leukemia

    PubMed Central

    Gribben, John G; Hosing, Chitra; Maloney, David G.

    2012-01-01

    The indolent lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) remain incurable with standard therapy. Autologous hematopoietic stem cell transplantation (HSCT[JHA1]) is feasible and has low treatment related mortality in follicular lymphoma, but there are questions relating to optimal timing of the procedure, conditioning regimen and late effects. Myeloablative allogeneic HSCT is associated with high treatment related morbidity and mortality, few late relapses, but is applicable to only a small number of patients. The major focus of HSCT in these lymphomas has been with reduced intensity conditioning (RIC) allogeneic HSCT, which is applicable to the age distribution of these diseases and which exploit the graft versus lymphoma effect in these diseases. Steps to further decrease the morbidity and mortality of the RIC HSCT and in particular to reduce the incidence of chronic extensive graft versus host disease while maintaining tumor control remain the major focus. Many potential treatments are available for indolent lymphomas and CLL, and appropriate patient selection and the timing of HSCT remain controversial. The use of HSCT must always be weighed against the risk of the underlying disease, particularly in a setting where improvements in treatment are leading to improved outcome. PMID:21195313

  19. Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2013-07-01

    B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  20. Lenalidomide and Vaccine Therapy in Treating Patients With Early-Stage Asymptomatic Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-06-10

    Chronic Lymphocytic Leukemia; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma

  1. In vivo protection of activated Tyr22-dihydrofolate reductase gene-modified canine T lymphocytes from methotrexate

    PubMed Central

    Gori, Jennifer L.; Beard, Brian C.; Williams, Nathaniel P.; Ironside, Christina; Swanson, Debra; McIvor, R. Scott; Kiem, HP

    2013-01-01

    Background Nonmyeloablative allogeneic hematopoietic stem cell (HSC) transplantation can cure malignant and nonmalignant diseases affecting the hematopoietic system, such as severe combined immunodeficiencies, aplastic anemia and hemoglobinopathies. Although nonmyeloablative is favored over myeloablative transplantation for many patients, graft rejection remains problematic. One strategy to decrease rejection is to protect donor activated T cells in the graft from methotrexate (MTX) by genetically modifying the cells to express MTX-resistant dihydrofolate reductase (Tyr22-DHFR), leaving the immunosuppressive effects of MTX to act solely on activated host T lymphocytes, shifting the balance to favor allogeneic engraftment. Methods To evaluate MTX resistance of Tyr22-DHFR+ T lymphocytes in vivo, we transplanted dogs with autologous CD34+ cells modified with YFP and DHFR-GFP lentivirus vectors. Dogs were then treated with a standard MTX regimen (days 1, 3, 6, and 11) following immune activation with a foreign antigen as a surrogate assay to mimic early transplantation. Results DHFR-GFP+ gene marking was maintained in CD3+CD25+ and CD4+ T lymphocytes after MTX treatment while the level of T lymphocytes that expressed only a fluorescent reporter (YFP+) decreased. These data show that Tyr22-DHFR expression protects T lymphocytes from MTX toxicity in dogs, highlighting a clinically relevant application for preserving donor T lymphocytes during post transplantation immunosuppression. Conclusions These findings have implications for clinical translation of MTX-resistant T cells to facilitate engraftment of allogeneic cells following nonmyeloablative conditioning and minimize the risk of rejection. In summary, Tyr22-DHFR expression in T lymphocytes provides chemoprotection from MTX-mediated elimination in the context of immune activation in vivo. PMID:23666780

  2. ALLOGENEIC NATURAL KILLER CELLS FOR REFRACTORY LYMPHOMA

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; McKenna, David H.; Curtsinger, Julie; Panoskaltsis-Mortari, Angela; Lindgren, Bruce R.; Cooley, Sarah; Weisdorf, Daniel; Miller, Jeffrey S.

    2014-01-01

    We reported that IL-2 activated autologous NK cells can induce, but not maintain durable remissions in lymphoma patients. We hypothesized that allogeneic NK cells may overcome class I MHC-mediated inhibition of NK cell killing. In a pilot study we evaluated infusion of haploidentical donor NK cells for anti-tumor efficacy. Six patients with advanced B-cell non-Hodgkin lymphoma (NHL) received rituximab, cyclophosphamide, and fludarabine as immunosupression to permit homeostatic NK cell expansion, followed by CD3-depleted NK cell enriched cell products followed by subcutaneous IL-2 administration (10×106 units every other day × 6 doses). At 2 months, four patients showed an objective clinical response. We observed early donor cell persistence in 2 patients (blood and in tumor-bearing node), but this was not detectable beyond 7 days. All patients demonstrated substantial increases in host regulatory T cells (Treg) after NK cell and IL-2 therapy (180±80 cells/μl vs baseline: 58±24 cells/μl, p=0.04) which may have limited donor cell expansion in vivo. These findings suggest safety and feasibility of allogeneic NK cell therapy in patients with lymphoma; however host Treg and inadequate immunodepletion may contribute to a hostile milieu for NK cell survival and expansion. Cell therapy trials should incorporate novel strategies to limit Treg expansion. PMID:20680271

  3. Solid cancers after allogeneic hematopoietic cell transplantation

    PubMed Central

    Curtis, Rochelle E.; Socié, Gérard; Sobocinski, Kathleen A.; Gilbert, Ethel; Landgren, Ola; Travis, Lois B.; Travis, William D.; Flowers, Mary E. D.; Friedman, Debra L.; Horowitz, Mary M.; Wingard, John R.; Deeg, H. Joachim

    2009-01-01

    Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non–squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients. PMID:18971419

  4. Monitoring of cardiac antirejection therapy with /sup 111/In lymphocytes

    SciTech Connect

    Lerch, R.A.; Bergmann, S.R.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-06-01

    To determine whether lymphocytes labeled with /sup 111/In permit noninvasive assessment of antirejection therapy, we performed 40 allogeneic heterotopic cardiac transplants in rats. Antirejection therapy with azathioprine (30 mg/kg) and sodium salicylate (200 mg/kg) prolonged contractile function of the graft from 7.5 +/- 1.5 (s.d.) days in controls to 19.4 +/- 3.7 days in treated animals. Six to seven days after transplantation, autologous lymphocytes labeled with /sup 111/In were injected intravenously in seven untreated and eight treated rats. Scintigraphy and organ counting were performed 24 hr after administration of labeled cells. At sacrifice all grafts in untreated rats exhibited contractile failure, whereas grafts in all treated rats were beating well. Transplants in untreated recipients exhibited marked accumulation of /sup 111/In lymphocytes detectable scintigraphically, with ratios of 7.7 +/- 1.9 for the activity in the transplant over that in the native heart (HT/HO), as obtained by well counting. In contrast, accumulation was not scintigraphically detectable in transplants of treated rats, with HT/HO ratios of 2.6 +/- 1.8 (p less than 0.005). The results suggested that imaging with /sup 111/In-labeled lymphocytes will permit noninvasive assessment of antirejection therapy.

  5. Allogeneic Transplantation Using Timed Sequential Busulfan and Fludarabine Conditioning

    ClinicalTrials.gov

    2015-12-18

    Leukemia; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Myeloproliferative Diseases; Non-Hodgkins Lymphoma; Hodgkins Lymphoma; Multiple Myeloma; Myelodysplastic Syndrome

  6. Hair follicle: a reliable source of recipient origin after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hong, Y C; Liu, H M; Chen, P S; Chen, Y J; Lyou, J Y; Hu, H Y; Yi, M F; Lin, J S; Tzeng, C-H

    2007-11-01

    Blood, buccal swab and hair follicles are among the most commonly used sources for forensic science, parentage testing and personal identification. A total of 29 patients who have had a sustained engraftment from 15 months to 21.5 years after allogeneic hematopoietic stem cell transplantation (HSCT) without rejection, relapse or chronic GVHD involving oral mucosa were enrolled for a chimerism study. PCR-amplified short tandem repeat analyses were conducted per patient every 3 months for at least three consecutive times. The results for blood were all donor type except one who had a mixed chimerism, 14.5 years after receiving a transplant for lymphoma. As for buccal swab, mixed chimerism ranging from 10 to 96% donor origin was noted for 28 recipients except the one who had mixed chimerism of blood and retained total recipient type. In contrast, hair follicles were 100% recipient type for the entire group. It is concluded that the hair follicle is devoid of adult stem cell plasticity and may serve as a reliable source of recipient's origin when pre-transplant DNA fingerprinting or reference DNA is not available for people who have successfully received allogeneic HSCT while in need of a personal identification. PMID:17704789

  7. Systematic Nutritional Support in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

    PubMed

    Fuji, Shigeo; Einsele, Hermann; Savani, Bipin N; Kapp, Markus

    2015-10-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established treatment modality for various hematological diseases. However, in allogeneic HSCT, patients often suffer from severe gastrointestinal complications caused by the conditioning regimen and acute/chronic graft-versus-host disease, which requires support by multidisciplinary nutritional support teams (NST). In addition, pretransplantation nutritional status can affect the clinical outcome after allogeneic HSCT. Therefore, it is important to refer the patient to a NST when becoming aware of nutritional problems before allogeneic HSCT. It is also important to follow nutritional status over the long term, as patients often suffer from various nutritional problems, such as malnutrition and metabolic syndrome, even late after allogeneic HSCT. In summary, NST can contribute to the improvement of nutritional status and possibly prognosis at every stage before and after allogeneic HSCT. Here, we aim to give a comprehensive overview of current understanding about nutritional support in allogeneic HSCT and try to provoke a constructive discussion to stimulate further investigation. PMID:26172477

  8. Multiple isolated extramedullary relapse of acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplant: a case report and review of literature.

    PubMed

    Kothari, Shalin; Herzig, Geoffrey; Slone, Stephen; Herzig, Roger

    2013-12-01

    Isolated extramedullary disease (EMD) is uncommon, especially in acute promyelocytic leukemia (APL) after allogeneic hematopoietic stem cell transplantation (HSCT). We review the literature and present a 32 year old woman with APL who developed multiple EMDs after allogeneic HSCT within the calvarium, and later found to have various isolated lesions including femur, humerus and thoraco lumbar vertebrae. She was treated with local radiotherapy (XRT) to EMD lesions, all-trans retinoic acid, arsenic trioxide and donor lymphocyte infusion at different time points in her clinical course, without success. Out of reported cases in clinical setting as ours, average onset of isolated EMD is 25 months and median survival 14 months. Effective treatment of isolated EMD after HSCT is not yet clear, but ATO in combination with local XRT, tamibarotene and second HSCT have shown good results in some reported cases, but accumulation of more cases is needed to elucidate optimal therapy in such setting. PMID:23476896

  9. Allogeneic and autologous bone marrow transplantation for acute nonlymphocytic leukemia.

    PubMed

    Hurd, D D

    1987-12-01

    Current results show that 50% of young patients with ANLL who undergo allogeneic BMT experience prolonged DFS and may be cured. Encouraging results with high-dose chemo/radiotherapy and autologous BMT are likewise being reported. In addition, some studies using intensive postremission treatment without BMT have shown results comparable to many transplant series. As better ways of preventing GVHD are found, the morbidity and mortality of allogeneic BMT should be reduced and the benefits of transplantation for curing patients with ANLL should be increased. However, the applicability of allogeneic BMT will remain limited due to the availability of compatible donors whether related or unrelated. Further studies are needed in the use of postremission intensive therapy with and without autologous bone marrow support. However, results to date should engender the same degree of enthusiastic optimism that followed the early reports of improved outcome with allogeneic BMT when applied to first remission patients. PMID:3321445

  10. Extracoporeal photopheresis treatment of acute graft-versus-host disease following allogeneic haematopoietic stem cell transplantation

    PubMed Central

    Flinn, Aisling M.; Gennery, Andrew R.

    2016-01-01

    Acute graft-versus-host disease (aGvHD) continues to be a major obstacle to allogeneic haematopoietic stem cell transplantation. Thymic damage secondary to aGvHD along with corticosteroids and other non-selective T lymphocyte-suppressive agents used in the treatment of aGvHD concurrently impair thymopoiesis and negatively impact on immunoreconstitution of the adaptive immune compartment and ultimately adversely affect clinical outcome. Extracorporeal photopheresis (ECP) is an alternative therapeutic strategy that appears to act in an immunomodulatory fashion, potentially involving regulatory T lymphocytes and dendritic cells. By promoting immune tolerance and simultaneously avoiding systemic immunosuppression, ECP could reduce aGvHD and enable a reduction in other immunosuppression, allowing thymic recovery, restoration of normal T lymphopoiesis, and complete immunoreconstitution with improved clinical outcome. Although the safety and efficacy of ECP has been demonstrated, further randomised controlled studies are needed as well as elucidation of the underlying mechanisms responsible and the effect of ECP on thymic recovery. PMID:27408705

  11. Morphological and immunohistological changes in the skin in allogeneic bone marrow recipients.

    PubMed Central

    Sloane, J P; Thomas, J A; Imrie, S F; Easton, D F; Powles, R L

    1984-01-01

    Skin biopsies from leukaemic patients undergoing allogeneic bone marrow transplantations and treated prophylactically with cyclosporin A were analysed using histological, morphometric, and immunohistological techniques. Samples from donors were used to establish normal values. Biopsies taken from recipients two days before grafting were all histologically normal, but on immunohistological staining half of them showed a reduction in the number of epidermal Langerhans' cells and 29% a reduction in T inducer lymphocytes. Thirty two biopsies were taken from patients with rashes at various times after transplantation: 14 showed lichenoid changes consistent with graft versus host disease, three eczematous tissue reactions, two vesicular lesions, and 12 no histological abnormality. One sample showed changes intermediate between the lichenoid and eczematous forms. The numbers of epidermal Langerhans' cells were low during the first few weeks after transplantation and were normal or raised later regardless of histological appearances. Unlike epidermal Langerhans' cells, significant reductions in the numbers of lymphocytes were not seen. Lesions of all histological types contained mixtures of T inducer and T suppressor/cytotoxic cells, although the eczematous and vesicular lesions contained higher proportions of T inducer cells. Epidermal infiltrates invariably contained T suppressor/cytotoxic cells but infiltration of epidermis by T inducer cells occurred only in the presence of normal numbers of epidermal Langerhans' cells. Natural killer cells were not identified. The immunological appearances of the various histological subgroups thus change with time after transplantation. Images PMID:6381547

  12. Evidence for the presence of a low molecular-weight activator of suppressor monocytes (LASM) in dialysates of T lymphocytes.

    PubMed

    Nekam, K; Strelkauskas, A J; Fudenberg, H H; Donnan, G G; Goust, J M

    1981-05-01

    Lysates of peripheral blood T lymphocytes from healthy individuals were found to contain a low molecular-weight peptide that inhibited phytohaemagglutinin-induced DNA synthesis in vitro by autologous or allogeneic peripheral blood mononuclear cells. The peptide was dialysable, partially heat stable, resistant to trypsin, RNase, and DNase but not to pronase, and was not part of the membrane receptor involved in rosette formation by T lymphocytes with sheep erythrocytes. It was found to act through monocytes, inducing the synthesis of second mediator responsible for the inhibition of lymphocyte DNA synthesis. This inducer of inhibition, designated as "low molecular-weight activator of suppressor monocytes' (LASM), may have a role in the depression of cellular immune response seen in various pathological conditions involving the destruction of T lymphocytes. PMID:6972906

  13. Evidence for the presence of a low molecular-weight activator of suppressor monocytes (LASM) in dialysates of T lymphocytes.

    PubMed Central

    Nekam, K; Strelkauskas, A J; Fudenberg, H H; Donnan, G G; Goust, J M

    1981-01-01

    Lysates of peripheral blood T lymphocytes from healthy individuals were found to contain a low molecular-weight peptide that inhibited phytohaemagglutinin-induced DNA synthesis in vitro by autologous or allogeneic peripheral blood mononuclear cells. The peptide was dialysable, partially heat stable, resistant to trypsin, RNase, and DNase but not to pronase, and was not part of the membrane receptor involved in rosette formation by T lymphocytes with sheep erythrocytes. It was found to act through monocytes, inducing the synthesis of second mediator responsible for the inhibition of lymphocyte DNA synthesis. This inducer of inhibition, designated as "low molecular-weight activator of suppressor monocytes' (LASM), may have a role in the depression of cellular immune response seen in various pathological conditions involving the destruction of T lymphocytes. PMID:6972906

  14. Response to Intravenous Allogeneic Equine Cord Blood-Derived Mesenchymal Stromal Cells Administered from Chilled or Frozen State in Serum and Protein-Free Media

    PubMed Central

    Williams, Lynn B.; Co, Carmon; Koenig, Judith B.; Tse, Crystal; Lindsay, Emily; Koch, Thomas G.

    2016-01-01

    Equine mesenchymal stromal cells (MSC) are commonly transported, chilled or frozen, to veterinary clinics. These MSC must remain viable and minimally affected by culture, transport, or injection processes. The safety of two carrier solutions developed for optimal viability and excipient use were evaluated in ponies, with and without allogeneic cord blood-derived (CB) MSC. We hypothesized that neither the carrier solutions nor CB-MSC would elicit measurable changes in clinical, hematological, or biochemical parameters. In nine ponies (study 1), a bolus of HypoThermosol® FRS (HTS-FRS), CryoStor® CS10 (CS10), or saline was injected IV (n = 3/treatment). Study 2, following a 1-week washout period, 5 × 107 pooled allogeneic CB-MSCs were administered IV in HTS-FRS following 24 h simulated chilled transport. Study 3, following another 1-week washout period 5 × 107 pooled allogeneic CB-MSCs were administered IV in CS10 immediately after thawing. Nine ponies received CB-MSCs in study 2 and 3, and three ponies received the cell carrier media without cells. CB-MSCs were pooled in equal numbers from five unrelated donors. In all studies, ponies were monitored with physical examination, and blood collection for 7 days following injection. CD4 and CD8 lymphocyte populations were also evaluated in each blood sample. In all three studies, physical exam, complete blood cell count, serum biochemistry, and coagulation panel did not deviate from established normal ranges. Proportions of CD4+ and CD8+ lymphocytes increased at 168 h postinjection in CB-MSC treatment groups regardless of the carrier solution. Decreases in CD4+/CD8+ double positive populations were observed at 24 and 72 h in CB-MSC-treated animals. There was no difference in viability between CB-MSCs suspended in HTS-FRS and CS10. HTS-FRS and CS10 used for low volume excipient injection of MSC suspensions were not associated with short-term adverse reactions. HTS-FRS and CS10 both adequately

  15. Novel mode of action of the calcium antagonist mibefradil (Ro 40-5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium.

    PubMed Central

    Blaheta, R A; Hailer, N P; Brude, N; Wittig, B; Oppermann, E; Leckel, K; Harder, S; Scholz, M; Weber, S; Encke, A; Markus, B H

    1998-01-01

    Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy. PMID:9741343

  16. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies

    PubMed Central

    Hoyos, Valentina; Savoldo, Barbara; Dotti, Gianpietro

    2012-01-01

    Modern chemotherapy regimens and supportive care have produced remarkable improvements in the overall survival of patients with hematologic malignancies. However, the development of targeted small molecules, monoclonal antibodies, and biological therapies that demonstrate greater efficacy and lower toxicity remains highly desirable in hematology, and oncology in general. In the context of biological therapies, T-lymphocyte based treatments have enormous potential. Donor lymphocyte infusion in patients relapsed after allogeneic hematopoietic stem cell transplant pioneered the concept that T lymphocytes can effectively control tumor growth, and this was then followed by the development of cell culture strategies to generate T lymphocytes with selective activity against tumor cells. Over the past decade, it has become clear that the adoptive transfer of ex vivo expanded antigen-specific cytotoxic T lymphocytes promotes sustained antitumor effects in patients with virus-associated lymphomas, such as Epstein-Barr virus related post-transplant lymphomas and Hodgkin's lymphomas. Because of this compelling clinical evidence and the concomitant development of methodologies for robust gene transfer to human T lymphocytes, the field has rapidly evolved, offering new opportunities to extend T-cell based therapies. This review summarizes the most recent biological and clinical developments using genetically manipulated T cells for the treatment of hematologic malignancies. PMID:22929977

  17. Repair of osteochondral defects by mosaicplasty and allogeneic BMSCs transplantation

    PubMed Central

    Ma, Xin; Sun, Yuan; Cheng, Xiangguo; Gao, Youshui; Hu, Bin; Wen, Gen; Qian, Yebin; Gu, Wenqi; Mao, Yanjie; Liu, Wanjun

    2015-01-01

    Objective: To investigate the feasibility and efficacy of repairing osteochondral defects with mosaicplasty and allogeneic bone marrow mesenchymal stem cells (BMSCs) transplantation. Methods: BMSCs were harvested from rabbits and maintained in vitro. Cells of third passage were mixed with pluronic F-127. Osteochondral defect animal model was established in rabbits and then this defect was treated with autologous osteochondral grafts with or without BMSCs above mentioned. In control group, pure pluronic F-127 was filled in the defect. Histological and immunohistological examinations were performed for the evaluation of therapeutic effectiveness. Results: Autologous osteochondral grafts in both groups were not loose, prolapsed and depressed. In BMSCs group, the tissues in the “death space” became hyaline cartilage. The arrangement of chondrocytes was regular. At 4, 8, 12 and 16 weeks, O’Driscoll and Keeley and Salter score were 14.00±1.00, 16.75±1.71, 18.00±0.82 and 20.50±1.29 in BMSCs group, which were significantly higher than those in control group (7.67±0.58, 8.00±0.82, 8.50±0.58 and 9.00±0.82, respectively). There were significant differences among different treatments (F=584.028, P=0.000), but the score was comparable between right defect and left defect (F=0.028, P=0.890). In addition, significant difference was also observed at different time points (F=18.364, P=0.000), but there was no interaction between time and treatment (F=6.939, P=0.015). Moreover, interactions among other factors were also not observed. Conclusion: Mosaicplasty and BMSC transplantation are effective to repair the osteochondral defects and integrate the “death space”, achieving a better therapeutic efficacy. Thus, this combined therapy may become an effective strategy for the therapy of osteochondral defects. PMID:26131203

  18. FDG PET/CT in Acute Tumefactive Multiple Sclerosis Occurring in a Case of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Dong, Aisheng; Gao, Mingjun; Wang, Yang; Gao, Lei; Zuo, Changjing

    2016-09-01

    Tumefactive multiple sclerosis refers to the presentation of large demyelinating lesions (≥2 cm in diameter) mimicking brain tumors clinically and radiologically. We present the MRI and FDG PET/CT findings in a case with tumefactive multiple sclerosis, who had chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Head MRI showed 7 cerebral lesions with incomplete ring enhancement. All but one lesion had size more than 2 cm. All these demyelinating lesions showed increased uptake at the rims of the lesions with central hypometabolism. Stereotactic brain biopsy of the right frontal lesion revealed extensive macrophage and lymphocyte infiltration. PMID:26909714

  19. Chronic lymphocytic leukaemia.

    PubMed

    Scarfò, Lydia; Ferreri, Andrés J M; Ghia, Paolo

    2016-08-01

    Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among the adults in the Western World. CLL (and the corresponding nodal entity small lymphocytic lymphoma, SLL) is classified as a lymphoproliferative disorder characterised by the relentless accumulation of mature B-lymphocytes showing a peculiar immunophenotype in the peripheral blood, bone marrow, lymph nodes and spleen. CLL clinical course is very heterogeneous: the majority of patients follow an indolent clinical course with no or delayed treatment need and with a prolonged survival, while others experience aggressive disease requiring early treatment followed by frequent relapses. In the last decade, the improved understanding of CLL pathogenesis shed light on premalignant conditions (i.e., monoclonal B-cell lymphocytosis, MBL), defined new prognostic and predictive markers, improving patient stratification, but also broadened the therapeutic armamentarium with novel agents, targeting fundamental signaling pathways. PMID:27370174

  20. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2015-11-10

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  1. Who is fit for allogeneic transplantation?

    PubMed

    Deeg, H Joachim; Sandmaier, Brenda M

    2010-12-01

    The use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplantation candidates. Indications remain diagnosis-dependent. As novel nontransplantation modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with comorbid conditions. Thus, patients with high-risk malignancies who have substantial comorbidities or are of advanced age are at high risk of both relapse and nonrelapse mortality and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy is generally associated with increased transplantation success. In addition, to handle the stress associated with HCT, patients need a good social support system and a secure financial net. They must be well informed, not only about the transplantation process, but also about expected or potential post-HCT events, including graft-versus-host disease and delayed effects that may become manifest only years after HCT. PMID:20702782

  2. Allogeneic Hematopoietic Cell Transplant for Prolymphocytic Leukemia

    PubMed Central

    Kalaycio, Matt E.; Kukreja, Manisha; Woolfrey, Ann E.; Szer, Jeffrey; Cortes, Jorge; Maziarz, Richard T.; Bolwell, Brian J.; Buser, Andreas; Copelan, Edward; Gale, Robert Peter; Gupta, Vikas; Maharaj, Dipnarine; Marks, David I; Pavletic, Steven Z.; Horowitz, Mary M.; Arora, Mukta

    2009-01-01

    The poor prognosis of patients with prolymphocytic leukemia (PLL) has led some clinicians to recommend allogeneic hematopoietic cell transplant (HCT). However, the data to support this approach is limited to case-reports and small case-series. We reviewed the database of the Center for International Blood & Marrow Transplant Research to determine outcomes after allotransplant for patients with PLL. We identified 47 patients with a median age of 54 years (range, 30–75). With a median follow-up of 13 months, progression-free survival was 33% (95% Confidence Interval 20–47%) at 2 years. The most common cause of death was relapse or progression in 49%. The cumulative incidence of treatment-related mortality at 1-year post transplant was 28%. The small patient population prohibited prognostic factor analysis but these data support consideration of allotransplant for PLL. Further study of a larger population of patients is needed to determine which patients are more likely to benefit. PMID:19961946

  3. Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Zinöcker, Severin; Dressel, Ralf; Wang, Xiao-Nong; Dickinson, Anne M.; Rolstad, Bent

    2012-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient

  4. Efficacy of immune suppression tapering in treating relapse after reduced intensity allogeneic stem cell transplantation

    PubMed Central

    Kekre, Natasha; Kim, Haesook T.; Thanarajasingam, Gita; Armand, Philippe; Antin, Joseph H.; Cutler, Corey; Nikiforow, Sarah; Ho, Vincent T.; Koreth, John; Alyea, Edwin P.; Soiffer, Robert J.

    2015-01-01

    For patients who relapse after allogeneic hematopoietic stem cell transplantation while still on immune suppression, there is anecdotal evidence that tapering the immune suppression may result in graft-versus-tumor activity. We reviewed the medical records of all patients with documented histological or radiographic disease recurrence within 1 year of stem cell transplantation while on immune suppression at our institution. The median time to relapse was 110 days (range, 18–311) after transplant. Among 123 patients with relapse treated with immune suppression tapering without chemotherapy, radiation, or donor lymphocyte infusion, 34 responded (33/101 reduced intensity conditioning transplant and 1/22 myeloablative conditioning transplant, 32.7% and 4.5% respectively; P=0.007). The median time to response after initiation of immune suppression tapering was 82 days (range, 16–189). Thirty-three patients (97.1%) had development or progression of acute or chronic graft-versus-host disease as a consequence of immune suppression tapering, at a median time of 39 days (range, 16–98). Six patients subsequently relapsed late after initial response to immune suppression tapering at a median time of 2 years (range, 0.9–3.8). The median overall survival from immune suppression tapering for responders was 5.1 years (range, 1.9-not estimable). When clinically feasible, immune suppression tapering alone in patients who relapse early after reduced intensity conditioning allogeneic stem cell transplantation can produce durable remissions, but is almost always associated with graft-versus-host disease. PMID:26088931

  5. The lymph node in chronic lymphocytic leukemia.

    PubMed

    Dick, F R; Maca, R D

    1978-01-01

    Lymph nodes were examined from 41 cases of typical chronic lymphocytic leukemia (CLL). Degree of immaturity was graded as absent to minimal (Grade I), moderate (Grade II) and marked (Grade III). A moderate degree of immaturity was found in the lymph node in 14 of 41 cases even though the cells seen on the initial bone marrow and peripheral blood smears obtained from these patients were essentially all mature. The morphology of these nodes could be confused with poorly differentiated lymphocytic or mixed lymphocytic-histiocytic lymphoma in terms of the degree of immaturity present. A marked degree of immaturity present. A marked degree of immaturity was found in 5 cases; the morphology of these cases resembled histiocytic lymphoma. In the remaining 22 cases immaturity was essentially absent. The morphology of these cases was similar to that of diffuse well differentiated lymphocytic lymphoma. Our studies suggest that a moderate degree of immaturity in the lymph node of patients with CLL does not indicate that these patients will have a marked shortening of their survival. PMID:580071

  6. Practical approach to management of chronic lymphocytic leukemia.

    PubMed

    Smolej, Lukáš; Šimkovič, Martin

    2016-04-01

    Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL. PMID:27186193

  7. Practical approach to management of chronic lymphocytic leukemia

    PubMed Central

    Šimkovič, Martin

    2015-01-01

    Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL. PMID:27186193

  8. Timed Sequential Busulfan and Post Transplant Cyclophosphamide for Allogeneic Transplantation

    ClinicalTrials.gov

    2016-08-05

    Other Diseases of Blood and Blood-forming Organs; Acute Myeloid Leukemia; Acute Lymphocytic Leukemia; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome; Myeloproliferative Syndrome; Non-Hodgkins Lymphoma; Hodgkins Lymphoma; Multiple Myeloma

  9. Allogeneic hematopoietic stem cell transplantation in mycosis fungoides*

    PubMed Central

    Atalla, Angelo; Hallack Neto, Abrahão Elias; Siqueira, Denise Bittencourt; Toledo, Gabriela Cumani

    2013-01-01

    Mycosis Fungoides is typically an indolent disease in early stages. However, approximately 30% of patients have advanced staged disease at presentation and 20% will develop it at some time. These patients have a poorer prognosis with a median survival of 2-4 years. The only curative option for mycosis fungoides may be hematopoietic allogeneic stem cell transplantation. We report the case of a patient with mycosis fungoides in an advanced stage (IIB), refractory to treatment options. She underwent allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The patient remains in complete remission nineteen months after allo-HSCT. Allogeneic transplantation can alter the natural history of mycosis fungoides and should be considered in patients who have refractory disease or short-lived responses with standard therapies. PMID:24346924

  10. Autologous and allogeneic serum eye drops. The Dutch perspective.

    PubMed

    van der Meer, Pieter F; Seghatchian, Jerard; de Korte, Dirk

    2015-08-01

    If regular artificial tears are ineffective for treatment of ocular surface disorders (including extreme dry eye syndrome), serum eye drops (SEDs) may provide a way to relieve the symptoms. However, not all patients are eligible to donate blood to produce autologous SEDs. Therefore, the use of allogeneic SEDs (obtained from voluntary blood donors) should be explored as an alternative for autologous SEDs. The Dutch blood bank organization is currently looking into the possibilities to provide allogeneic SEDs, as (GMP) regulations become stricter, making it for hospitals more difficult to provide autologous SEDs. To demonstrate effectiveness of both autologous and allogeneic SEDs, a clinical trial is planned. The current status of SEDs in The Netherlands is described. This paper is based on summary of the presentation given at the DGTI meeting in Dresden. PMID:26138910

  11. Induction of Allogeneic Unresponsiveness in Adult Dogs

    PubMed Central

    Rapaport, F. T.; Bachvaroff, R. J.; Watanabe, K.; Hirasawa, H.; Mollen, N.; Ferrebee, J. W.; Amos, D. B.; Cannon, F. D.; Blumenstock, D. A.

    1978-01-01

    the early postirradiation period for the induction of allogeneic unresponsiveness in large adult mammals. PMID:76636

  12. Prethymic nylon wool-passed bone marrow cells, substituting for helper T cells, can augment the generation of cytotoxic T lymphocytes from their precursors.

    PubMed

    Tanabe, M J

    1991-01-01

    Nylon wool-passed bone marrow (NW-BM) cells treated with anti-Thy.1 monoclonal antibody and complement were added to a mixed lymphocyte culture which contained a limiting number of lymph node cells, as responder cells, and a sufficient number of mitomycin-c-treated allogeneic spleen cells as stimulator cells. NW-BM cells of the same MHC haplotype as responder cells enhanced the generation of allo-specific cytotoxic T lymphocytes (CTL) not only at a relatively high dose (3 x 10(3) cells/well) of responder cells, but also at an extremely dilute dose (1 x 10(3) cells/well). NW-BM cells which had a third-party MHC haplotype, a haplotype different from both responder and stimulator cells, also enhanced the generation of CTL at relatively high doses, but not at low doses, of responder cells. NW-BM cells which had MHC haplotypes identical with those of responder cells induced CTL from helper T cell-depleted responder cells, but NW-BM cells which had the third-party haplotype did not. These results showed that the enhancing effects of NW-BM cells of the same MHC haplotype as responder cells might be due to a specific helper effect and the enhancing effect of NW-BM cells of the third-party haplotype might be due to a nonspecific filler effect, which only conditioned the cultured cells. It was also found that, to exhibit the helper effect, NW-BM cells had to possess MHC class II, but not MHC class I, molecules in common with CTL precursors. This study showed that in the induction of CTL, prethymic NW-BM cells had a capability comparable to that of mature helper T cells. PMID:1839692

  13. Engraftment kinetics and hematopoietic chimerism after reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation.

    PubMed

    Blau, I W; Schmidt-Hieber, Martin; Leschinger, N; Göldner, H; Knauf, W; Hopfenmüller, W; Thiel, E; Blau, O

    2007-08-01

    Reduced-intensity conditioning with fludarabine and treosulfan before allogeneic stem cell transplantation (SCT) was introduced several years ago. Although its feasibility has recently been proven, only limited data are available on myelotoxicity, engraftment kinetics, and the significance of hematopoietic chimerism using this novel conditioning regimen. To clarify these open questions, we analyzed 27 patients with various hematological diseases, who received allogeneic SCT preceded by fludarabine/treosulfan conditioning. Further assessment endpoints included graft-vs-host disease (GvHD), mortality, and overall survival (OS). Allogeneic SCT was followed by neutropenia (absolute neutrophil count < or = 0.5 x 10(9)/l) and thrombocytopenia (platelets < or = 20 x 10(9)/l) in all patients. All patients showed stable neutrophil engraftment, and all except one had stable platelet engraftment. Grades II-IV acute GvHD was found in 48% of patients, whereas 52% developed chronic GvHD. The treatment-related mortality on day +100, 1 year after SCT, and at the last follow-up was 11, 26, and 33%, respectively. We found complete chimerism rates of 46, 57, and 72% on days +28, +56, and at the last follow-up or before death, respectively. The underlying malignancy tended to relapse more frequently in patients with mixed chimerism than in those with complete chimerism on day +28 as well as on day +56 (not significant). Additionally, no significant association was found between hematopoietic chimerism and donor type, GvHD, or OS, respectively. We conclude that reduced-intensity conditioning with fludarabine and treosulfan before allogeneic SCT is myeloablative, provides stable engraftment, and leads to complete chimerism in the majority of patients. PMID:17468869

  14. Polychlorinated biphenyls (PCBs) depress allogeneic natural cytotoxicity by earthworm coelomocytes

    SciTech Connect

    Suzuki, M.M.; Cooper, E.L.; Eyambe, G.S.; Goven, A.J.; Fitzpatrick, L.C.; Venables, B.J. |

    1995-10-01

    Coelomocytes of the earthworm Lumbricus terrestris caused significant spontaneous allogeneic cytotoxicity in a 24-h trypan blue assay, but not in an assay using lactate dehydrogenase (LDH) release. Allogeneic cytotoxicity assays using cells from worms exposed to polychlorinated biphenyls (PCBs) suggest that PCBs can suppress a natural killing (NK-like) reaction. The implications of this work are twofold: understanding the evolution of natural killing (NK-like) activity and providing preliminary information on how spontaneous killing, a component of cellular immunity, may be compromised by pollutants.

  15. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

    PubMed Central

    Craddock, Charles; Labopin, Myriam; Robin, Marie; Finke, Juergen; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Bourhis, Jean Henri; Sengelov, Henrik; Blaise, Didier; Luft, Thomas; Hallek, Michael; Kröger, Nicolaus; Nagler, Arnon; Mohty, Mohamad

    2016-01-01

    Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixty-nine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%–37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required. PMID:27081178

  16. Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-01-16

    B-cell Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia

  17. Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA

    PubMed Central

    Chinen, Yasutsugu; Higa, Takeshi; Tomatsu, Shunji; Suzuki, Yasuyuki; Orii, Tadao; Hyakuna, Nobuyuki

    2014-01-01

    Mucopolysaccharidosis IVA (MPS IVA) is one of the lysosomal storage diseases. It is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of the specific glycosaminoglycans keratan sulfate and chondroitin-6-sulfate. This accumulation has a direct impact on cartilage and bone development, resulting in systemic skeletal dysplasia. There is no curative therapy for this skeletal dysplasia. This report describes long-term therapeutic efficacy in a 15-year-old boy with a severe form of MPS IVA who received successful allogeneic bone marrow transplantation (BMT) from his HLA-identical carrier sister. The level of the GALNS enzyme in the recipient’s lymphocytes reached almost half of normal level within two years after BMT. For the successive 9+ years post-BMT, GALNS activity in his lymphocytes maintained the same level as the donor’s, and the level of urinary uronic acid was reduced. Lumbar bone mineral density increased around 50% one year later post-BMT and was kept consistent. Radiographs showed that the figures of trochanter major and minor appeared, while the epiphyseal dysplasia in the femoral cap was almost unchanged. Loud snoring and apnea disappeared. Vital capacity increased to around 20% for the first two years and was maintained. Activity of daily life (ADL) was improved in work/study efficacy, respiratory status, sleep, joint pain, and frequency of infection. In conclusion, the long-term study of hematopoetic stem cell transplantation has shown clinical improvements in respiratory function, radiograph findings, ADL, and biochemical findings, suggesting that it is a potential therapeutic option for patients with MPS IVA. PMID:25593792

  18. Actinomycosis after allogeneic hematopoietic stem cell transplantation despite penicillin prophylaxis.

    PubMed

    Barraco, F; Labussière-Wallet, H; Valour, F; Ducastelle-Leprêtre, S; Nicolini, F-E; Thomas, X; Ferry, T; Dumitrescu, O; Michallet, M; Ader, F

    2016-08-01

    Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients. PMID:27203624

  19. Allogenic benefit in stem cell therapy: cardiac repair and regeneration.

    PubMed

    Al-Daccak, R; Charron, D

    2015-09-01

    Stem cell (SC)-based therapies are a developing mean to repair, restore, maintain, or enhance organ functioning through life span. They are in particular a fast track to restore function in failing heart. Various types of SCs have been used in experimental and clinical studies showing the potential of these cells to revolutionize the treatment of heart diseases. Autologous cells have been privileged to overpass immunological barriers. The field has progressed tremendously and the hurdles, which have been largely overlooked in the excitement over the expected benefit the immunogenicity, have been revealed. Also, manufacturing of patient-specific clinical grade SC product, whether adult stem or reprogrammed induced pluripotent SCs, and the availability of these cells in sufficient amounts and status when needed is questionable. In contrast, adult SCs derived from healthy donors, thus allogeneic, have the advantage to be immediately available as an 'off-the-shelf' therapeutic product. The challenge is to overcome the immunological barriers to their transplantation. Recent research provided new insights into the mode of action and immune behavior of SCs in autologous as well as allogeneic settings. Lessons are learned and immune paradigms are changing: allogenicity, if balanced could be part of the dynamic and durable mechanisms that are critical to sustain cardiac regeneration and repair. We discuss the hurdles, lessons, and advances accomplished in the field through the progressive journey of cardiac-derived stem/progenitor cells toward allogeneic cardiac regenerative/reparative therapy. PMID:26206374

  20. Cell salvage for minimising perioperative allogeneic blood transfusion

    PubMed Central

    Carless, Paul A; Henry, David A; Moxey, Annette J; O’Connell, Dianne; Brown, Tamara; Fergusson, Dean A

    2014-01-01

    Background Concerns regarding the safety of transfused blood have prompted reconsideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. Objectives To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. Search methods We identified studies by searching CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to June 2009), EMBASE (1980 to June 2009), the internet (to August 2009) and bibliographies of published articles. Selection criteria Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage (autotransfusion) or to a control group who did not receive the intervention. Data collection and analysis Data were independently extracted and the risk of bias assessed. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random-effects model. The primary outcomes were the number of patients exposed to allogeneic red cell transfusion and the amount of blood transfused. Other clinical outcomes are detailed in the review. Main results A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR 0.62; 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD −0.68; 95% CI −0.88 to −0.49). Cell salvage did not appear to impact adversely on clinical outcomes. Authors’ conclusions

  1. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-02-16

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  2. Tositumomab and Iodine I 131 Tositumomab in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma in First Remission

    ClinicalTrials.gov

    2015-08-04

    Lymphoid Leukemia in Remission; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  3. Extramedullary relapse after allogeneic bone marrow transplantation plus buffy-coat in two high risk patients.

    PubMed

    Salutari, P; Sica, S; Micciulli, G; Rutella, S; Di Mario, A; Leone, G

    1996-01-01

    In order to obtain an additional graft versus leukemia effect (GVL) and rapid engraftment, donor leukocyte infusion (DLI) was added to unseparated, sex-mismatched allogeneic bone marrow transplantation in two male patients (age 21, 26) affected by high risk hematological malignancies (refractory T-ALL, refractory B-LBL in leukemic phase). Graft versus host disease (GVHD) prophylaxis consisted of methotrexate (MTX) alone. DLI were obtained after G-CSF 16 ug/kg/day sc. A total of 2.36 and 5.8 x 10(6)/kg MNC, 5.4 and 11 x 10(6)/kg CD34+ cells, 1.3 and 1.3 x 10(6)/kg CD3+ lymphocytes, respectively, were infused. Hemopoietic recovery occurred promptly. Complete chimerism was detected by cytogenetic examination. One patient developed an extramedullary relapse that first involved the cranial nerves, and then the testes, soft tissue and skin; the other patient developed central nervous system disease and then bilateral paravertebral masses with progressive paraplegia. Despite complete medullary remission with normal female karyotype, both patients died from extramedullary progression of their disease. Our observation shows that, at least in high risk patients, no additional GVHD or GVL effect was evident after donor leukocyte infusion. Extramedullary relapse was not prevented despite good control of medullary disease. PMID:8641654

  4. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients.

    PubMed

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-09-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  5. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients

    PubMed Central

    Yew, P Y; Alachkar, H; Yamaguchi, R; Kiyotani, K; Fang, H; Yap, K L; Liu, H T; Wickrema, A; Artz, A; van Besien, K; Imoto, S; Miyano, S; Bishop, M R; Stock, W; Nakamura, Y

    2015-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID:26052909

  6. Establishment of banking system for allogeneic cultured dermal substitute.

    PubMed

    Kuroyanagi, Yoshimitsu; Kubo, Kentaro; Matsui, Hiromich; Kim, Hyun Jung; Numari, Shinichiro; Mabuchi, Yho; Kagawa, Shizuko

    2004-01-01

    Allogeneic cultured dermal substitute (CDS) was prepared by culturing fibroblasts on a two-layered spongy matrix of hyaluronic acid (HA) and atelo-collagen (Col). Allogeneic CDS can be cryopreserved and transported to other hospitals in a frozen state. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), platelet derived growth factor (PDGF)-AA, transforming growth factor (TGF)-beta1, keratinocytes growth factor (KGF), interleukin (IL)-6 and IL-8 were contained in the culture medium which was used in preparing CDS over a cultivation period of one week (fresh CDS culture medium sample). After thawing a cryopreserved CDS, the CDS was recultured in a culture medium for one week. VEGF, bFGF, HGF, TGF-beta1 and IL-8 were contained in the culture medium which was used in reculturing CDS for one week (cryopreserved CDS culture medium sample), although some cytokines were detected at a lower level than those before freezing. This finding suggests that the cryopreserved CDS retains its ability to release these cytokines. Clinical research on allogeneic CDS, which was newly developed at the R & D Center for Artificial Skin of Kitasato University, has been carried out in medical centers across Japan with the support of the Millennium Project of the Ministry of Health, Labor and Welfare. It was demonstrated that the allogeneic CDS functions as an excellent cell therapy for intractable skin ulcers as well as burn injuries. The spongy matrix itself, as well as the cytokines released from the allogeneic CDS, seemed to be beneficial for the treatment of intractable skin defect. PMID:14720283

  7. FTY720 prolongs clear corneal allograft survival with a differential effect on different lymphocyte populations

    PubMed Central

    Mayer, K; Birnbaum, F; Reinhard, T; Reis, A; Braunstein, S; Claas, F; Sundmacher, R

    2004-01-01

    Background: FTY720 is a potent immunomodulator with unique effects on lymphocyte homing and has recently proved to be safe and effective in renal transplantation in man. The authors investigated the potency of FTY720 in inhibiting allograft rejection in the rat model of orthotopic allogeneic penetrating keratoplasty. Methods: Penetrating keratoplasties were performed using Fisher rats as donors and Lewis rats as recipients or donors: group 1 (n = 10), allogeneic control; group 2 (n = 10), Lewis/Lewis syngeneic control; group 3 (n = 9), mycophenolate mofetile (MMF) 40 mg/kg; group 4 (n = 10), FTY720 1.2 mg/kg; group 5 (n = 8), FTY720 0.3 mg/kg. Four animals from each group were sacrificed for immunohistological evaluation on day 14. Medication in the therapy groups was given for 18 days. Results: The mean (SD) rejection free graft survival time was 11.3 (0.8) days for the allogeneic control (group 1), 24.6 (2.5) days for group 3 (MMF), 44.5 (5.7) days for group 4 (FTY720 1.2 mg/kg), and 35.3 (5.7) days for group 5 (FTY720 0.3 mg/kg) (p<0.05). The allogeneic control showed a dense infiltration with CD4+, CD8+, CD161+ (NK-cells), CD25+ (IL2 receptor), and macrophages. In the therapy groups the density of infiltrating CD4+, CD8+, CD161+ (NK-cells), and CD25+ (IL2 receptor) cells was notably reduced compared with the allogeneic control (p<0.05). In group 5 however, the reduction of infiltration by CD4+ cells was higher than the reduction of infiltration by CD8+ (p<0.05) and CD161+ (NK) cells. Discussion: Oral immunosuppression with FTY720 significantly prolongs corneal allograft survival in this transplant model. The results suggest that FTY720 has a different effect on certain lymphocyte populations. CD4+ cells seem to be more affected than CD8+ cells and NK-cells. PMID:15205237

  8. Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine.

    PubMed Central

    Hiestand, P C; Mekler, P; Nordmann, R; Grieder, A; Permmongkol, C

    1986-01-01

    Lymphocyte responsiveness in rats was found to depend on serum prolactin levels. Blocking pituitary prolactin release with bromocriptine severely reduces lymphocyte reactivity in vitro (mixed lymphocyte reaction) as well as in vivo (graft-versus-host reaction). In addition, evidence for a prolactin/growth hormone-related mRNA species produced in mitogen- and antigen-stimulated lymphocytes has been obtained. Prolactin was shown to compete in a dose-dependent fashion with the immunosuppressant cyclosporine (cyclosporin A) for a common binding site on the surface of T lymphocytes. Further, stimulation of prolactin secretion reversed the immunosuppression induced by cyclosporine. We conclude that prolactin is involved in the maintenance of T-cell immunocompetence and that the immunosuppressive effects of cyclosporine may be mediated by the displacement of prolactin from binding sites on lymphocytes. Images PMID:2939454

  9. Lymphocyte function in myasthenia gravis.

    PubMed Central

    Kawanami, S; Kanaide, A; Itoyama, Y; Kuroiwa, Y

    1979-01-01

    Mitogen-induced blastoid transformation of peripheral blood lymphocytes from patients with myasthenia gravis was studied using a microplate culture technique and evaluated with 3H-thymidine incorporation. It was found that both phytohaemagglutinin and pokeweed mitogen responses decreased significantly in patients with myasthenia gravis. In myasthenic crisis, indices of stimulation by phytohaemagglutination became very low. The autologous plasma neither inhibited nor facilitated mitogenic responses of lymphocytes. The decreased mitogen responsiveness of lymphocytes suggests that part of the T lymphocyte function is subnormal in myasthenia. PMID:490180

  10. Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-05-04

    Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  11. Fludarabine Based Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies

    ClinicalTrials.gov

    2014-03-27

    Acute Myeloid Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Malignant Lymphoma; Hodgkin's Disease; Multiple Myeloma; Lymphocytic Leukemia; Myeloproliferative Disorder; Polycythemia Vera; Myelofibrosis; Aplastic Anemia

  12. Lymphocytic Interstitial Pneumonia.

    PubMed

    Panchabhai, Tanmay S; Farver, Carol; Highland, Kristin B

    2016-09-01

    Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin-walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process. PMID:27514593

  13. Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation.

    PubMed

    Machaczka, Maciej; Nahi, Hareth; Karbach, Holger; Klimkowska, Monika; Hägglund, Hans

    2012-06-01

    Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M-HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1-positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals. PMID:21533602

  14. Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population

    PubMed Central

    Vasu, Sumithira; Leitman, Susan F.; Tisdale, John F.; Hsieh, Matthew M.; Childs, Richard W.; Barrett, A. John; Fowler, Daniel H.; Bishop, Michael R.; Kang, Elizabeth M.; Malech, Harry L.; Dunbar, Cynthia E.; Khuu, Hanh M.; Wesley, Robert; Yau, Yu Y.

    2008-01-01

    A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 μg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34+ cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/μL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34+ cell counts than donors who did not (94 vs 79 cells/μL, P < .001). In multivariate analysis, higher post–G-CSF CD34+ cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre–G-CSF platelet count, pre–G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post–G-CSF CD34+ cell counts. PMID:18523146

  15. Decreased deformability of lymphocytes in chronic lymphocytic leukemia

    NASA Astrophysics Data System (ADS)

    Zheng, Yi; Wen, Jun; Nguyen, John; Cachia, Mark A.; Wang, Chen; Sun, Yu

    2015-01-01

    This paper reports the first study of stiffness/deformability changes of lymphocytes in chronic lymphocytic leukemia (CLL) patients, demonstrating that at the single cell level, leukemic metastasis progresses are accompanied by biophysical property alterations. A microfluidic device was utilized to electrically measure cell volume and transit time of single lymphocytes from healthy and CLL patients. The results from testing thousands of cells reveal that lymphocytes from CLL patients have higher stiffness (i.e., lower deformability), as compared to lymphocytes in healthy samples, which was also confirmed by AFM indentation tests. This observation is in sharp contrast to the known knowledge on other types of metastatic cells (e.g., breast and lung cancer cells) whose stiffness becomes lower as metastasis progresses.

  16. What Is Acute Lymphocytic Leukemia (ALL)?

    MedlinePlus

    ... key statistics about acute lymphocytic leukemia? What is acute lymphocytic leukemia? Cancer starts when cells in the body begin ... leukemias). The rest of this document focuses on acute lymphocytic leukemia (ALL) in adults. For information on ALL in ...

  17. Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity.

    PubMed Central

    Vizler, C.; Rosato, A.; Calderazzo, F.; Quintieri, L.; Fruscella, P.; Wainstok de Calmanovici, R.; Mantovani, A.; Vecchi, A.; Zanovello, P.; Collavo, D.

    1998-01-01

    In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-gamma monoclonal antibody (MAb) co-administration. These results strongly suggest that the anti-tumour effect of IL-12 is principally mediated by IFN-gamma release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis. PMID:9484826

  18. Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells.

    PubMed

    Villa, Nancy Y; Wasserfall, Clive H; Meacham, Amy M; Wise, Elizabeth; Chan, Winnie; Wingard, John R; McFadden, Grant; Cogle, Christopher R

    2015-06-11

    Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens. PMID:25904246

  19. Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells

    PubMed Central

    Villa, Nancy Y.; Wasserfall, Clive H.; Meacham, Amy M.; Wise, Elizabeth; Chan, Winnie; Wingard, John R.; McFadden, Grant

    2015-01-01

    Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens. PMID:25904246

  20. High-throughput allogeneic antibody detection using protein microarrays.

    PubMed

    Paul, Jed; Sahaf, Bita; Perloff, Spenser; Schoenrock, Kelsi; Wu, Fang; Nakasone, Hideki; Coller, John; Miklos, David

    2016-05-01

    Enzyme-linked immunosorbent assays (ELISAs) have traditionally been used to detect alloantibodies in patient plasma samples post hematopoietic cell transplantation (HCT); however, protein microarrays have the potential to be multiplexed, more sensitive, and higher throughput than ELISAs. Here, we describe the development of a novel and sensitive microarray method for detection of allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome, called HY antigens. Six microarray surfaces were tested for their ability to bind recombinant protein and peptide HY antigens. Significant allogeneic immune responses were determined in male patients with female donors by considering normal male donor responses as baseline. HY microarray results were also compared with our previous ELISA results. Our overall goal was to maximize antibody detection for both recombinant protein and peptide epitopes. For detection of HY antigens, the Epoxy (Schott) protein microarray surface was both most sensitive and reliable and has become the standard surface in our microarray platform. PMID:26902899

  1. Regulatory T Cells in Allogeneic Stem Cell Transplantation

    PubMed Central

    Nagler, Arnon

    2013-01-01

    Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their “first-in-man” clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation. PMID:23737813

  2. Pancytopenia after allogeneic bone marrow transplant due to copper deficiency.

    PubMed

    Hudspeth, Michelle; Turner, Amy; Miller, Nicole; Lazarchick, John

    2014-05-01

    Pancytopenia occurring 1 year or later after allogeneic bone marrow transplantation typically prompts a primary consideration for relapse. We present the case of a 15-year old-girl who underwent transplantation for therapy-related myelodysplasia secondary to Ewing sarcoma treatment who developed pancytopenia with myelodysplasia 1 year after transplant due to copper deficiency. Copper deficiency is an important consideration in the evaluation of pancytopenia and myelodysplasia in pediatric patients. PMID:23652881

  3. Aspergillus Thyroiditis after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ataca, Pinar; Atilla, Erden; Saracoglu, Pelin; Yilmaz, Gulden; Civriz Bozdag, Sinem; Toprak, Selami Kocak; Yuksel, Meltem Kurt; Ceyhan, Koray; Topcuoglu, Pervin

    2015-01-01

    Aspergillus thyroiditis is a rare disorder detected in immunocompromised patients during disseminated infections. Early management is essential to prevent high mortality. A 61-year-old allogeneic stem cell male recipient presented with painful thyroid nodular enlargement. He had low TSH and low free T4 levels. The thyroid ultrasound showed a hypoechoic nodule; biopsy indicated suppurative Aspergillus thyroiditis. He was successfully treated by amphotericin B. PMID:26640727

  4. Financial burden in recipients of allogeneic hematopoietic cell transplantation.

    PubMed

    Khera, Nandita; Chang, Yu-hui; Hashmi, Shahrukh; Slack, James; Beebe, Timothy; Roy, Vivek; Noel, Pierre; Fauble, Veena; Sproat, Lisa; Tilburt, Jon; Leis, Jose F; Mikhael, Joseph

    2014-09-01

    Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure. PMID:24867778

  5. Strength comparison of allogenic bone screws, bioabsorbable screws, and stainless steel screw fixation.

    PubMed

    Rano, James A; Savoy-Moore, Ruth T; Fallat, Lawrence M

    2002-01-01

    Allogenic bone screws are new to the fixation market and have yet to be tested against current fixation materials. An in vitro comparison of the same sizes of stainless steel, bioabsorbable, and allogenic bone screws was undertaken to assess screw resistance to the forces of bending, pullout, and shear. Using aluminum plates to support the screws, forces up to 1000 Newtons were applied to six to eight samples of each type of screw. During each test, stainless steel screws withstood the maximum force that could be exerted by the testing apparatus without failing (bending, 113.9 +/- 11.8 N mean +/- SE; pullout 999.1 +/- 33.7 N; and shear, 997.5 +/- 108.8 N). In each test, compared to bioabsorbable screws, allogenic bone screws failed faster (pullout, allogenic: 12.4 +/- 1.1 seconds vs. bioabsorbable, 120.6 +/- 13.8 seconds; p = .001; bending, allogenic: 53.4 +/- 4.8 seconds vs. bioabsorbable, 201.9 +/- 11.1 seconds; p = .001; shear, allogenic 13.5 +/- 1.4 seconds vs. bioabsorbable, 43.8 +/- 0.9 seconds; p = .001) under equivalent (pullout: bioabsorbable, 385.0 +/- 18.4 N vs. allogenic, 401.0 +/- 35.9 N; p = .001) or lower (bending, allogenic: 4.7 +/- 0.2 N vs. bioabsorbable, 11.0 +/- 0.9 N; p = .675; shear, allogenic: 312.1 +/- 15.5 N vs. bioabsorbable 680.9 +/- 8.5 N; p = .001) loads, and in a highly variable fashion. Overall, the bioabsorbable screws withstood the forces of bending, pullout, and shear better than the allogenic screws, and stainless steel screws outperformed both bioabsorbable and allogenic screws. Despite these results, allogenic screws could still be useful in compliant patients who would benefit from their osteoconductive properties. PMID:11858609

  6. Role of allogeneic stem cell transplantation in mantle cell lymphoma.

    PubMed

    Cohen, Jonathon B; Burns, Linda J; Bachanova, Veronika

    2015-04-01

    Despite a wide spectrum of treatment options, mantle cell lymphoma (MCL) remains a challenging hematologic malignancy to manage. Advances in front-line therapy, including the monoclonal antibody rituximab and increasing use of cytarabine, have improved remission rates. Autologous hematopoietic cell transplantation (HCT) can effectively consolidate remission of MCL, leading to encouraging survival beyond 5 yr. However, nearly all patients with MCL will relapse and require salvage therapy. Novel agents such as ibrutinib, bortezomib, and lenalidomide have dramatically expanded the options for treating relapsed MCL. In this review, we summarize the clinical evidence supporting the use of allogeneic donor HCT in MCL and make recommendations on indications for its use. Data suggest that allogeneic donor HCT is the only curative therapy for patients with poor prognosis or aggressive MCL. Patient selection, timing, and optimal use remain a matter of scientific debate and given the rapidly changing therapeutic landscape of MCL, the outcomes of allogeneic HCT should be interpreted in the context of novel therapeutics. PMID:25154430

  7. SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Fernandes, Sandra; Brooks, Robert; Gumbleton, Matthew; Park, Mi-Young; Russo, Christopher M.; Howard, Kyle T.; Chisholm, John D.; Kerr, William G.

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize autologous and allogeneic HSCT. PMID:26052545

  8. Chimeric autologous/allogeneic constructs for skin regeneration.

    PubMed

    Rasmussen, Cathy Ann; Tam, Joshua; Steiglitz, Barry M; Bauer, Rebecca L; Peters, Noel R; Wang, Ying; Anderson, R Rox; Allen-Hoffmann, B Lynn

    2014-08-01

    The ideal treatment for severe cutaneous injuries would eliminate the need for autografts and promote fully functional, aesthetically pleasing autologous skin regeneration. NIKS progenitor cell-based skin tissues have been developed to promote healing by providing barrier function and delivering wound healing factors. Independently, a device has recently been created to "copy" skin by harvesting full-thickness microscopic tissue columns (MTCs) in lieu of autografts traditionally harvested as sheets. We evaluated the feasibility of combining these two technologies by embedding MTCs in NIKS-based skin tissues to generate chimeric autologous/allogeneic constructs. Chimeric constructs have the potential to provide immediate wound coverage, eliminate painful donor site wounds, and promote restoration of a pigmented skin tissue possessing hair follicles, sweat glands, and sebaceous glands. After MTC insertion, chimeric constructs and controls were reintroduced into air-interface culture and maintained in vitro for several weeks. Tissue viability, proliferative capacity, and morphology were evaluated after long-term culture. Our results confirmed successful MTC insertion and integration, and demonstrated the feasibility of generating chimeric autologous/allogeneic constructs that preserved the viability, proliferative capacity, and structure of autologous pigmented skin. These feasibility studies established the proof-of-principle necessary to further develop chimeric autologous/allogeneic constructs for the treatment of complex skin defects. PMID:25102552

  9. Prostaglandin E2 Production and T Cell Function in Mouse Adenovirus Type 1 Infection following Allogeneic Bone Marrow Transplantation

    PubMed Central

    McCarthy, Mary K.; Procario, Megan C.; Wilke, Carol A.; Moore, Bethany B.; Weinberg, Jason B.

    2015-01-01

    Adenovirus infections are important complications of bone marrow transplantation (BMT). We demonstrate delayed clearance of mouse adenovirus type 1 (MAV-1) from lungs of mice following allogeneic BMT. Virus-induced prostaglandin E2 (PGE2) production was greater in BMT mice than in untransplanted controls, but BMT using PGE2-deficient donors or recipients failed to improve viral clearance, and treatment of untransplanted mice with the PGE2 analog misoprostol did not affect virus clearance. Lymphocyte recruitment to the lungs was not significantly affected by BMT. Intracellular cytokine staining of lung lymphocytes demonstrated impaired production of INF-γ and granzyme B by cells from BMT mice, and production of IFN-γ, IL-2, IL-4, and IL-17 following ex vivo stimulation was impaired in lymphocytes obtained from lungs of BMT mice. Viral clearance was not delayed in untransplanted INF-γ-deficient mice, suggesting that delayed viral clearance in BMT mice was not a direct consequence of impaired IFN-γ production. However, lung viral loads were higher in untransplanted CD8-deficient mice than in controls, suggesting that delayed MAV-1 clearance in BMT mice is due to defective CD8 T cell function. We did not detect significant induction of IFN-β expression in lungs of BMT mice or untransplanted controls, and viral clearance was not delayed in untransplanted type I IFN-unresponsive mice. We conclude that PGE2 overproduction in BMT mice is not directly responsible for delayed viral clearance. PGE2-independent effects on CD8 T cell function likely contribute to the inability of BMT mice to clear MAV-1 from the lungs. PMID:26407316

  10. Activation of autoreactive T-lymphocytes by cultured syngeneic glomerular mesangial cells.

    PubMed

    Radeke, H H; Emmendörffer, A; Uciechowski, P; von der Ohe, J; Schwinzer, B; Resch, K

    1994-03-01

    The capacity of intrinsic, glomerular mesangial cells (MC) to cause an autoreactive response of syngeneic lymphocytes in vitro are presented. Initial experiments demonstrated the MHC class II dependent capacity of MC to present exogenous antigen to sensitized lymph node lymphocytes (LN) and to activate naive, allogeneic LN in the absence of a nominal antigen. However, the most striking finding of the present investigation was that mouse MC (C57BL/6 or DBA/2) augmented a significant activation of naive, syngeneic lymphocytes. The extent of the proliferative lymphocyte response was comparable to that observed after stimulation with allogeneic MC. Moreover, during syngeneic coculture substantial amounts of interferon bioactivity were generated. Equipotent concentrations of rm IFN-gamma were sufficient to induce class II MHC expression of mouse MC. In control experiments the macrophage cell line, IC-21 (C57BL/6), or freshly prepared DBA/2 mouse peritoneal macrophages did not elicit a syngeneic LN response. Using MC, which had not been pretreated, the MC-specific LN stimulation occurred after prolonged periods of coculture. The stimulation index (S.I.) was 9.77 after 144 hours compared with LN controls (S.I. = 1). However, a 48 hour pretreatment of MC with either rm IFN-gamma alone or in combination with rh TNF-alpha and/or the continuous presence of rm IL-1 alpha during coculture periods from 72 to 144 hours substantially enhanced the proliferative LN response. Analysis of non-adherent LN by flow cytometry (FACS) after 96 or 120 hours coculture with MC revealed an increased ratio of Thy1.2+ to B220+ cells with a predominant rise of L3T4+ T-helper cells compared to Lyt2+ cytotoxic T-cells. Furthermore, immune fluorescence microscopy showed that a fraction of Thy1.2+ lymphoblasts adhered to MC. FACS analysis of these adherent LN after detachment demonstrated that in comparison to cocultures with untreated MC, cocultures of LN with IFN-gamma/TNF-alpha pre-treated MC

  11. What Is Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... blood, and lymphoid tissue What is chronic lymphocytic leukemia? Cancer starts when cells in the body begin ... the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts in the ...

  12. Haploid Allogeneic Transplant Using the CliniMACS System

    ClinicalTrials.gov

    2015-02-26

    Acute Myelogenous Leukemia (AML) - Relapsed, Primary Refractory Disease or Poor Risk Factors; Chronic Myelogenous Leukemia (CML) - Accelerated or Second Chronic Phase; Myelodysplastic Syndrome (MDS) - High and Intermediate Risk; Non-Hodgkin's Lymphoma (NHL); Chronic Lymphocytic Leukemia (CLL) - Refractory

  13. [Chronic lymphocytic leukemia].

    PubMed

    Aoki, Sadao

    2016-03-01

    Currently, several novel drugs are available for chronic lymphocytic leukemia (CLL) in Western countries. Of these drugs, those that inhibit the B-cell receptor (BCR) signaling pathway are the most promising. Ibrutinib inhibits BTK in the BCR pathway and can be administered orally. The results of several clinical trials suggest that ibrutinib is highly effective against relapsed/resistant (RR) and treatment-naïve CLL. Furthermore, ibrutinib shows equivalent efficacy on CLL with the 17p deletion. Idelalisib, which also blocks the BCR pathway, inhibits PIK3delta and induces CLL cell death. Clinical trials have shown outstanding efficacy of idelalisib against RR-CLL, especially when administered with antiCD20 antibodies. This drug is also effective against CLL with the 17p deletion. ABT-199 is another novel drug; it inhibits BCL2 signaling, not the BCR pathway, and can be administered orally. The efficacy of ABT-199 against RR-CLL has been demonstrated in a number of clinical trials. These drugs have only mild toxicity and can be used for patients in poor general condition. Unfortunately, none of these drugs have yet been approved in Japan. Rapid resolution of the 'drug lag' problem is necessary. PMID:27076234

  14. [Large granular lymphocyte leukemia].

    PubMed

    Lazaro, Estibaliz; Caubet, Olivier; Menard, Fanny; Pellegrin, Jean-Luc; Viallard, Jean-François

    2007-11-01

    Large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic cells, either CD3(+) (T-cell) or CD3(-) (natural killer, or NK). Both subtypes can manifest as indolent or aggressive disorders. T-LGL leukemia is associated with cytopenias and autoimmune diseases and most often has an indolent course and good prognosis. Rheumatoid arthritis and Felty syndrome are frequent. NK-LGL leukemias can be more aggressive. LGL expansion is currently hypothesized to be a virus (Ebstein Barr or human T-cell leukemia viruses) antigen-driven T-cell response that involves disruption of apoptosis. The diagnosis of T-LGL is suggested by flow cytometry and confirmed by T-cell receptor gene rearrangement studies. Clonality is difficult to determine in NK-LGL but use of monoclonal antibodies specific for killer cell immunoglobulin-like receptor (KIR) has improved this process. Treatment is required when T-LGL leukemia is associated with recurrent infections secondary to chronic neutropenia. Long-lasting remission can be obtained with immunosuppressive treatments such as methotrexate, cyclophosphamide, and cyclosporine A. NK-LGL leukemias may be more aggressive and refractory to conventional therapy. PMID:17596907

  15. Quantifying T Lymphocyte Turnover

    PubMed Central

    De Boer, Rob J.; Perelson, Alan S.

    2013-01-01

    Peripheral T cell populations are maintained by production of naive T cells in the thymus, clonal expansion of activated cells, cellular self-renewal (or homeostatic proliferation), and density dependent cell life spans. A variety of experimental techniques have been employed to quantify the relative contributions of these processes. In modern studies lymphocytes are typically labeled with 5-bromo-2′-deoxyuridine (BrdU), deuterium, or the fluorescent dye carboxy-fluorescein diacetate succinimidyl ester (CFSE), their division history has been studied by monitoring telomere shortening and the dilution of T cell receptor excision circles (TRECs) or the dye CFSE, and clonal expansion has been documented by recording changes in the population densities of antigen specific cells. Proper interpretation of such data in terms of the underlying rates of T cell production, division, and death has proven to be notoriously difficult and involves mathematical modeling. We review the various models that have been developed for each of these techniques, discuss which models seem most appropriate for what type of data, reveal open problems that require better models, and pinpoint how the assumptions underlying a mathematical model may influence the interpretation of data. Elaborating various successful cases where modeling has delivered new insights in T cell population dynamics, this review provides quantitative estimates of several processes involved in the maintenance of naive and memory, CD4+ and CD8+ T cell pools in mice and men. PMID:23313150

  16. Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

    PubMed

    Ecsedi, Matyas; Schmohl, Jörg; Zeiser, Robert; Drexler, Beatrice; Halter, Jörg; Medinger, Michael; Duyster, Justus; Kanz, Lothar; Passweg, Jakob; Finke, Jürgen; Bethge, Wolfgang; Lengerke, Claudia

    2016-10-01

    Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60 = 90 %) as compared to non-ATG treated MF (MF-noATG 15/34 = 44.1 %, p < 0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77 = 56 %, p < 0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents). PMID:27480090

  17. Allogeneic Murine Mesenchymal Stem Cells: Migration to Inflamed Joints In Vivo and Amelioration of Collagen Induced Arthritis When Transduced to Express CTLA4Ig

    PubMed Central

    Barry, Frank; Ritter, Thomas; O'Flatharta, Cathal; Howard, Linda; Shaw, Georgina; Anegon, Ignacio; Murphy, Mary

    2013-01-01

    Despite the immunosuppressive, homing, and regenerative capabilities of mesenchymal stem cells (MSCs), their ability to migrate to arthritic joints and influence the course of arthritis in vivo remains poorly understood. The objective of this study was to determine if allogeneic MSCs migrate to inflamed joints in vivo and to determine if MSCs expressing the costimulation blocker cytotoxic T lymphocyte associated antigen-4 coupled to immunoglobulin-G (CTLA4Ig) could be used to ameliorate collagen induced arthritis (CIA). The migration of systemically delivered inbred mouse strain (FVB) MSCs to migrate to inflamed joints in CIA was studied using real-time quantitative polymerase chain reaction. Furthermore, the effect of BALB/c MSCs modified with an adenoviral vector to express CTLA4Ig, on T cell function in vitro and on CIA in vivo was assessed. After systemic delivery of FVB MSCs, eGFP DNA was detectable in the joints of mice with CIA confirming that some MSCs had reached to inflamed joints. BALB/c MSCs suppressed the secretion of both TNFα and IFNγ, and reduced the ratio of Th1:Th2 cytokine expression, by DBA/1 T cells in vitro irrespective of viral modification. The expression of CTLA4Ig did not augment this effect. Despite a worsening of disease scores after infusion of BALB/c MSCs in vivo, BALB/c MSCs expressing CTLA4Ig significantly delayed the onset of inflammatory arthritis in CIA. These data demonstrate that allogeneic MSCs can migrate to the inflamed joints of CIA in vivo and that genetically modified allogeneic MSCs may be considered for development of gene therapy strategies for inflammatory arthritis PMID:23895495

  18. Long-term outcomes of patients with persistent indolent B cell malignancies undergoing nonmyeloablative allogeneic transplantation.

    PubMed

    Cassaday, Ryan D; Storer, Barry E; Sorror, Mohamed L; Sandmaier, Brenda M; Guthrie, Katherine A; Maloney, David G; Rajendran, Joseph G; Pagel, John M; Flowers, Mary E; Green, Damian J; Rezvani, Andrew R; Storb, Rainer F; Press, Oliver W; Gopal, Ajay K

    2015-02-01

    Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent i

  19. DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation.

    PubMed

    Li, Ya-Ting; Xie, Ming-Kun; Wu, Jin

    2014-11-01

    Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender-matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID:25279149

  20. DNA profiling in peripheral blood, buccal swabs, hair follicles and semen from a patient following allogeneic hematopoietic stem cells transplantation

    PubMed Central

    LI, YA-TING; XIE, MING-KUN; WU, JIN

    2014-01-01

    Allogeneic peripheral blood stem cells transplantation (allo-PBSCT) or allogeneic bone marrow transplantation (allo-BMT) have been widely used to treat patients exhibiting certain severe illnesses. However, previous studies have shown that the biological materials of allo-PBSCT or allo-BMT recipients may not constitute credible materials for personal identification. In the present study, four types of commonly used samples were collected from a male individual following gender-matched allo-BMT. Autosomal short tandem repeat (STR) and Y-STR markers analysis, based on polymerase chain reaction, were used to evaluate the chimerism status. The results showed that the blood sample were all donor type, the buccal swab sample were mixed chimerism, and the sperm and hair follicle samples maintained a recipient origin of 100%. In conclusion, identical results were obtained by the two methods and it was confirmed that DNA extracted from hair follicles and sperm can be used as a reference for the pre-transplant genotype DNA profile of the recipient in the gender-match allo-BMT or -PBSCT. PMID:25279149

  1. Allogeneic clonal mesenchymal stem cell therapy for refractory graft-versus-host disease to standard treatment: a phase I study.

    PubMed

    Yi, Hyeon Gyu; Yahng, Seung-Ah; Kim, Inho; Lee, Je-Hwan; Min, Chang-Ki; Kim, Jun Hyung; Kim, Chul Soo; Song, Sun U

    2016-01-01

    Severe graft-versus-host disease (GVHD) is an often lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). The safety of clinical-grade mesenchymal stem cells (MSCs) has been validated, but mixed results have been obtained due to heterogeneity of the MSCs. In this phase I study, the safety of bone marrow-derived homogeneous clonal MSCs (cMSCs) isolated by a new subfractionation culturing method was evaluated. cMSCs were produced in a GMP facility and intravenously administered to patients who had refractory GVHD to standard treatment resulting after allogeneic HSCT for hematologic malignancies. After administration of a single dose (1×10(6) cells/kg), 11 patients were evaluated for cMSC treatment safety and efficacy. During the trial, nine patients had 85 total adverse events and the rate of serious adverse events was 27.3% (3/11 patients). The only one adverse drug reaction related to cMSC administration was grade 2 myalgia in one patient. Treatment response was observed in four patients: one with acute GVHD (partial response) and three with chronic GVHD. The other chronic patients maintained stable disease during the observation period. This study demonstrates single cMSC infusion to have an acceptable safety profile and promising efficacy, suggesting that we can proceed with the next stage of the clinical trial. PMID:26807024

  2. Immunological aspects of allogeneic and autologous mesenchymal stem cell therapies.

    PubMed

    Hoogduijn, M J; Roemeling-van Rhijn, M; Korevaar, S S; Engela, A U; Weimar, W; Baan, C C

    2011-12-01

    Mesenchymal stem cells (MSCs) have potential for therapeutic application as an immunomodulatory and regenerative agent. The immunogenicity and survival of MSCs after infusion are, however, not clear and evidence suggests that allogeneic but also autologous MSCs disappear rapidly after infusion. This may be associated with the susceptibility of MSCs to lysis by natural killer (NK) cells, possibly a result of culture-induced stress. In the present study we examined whether NK cell-mediated lysis of MSCs could be inhibited by immunosuppressive drugs. Human MSCs were isolated from adipose tissue and expanded in culture. Peripheral blood mononuclear cells were activated with interleukin (IL)-2 (200 U/ml) and IL-15 (10 ng/ml) for 7 days. CD3(-)CD16(+)CD56(+) NK cells were then isolated by fluorescence-activated cell sorting and added to europium-labeled MSCs for 4 hr in the presence or absence of immunosuppressive drugs. Lysis of MSCs was determined by spectrophotometric measurement of europium release. Nonactivated NK cells were not capable of lysing MSCs. Cytokine-activated NK cells showed upregulated levels of granzyme B and perforin and efficiently lysed allogeneic and autologous MSCs. Addition of tacrolimus, rapamycin or sotrastaurin to the lysis assay did not inhibit MSC killing. Furthermore, preincubation of activated NK cells with the immunosuppressive drugs for 24 hr before exposure to MSCs had no effect on MSC lysis. Last, addition of the immunosuppressants before and during the activation of NK cells, reduced NK cell numbers but did not affect their capacity to lyse MSCs. We conclude that the immunosuppressive drugs tacrolimus, rapamycin, and sotrastaurin are not capable of inhibiting the lysis of allogeneic and autologous MSCs by activated NK cells. Other approaches to controlling lysis of MSCs should be investigated, as controlling lysis may determine the efficacy of MSC therapy. PMID:21732766

  3. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

    PubMed

    Halter, Joerg P; Michael, W; Schüpbach, M; Mandel, Hanna; Casali, Carlo; Orchard, Kim; Collin, Matthew; Valcarcel, David; Rovelli, Attilio; Filosto, Massimiliano; Dotti, Maria T; Marotta, Giuseppe; Pintos, Guillem; Barba, Pere; Accarino, Anna; Ferra, Christelle; Illa, Isabel; Beguin, Yves; Bakker, Jaap A; Boelens, Jaap J; de Coo, Irenaeus F M; Fay, Keith; Sue, Carolyn M; Nachbaur, David; Zoller, Heinz; Sobreira, Claudia; Pinto Simoes, Belinda; Hammans, Simon R; Savage, David; Martí, Ramon; Chinnery, Patrick F; Elhasid, Ronit; Gratwohl, Alois; Hirano, Michio

    2015-10-01

    Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation

  4. Reduced Intensity Allogeneic Transplantation Provides High Event-Free And Overall Survival In Patients With Advanced Indolent B Cell Malignancies: CALGB 109901

    PubMed Central

    Shea, Thomas; Johnson, Jeffrey; Westervelt, Peter; Farag, Sherif; McCarty, John; Bashey, Asad; Isola, Luis; Baxter-Lowe, Lee-Anne; Kelly, Michael; Owzar, Kouros; Linker, Charles

    2011-01-01

    CALGB conducted a Phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor and conditioning with cyclophosphamide (1 g/m2/d × 3) and fludarabine phosphate (25 mg/m2/d × 5). GVH prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of two prior regimens were accrued. Sixteen patients had follicular NHL and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia, and 2 prolymphocytic leukemia pts. The six-month treatment-related mortality (TRM) was 2.4% and three-year TRM was 9%. Three-year event-free and overall survival were.75 and .81 for the follicular patients, .59 and .71 for the CLL/PLL patients, and .55 and .64 for the other histologies. The incidence of grade 2–4 acute graft vs host disease (GVHD) was 29% and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study. PMID:21296675

  5. Perioperative Allogeneic Blood Transfusion Is Associated With Surgical Site Infection After Abdominoperineal Resection-a Space for the Implementation of Patient Blood Management Strategies.

    PubMed

    Kaneko, Kensuke; Kawai, Kazushige; Tsuno, Nelson H; Ishihara, Soichiro; Yamaguchi, Hironori; Sunami, Eiji; Watanabe, Toshiaki

    2015-05-01

    Allogeneic blood transfusion (ABT) has been reported as a major risk factor for surgical site infection (SSI) in patients undergoing colorectal surgery. However, the association of ABT with SSI in patients undergoing abdominoperineal resection (APR) and total pelvic exenteration (TPE) still remains to be evaluated. Here, we aim to elucidate this association. The medical records of all patients undergoing APR and TPE at our institution in the period between January 2000 and December 2012 were reviewed. Patients without SSI (no SSI group) were compared with patients who developed SSI (SSI group), in terms of clinicopathologic features, including ABT. In addition, data for 262 patients who underwent transabdominal rectal resection at our institution in the same period were also enrolled, and their data on differential leukocyte counts were evaluated. Multivariate analysis showed that intraoperative transfusion was an independent predictive factor for SSI after APR and TPE (P = 0.004). In addition, the first-operative day lymphocyte count of patients undergoing APR, TPE, and transabdominal rectal resection was significantly higher in nontransfusion patients compared with transfusion ones (P = 0.026). ABT in the perioperative period of APR and TPE may have an important immunomodulatory effect, leading to an increased incidence of SSI. This fact should be carefully considered, and efforts to avoid allogeneic blood exposure while still achieving adequate patient blood management would be very important for patients undergoing APR and TPE as well. PMID:26011197

  6. T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Uzunel, Mehmet; Sairafi, Darius; Remberger, Mats; Mattsson, Jonas; Uhlin, Michael

    2014-07-15

    In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation. PMID:24617310

  7. Perioperative Allogeneic Blood Transfusion Is Associated With Surgical Site Infection After Abdominoperineal Resection—a Space for the Implementation of Patient Blood Management Strategies

    PubMed Central

    Kaneko, Kensuke; Kawai, Kazushige; Tsuno, Nelson H.; Ishihara, Soichiro; Yamaguchi, Hironori; Sunami, Eiji; Watanabe, Toshiaki

    2015-01-01

    Allogeneic blood transfusion (ABT) has been reported as a major risk factor for surgical site infection (SSI) in patients undergoing colorectal surgery. However, the association of ABT with SSI in patients undergoing abdominoperineal resection (APR) and total pelvic exenteration (TPE) still remains to be evaluated. Here, we aim to elucidate this association. The medical records of all patients undergoing APR and TPE at our institution in the period between January 2000 and December 2012 were reviewed. Patients without SSI (no SSI group) were compared with patients who developed SSI (SSI group), in terms of clinicopathologic features, including ABT. In addition, data for 262 patients who underwent transabdominal rectal resection at our institution in the same period were also enrolled, and their data on differential leukocyte counts were evaluated. Multivariate analysis showed that intraoperative transfusion was an independent predictive factor for SSI after APR and TPE (P = 0.004). In addition, the first–operative day lymphocyte count of patients undergoing APR, TPE, and transabdominal rectal resection was significantly higher in nontransfusion patients compared with transfusion ones (P = 0.026). ABT in the perioperative period of APR and TPE may have an important immunomodulatory effect, leading to an increased incidence of SSI. This fact should be carefully considered, and efforts to avoid allogeneic blood exposure while still achieving adequate patient blood management would be very important for patients undergoing APR and TPE as well. PMID:26011197

  8. H-2 restriction as a consequence of intentional priming: T cells of fully allogeneic chimeric mice as well as of normal mice respond to foreign antigens in the context of H-2 determinants not encountered on thymic epithelial cells.

    PubMed

    Stockinger, H; Pfizenmaier, K; Hardt, C; Rodt, H; Röllinghoff, M; Wagner, H

    1980-12-01

    Fully allogeneic chimeras were able to develop in vitro alloantigen-specific, as well as H-2-restricted, Sendai virus-specific cytotoxic T-lymphocyte (CTL) response. Depending on the immunization regimen used, Sendai virus-specific CTL responses were restricted to the H-2 antigens of either the stem cell donor or the thymus. Similarly, unprimed splenic T cells of normal mice were found to contain CTL-precursor cells that specifically reacted against Sendai virus or trinitrophenyl derivatives in the context of allogeneic major histocompatibility complex determinants that had not been encountered during their thymic differentiation. A frequency analysis of allogeneically versus syngeneically restricted virus-specific CTL precursors present in splenic T cells showed a ratio of about 1 to 6. These results provide evidence that H-2 restriction of trinitrophenyl- or Sendai virus-specific T cells is dictated by the complex type of the antigen-presenting cell and thus appears to be independent of the type of thymus in which the T cells have undergone maturation. PMID:6261255

  9. Secondary neuroendocrine tumor after allogeneic bone marrow transplantation.

    PubMed

    Tamura, Shinichi; Ishida, Hiroyuki; Naito, Takeshi; Kondo, Osamu; Inoue, Masami; Kawa, Keisei; Kawabata, Kenji; Hojo, Hiroshi; Ouchi, Kazutaka; Imamura, Toshihiko

    2015-12-01

    Here we report a case of aggressive neuroendocrine tumor (NET), which is an extremely rare secondary solid tumor that occurs after allogeneic hematopoietic cell transplantation (allo-HSCT). A patient with chronic active Epstein-Barr virus infection received allo-HSCT from an HLA-DR two allele-mismatched unrelated donor. Four years later, he developed NET with multiple metastases. He received thoraco-abdominal irradiation as a conditioning regimen, and developed repeated episodes of intestinal graft-versus-host disease, for which he received long-term immunosuppressive therapy. Although these factors may be potential contributing factors to the development of secondary NET, the exact pathogenesis remains unclear. PMID:26711919

  10. The repair of full-thickness articular cartilage defects. Immune responses to reparative tissue formed by allogeneic growth plate chondrocyte implants

    SciTech Connect

    Kawabe, N.; Yoshinao, M. )

    1991-07-01

    Growth plate cartilage cultivated in vitro was attached with a fibrin clot to a full-thickness articular cartilage defect on knee joints in allogeneic New Zealand rabbits. The healing of the defects was assessed by gross examination, light microscopy, and immunologic analysis for 24 weeks. Immunologic assessment of cell-mediated immunity, cytotoxicity of a humoral antibody by a 51 chromium release assay, and immunofluorescence studies were carried out. During the first two weeks following grafting, healing was excellent in 11 of the 17 defects. From three to 24 weeks, 11 of 42 defects examined had good results. Host lymphocytes had accumulated around the allograft at two to 12 weeks. Most of the implanted cartilage grown in vitro died and was replaced by fibrous tissue. The immunologic studies suggested that the implanted cartilage began to degenerate two to three weeks after implantation partially because of a humoral immune response but more importantly because of cell-mediated cytotoxicity.

  11. Deferasirox for Treating Patients Who Have Undergone Allogeneic Stem Cell Transplant and Have Iron Overload

    ClinicalTrials.gov

    2012-07-16

    Iron Overload; Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Disseminated Neuroblastoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Adult Burkitt Lymphoma; Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma; Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma; Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma; Noncontiguous Stage II Adult Lymphoblastic Lymphoma; Noncontiguous Stage II Grade 1 Follicular Lymphoma; Noncontiguous Stage II Grade 2 Follicular Lymphoma; Noncontiguous Stage II Grade 3 Follicular Lymphoma; Noncontiguous Stage II Mantle Cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Poor Prognosis Metastatic Gestational Trophoblastic Tumor; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult

  12. Prognosis of chronic lymphocytic leukemia from infrared spectra of lymphocytes

    NASA Astrophysics Data System (ADS)

    Schultz, Christian P.; Liu, Kan-Zhi; Johnston, James B.; Mantsch, Henry H.

    1997-06-01

    Peripheral mononuclear cells obtained from blood of normal individuals and from patients with chronic lymphocytic leukemia (CLL) were investigated by infrared spectroscopy and multivariate statistical analysis. Not only are the spectra of CLL cells different from those of normal cells, but hierarchical clustering also separated the CLL cells into a number of subclusters, based on their different DNA content, a fact which may provide a useful diagnostic tool for staging (progression of the disease) and multiple clone detection. Moreover, there is evidence for a correlation between the increased amount of DNA in the CLL cells and the in-vivo doubling time of the lymphocytes in a given patient.

  13. Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells.

    PubMed

    Orio, Francesco; Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90-99% of women and 60-90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40-50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  14. Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome.

    PubMed

    Lechowicz, M J; Lazarus, H M; Carreras, J; Laport, G G; Cutler, C S; Wiernik, P H; Hale, G A; Maharaj, D; Gale, R P; Rowlings, P A; Freytes, C O; Miller, A M; Vose, J M; Maziarz, R T; Montoto, S; Maloney, D G; Hari, P N

    2014-11-01

    We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free. PMID:25068422

  15. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION FOR MYCOSIS FUNGOIDES AND SEZARY SYNDROME

    PubMed Central

    Lechowicz, Mary Jo; Lazarus, Hillard M.; Carreras, Jeanette; Laport, Ginna G.; Cutler, Corey S.; Wiernik, Peter H.; Hale, Gregory A.; Maharaj, Dipnarine; Gale, Robert Peter; Rowlings, Phillip A.; Freytes, César O; Miller, Alan M.; Vose, Julie M.; Maziarz, Richard T.; Montoto, Silvia; Maloney, David G.; Hari, Parameswaran N.

    2014-01-01

    We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant (CIBMTR) from 2000–2009. Median time from diagnosis to transplant was 30 (4–206) months and most subjects were with multiply relapsed/refractory disease. Majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared to myeloablative recipients (median age 51 vs. 44 y p= 0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95 % CI 12–27%) and 22% (95 % CI 15–31%) respectively. Risk of disease progression was 50% (95% CI 41–60%) at 1 year and 61% (95% CI 50–71%) at 5 years. Progression free survival (PFS) at 1 and 5 years was 31% (95% CI 22–40%) and 17% (95% CI 9–26%) respectively. Overall survival at 1 and 5 years was 54% (95% CI 45–63%) and 32% (95% CI 22–44%) respectively. Allogeneic HCT in MF/SS results in 5 year survival in approximately one-third of patients and of those, half of them remain disease-free. PMID:25068422

  16. Long-term oral complications of allogeneic haematopoietic SCT.

    PubMed

    Hull, K M; Kerridge, I; Schifter, M

    2012-02-01

    This study assessed the incidence of long-term oral complications in 88 survivors of allogeneic haematopoietic cell transplantation (HCT). Patients examined were between 6 months and 6 years post-HCT and aged from 19 to 65 years. Subjects were investigated for both the subjective and objective features of long-term adverse oral effects of HCT. The most common oral symptoms reported were xerostomia (44%, n=39) and reduction in taste (20%, n=18). Only a minority of patients (15%) reported that oral disease had a significant adverse impact upon their quality of life. The majority of patients (53%) had clinical markers of oral chronic GVHD (cGVHD). The most frequently identified feature was salivary hypofunction, with 34% of subjects demonstrating a reduction in stimulated saliva. Oral mucosal changes consistent with cGVHD affected 21% of subjects. Oral cGVHD commonly occurs after allogeneic HCT, often coexists with cutaneous, hepatic or ocular cGVHD and may lead to debilitating symptoms. Transplant type and pre-existing acute GVHD are the major risk factors for oral cGVHD. The identification of risk factors specific for oral cGVHD may allow clinicians some foresight into identifying patients at high risk of developing oral cGVHD and encourage attention to education, regular oral surveillance and rigorous preventative oral health strategies both pre- and post-transplant. PMID:21441960

  17. Decellularized allogeneic intervertebral disc: natural biomaterials for regenerating disc degeneration

    PubMed Central

    Hu, Zhijun; Chen, Kai; Shan, Zhi; Chen, Shuai; Wang, Jiying; Mo, Jian; Ma, Jianjun; Xu, Wenbing; Qin, An; Fan, Shunwu

    2016-01-01

    Intervertebral disc degeneration is associated with back pain and disc herniation. This study established a modified protocol for intervertebral disc (IVD) decellularization and prepared its extracellular matrix (ECM). By culturing mesenchymal stem cells (MSCs)(3, 7, 14 and 21 days) and human degenerative IVD cells (7 days) in the ECM, implanting it subcutaneously in rabbit and injecting ECM microparticles into degenerative disc, the biological safety and efficacy of decellularized IVD was evaluated both in vitro and in vivo. Here, we demonstrated that cellular components can be removed completely after decellularization and maximally retain the structure and biomechanics of native IVD. We revealed that allogeneic ECM did not evoke any apparent inflammatory reaction in vivo and no cytotoxicity was found in vitro. Moreover, IVD ECM can induce differentiation of MSCs into IVD-like cells in vitro. Furthermore, allogeneic ECM microparticles are effective on the treatment of rabbit disc degeneration in vivo. In conclusion, our study developed an optimized method for IVD decellularization and we proved decellularized IVD is safe and effective for the treatment of degenerated disc diseases. PMID:26933821

  18. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    PubMed Central

    Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  19. Engraftment syndrome after allogeneic hematopoietic cell transplantation predicts poor outcomes.

    PubMed

    Chang, Lawrence; Frame, David; Braun, Thomas; Gatza, Erin; Hanauer, David A; Zhao, Shuang; Magenau, John M; Schultz, Kathryn; Tokala, Hemasri; Ferrara, James L M; Levine, John E; Reddy, Pavan; Paczesny, Sophie; Choi, Sung Won

    2014-09-01

    Engraftment syndrome (ES), characterized by fever, rash, pulmonary edema, weight gain, liver and renal dysfunction, and/or encephalopathy, occurs at the time of neutrophil recovery after hematopoietic cell transplantation (HCT). In this study, we evaluated the incidence, clinical features, risk factors, and outcomes of ES in children and adults undergoing first-time allogeneic HCT. Among 927 patients, 119 (13%) developed ES at a median of 10 days (interquartile range 9 to 12) after HCT. ES patients experienced significantly higher cumulative incidence of grade 2 to 4 acute GVHD at day 100 (75% versus 34%, P < .001) and higher nonrelapse mortality at 2 years (38% versus 19%, P < .001) compared with non-ES patients, resulting in lower overall survival at 2 years (38% versus 54%, P < .001). There was no significant difference in relapse at 2 years (26% versus 31%, P = .772). Suppression of tumorigenicity 2, interleukin 2 receptor alpha, and tumor necrosis factor receptor 1 plasma biomarker levels were significantly elevated in ES patients. Our results illustrate the clinical significance and prognostic impact of ES on allogeneic HCT outcomes. Despite early recognition of the syndrome and prompt institution of corticosteroid therapy, outcomes in ES patients were uniformly poor. This study suggests the need for a prospective approach of collecting clinical features combined with correlative laboratory analyses to better characterize ES. PMID:24892262

  20. Lymphocytic hypophysitis in the elderly.

    PubMed

    Sellayah, Renishka; Gonzales, Michael; Fourlanos, Spiros; King, James

    2015-11-01

    We report a 73-year-old woman with lymphocytic hypophysitis who presented with atypical clinical features and what appeared to be pituitary apoplexy on radiological analysis. Lymphocytic hypophysitis is a rare cause of pituitary dysfunction, and is thought to be an autoimmune disorder. It typically affects young peri-partum women, with clinical features that are related to pituitary hypofunction, and an uncertain natural history. It is difficult to radiologically differentiate lymphocytic hypophysitis from pituitary macroadenoma, therefore, the gold standard of diagnosis remains histological. It is rarely reported in the elderly (> 70 years old), however, given its unpredictable clinical course it remains an important differential diagnosis in patients of this age group who present with features suggestive of pituitary dysfunction. PMID:26094558

  1. Management of chronic lymphocytic leukemia

    PubMed Central

    Ghia, Paolo; Hallek, Michael

    2014-01-01

    In the last decade, the management of chronic lymphocytic leukemia has undergone profound changes that have been driven by an improved understanding of the biology of the disease and the approval of several new drugs. Moreover, many novel drugs are currently under evaluation for rapid approval or have been approved by regulatory agencies, further broadening the available therapeutic armamentarium for patients with chronic lymphocytic leukemia. The use of novel biological and genetic parameters combined with a careful clinical evaluation allows us to dissect some of the heterogeneity of the disease and to distinguish patients with a very mild onset and course, who often will not need any treatment, from those with an intermediate prognosis and a third group with a very aggressive course (high-risk leukemia). On this background, it becomes increasingly challenging to select the right treatment strategy. In this paper, we describe our own approach to the management of different patients with chronic lymphocytic leukemia. PMID:24881042

  2. Approach to Chronic Lymphocytic Meningitis.

    PubMed

    Khadilkar, Satish V; Nadkarni, Nilesh

    2015-09-01

    Chronic meningitis is a common clinical problem. Early diagnosis and appropriate therapy is important in improving the overall outcome and to prevent long-lasting sequels. As many etiological agents lead to the development of chronic lymphocytic meningitis, it is important to develop a systematic approach to the diagnosis; taking clues from history, examination and laboratory tests, to make an accurate diagnosis and institute appropriate therapy. This review focuses on the diagnostic approach towards the commonly encountered situation of chronic lymphocytic meningitis. Chronic meningitis is defined as meningeal inflammation that persists for more than 4 weeks. Chronic meningitis accounts for less than 10% of all the cases of meningitis.1 Causes of chronic lymphocytic meningitis are mainly divided into infectious and non-infectious listed in Table 1.2 Due to advancement in investigations, diseases causing chronic meningitis may be diagnosed earlier than 4 weeks and hence the definition should be considered as a rough guideline. PMID:27608867

  3. Preparative electrophoresis of living lymphocytes

    NASA Technical Reports Server (NTRS)

    Vanoss, C. J.; Bigazzi, P. E.; Gillman, C. F.; Allen, R. E.

    1974-01-01

    Vertical liquid columns containing low molecular weight dextran density gradients can be used for preparative lymphocyte electrophoresis on earth, in simulation of 0 gravity conditions. Another method that has been tested at 1 G, is the electrophoresis of lymphocytes in a upward direction in vertical columns. By both methods up to 10 to the 7th power lymphocytes can be separated at one time in a 30 cm glass column of 8 mm inside diameter, at 12 v/cm, in 2 hours. Due to convection and sedimentation problems, the separation at 1 G is less than ideal, but it is expected that at 0 gravity electrophoresis will prove to be a uniquely powerful cell separation tool. The technical feasibility of electrophoresing inert particles at 0 G has been proven earlier, during the flight of Apollo 16.

  4. Safety and Efficacy of Pentostatin and Low Dose TBI With Allogenic Peripheral Blood Stem Cell Transplant

    ClinicalTrials.gov

    2010-12-02

    Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndromes; Multiple Myeloma; Non-Hodgkins Lymphoma; Hodgkins Disease; Peripheral T-Cell Lymphoma

  5. Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

    PubMed Central

    Salit, Rachel B.; Fowler, Daniel H.; Wilson, Wyndham H.; Dean, Robert M.; Pavletic, Steven Z.; Dunleavy, Kieron; Hakim, Frances; Fry, Terry J.; Steinberg, Seth M.; Hughes, Thomas E.; Odom, Jeanne; Bryant, Kelly; Gress, Ronald E.; Bishop, Michael R.

    2012-01-01

    Purpose There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). Patients and Methods One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4+ count < 200/μL) or progressive disease. Results Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3+ (P < .001), CD4+ (P < .001), and CD8+ (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). Conclusion DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies. PMID:22312100

  6. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome

    PubMed Central

    Robinson, Stephen P.; Sureda, Anna; Canals, Carmen; Russell, Nigel; Caballero, Dolores; Bacigalupo, Andrea; Iriondo, Arturo; Cook, Gordon; Pettitt, Andrew; Socie, Gerard; Bonifazi, Francesca; Bosi, Alberto; Michallet, Mauricette; Liakopoulou, Effie; Maertens, Johan; Passweg, Jakob; Clarke, Fiona; Martino, Rodrigo; Schmitz, Norbert

    2009-01-01

    Background The role of reduced intensity conditioning allogeneic stem transplantation (RICalloSCT) in the management of patients with Hodgkin’s lymphoma remains controversial. Design and Methods To further define its role we have conducted a retrospective analysis of 285 patients with HL who underwent a RICalloSCT in order to identify prognostic factors that predict outcome. Eighty percent of patients had undergone a prior autologous stem cell transplantation and 25% had refractory disease at transplant. Results Non-relapse mortality was associated with chemorefractory disease, poor performance status, age >45 and transplantation before 2002. For patients with no risk factors the 3-year non-relapse mortality rate was 12.5% compared to 46.2% for patients with 2 or more risk factors. The use of an unrelated donor had no adverse effect on the non-relapse mortality. Acute graft versus host disease (aGVHD) grades II–IV developed in 30% and chronic GVHD in 42%. The development of cGVHD was associated with a lower relapse rate. The disease progression rate at one and five years was 41% and 58.7% respectively and was associated with chemorefractory disease and extent of prior therapy. Donor lymphocyte infusions were administered to 64 patients for active disease of whom 32% showed a clinical response. Eight out of 18 patients receiving donor lymphocyte infusions alone had clinical responses. Progression-free and overall survival were both associated with performance status and disease status at transplant. Patients with neither risk factor had a 3-year PFS and overall survival of 42% and 56% respectively compared to 8% and 25% for patients with one or more risk factors. Relapse within six months of a prior autologous transplant was associated with a higher relapse rate and a lower progression-free. Conclusions This analysis identifies important clinical parameters that may be useful in predicting the outcome of RICaIICalloSCT in Hodgkin’s lymphoma. PMID:19066328

  7. NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Porter, David L.; Alyea, Edwin P.; Antin, Joseph H.; DeLima, Marcos; Estey, Eli; Falkenburg, J.H. Frederik; Hardy, Nancy; Kroeger, Nicolaus; Leis, Jose; Levine, John; Maloney, David G.; Peggs, Karl; Rowe, Jacob M.; Wayne, Alan S.; Giralt, Sergio; Bishop, Michael R.; van Besien, Koen

    2010-01-01

    Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions (DLI) are commonly used for all diseases; although these interventions are remarkably effective for relapsed CML, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such there is an immediate need for well designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT. PMID:20699125

  8. NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation: Report from the Committee on Prevention of Relapse Following Allogeneic Cell Transplantation for Hematological Malignancies

    PubMed Central

    Alyea, Edwin P.; DeAngelo, Daniel J.; Moldrem, Jeffrey; Pagel, John M.; Przepiorka, Donna; Riddell, Stan; Sadelin, Michel; Young, James W.; Giralt, Sergio; Bishop, Michael

    2011-01-01

    Prevention of relapse after allogeneic hematopoietic stem cell transplantation is the most likely approach to improve survival of patients treated for hematologic malignancies. Herein we review the limits of currently available transplant therapies and the innovative strategies being developed to overcome resistance to therapy or to fill therapeutic modalities not currently available. These novel strategies include nonimmunologic therapies, such as targeted preparative regimens and posttransplant drug therapy, as well as immunologic interventions, including graft engineering, donor lymphocyte infusions, T cell engineering, vaccination and dendritic cell-based approaches. Several aspects of the biology of the malignant cells as well as the host have been identified that obviate success of even these newer strategies. To maximize the potential for success, we recommend pursuing research to develop additional targeted therapies to be used in the preparative regimen or as maintenance post-transplant, better characterize the T-cell and dendritic cells subsets involved in graft-versus-host disease and the graft-versus-leukemia/tumor effect, identify strategies for timing immunologic or nonimmunologic therapies to eliminate the noncycling cancer stem cell, identify more targets for immunotherapies, develop new vaccines that will not be limited by HLA, and develop methods to identify population at very high risk for relapse in order to accelerate clinical development and avoid toxicity in patients not at risk for relapse. PMID:20580849

  9. Distinguishing allogenic from autogenic causes of bed elevation change in late Quaternary alluvial stratigraphic records

    NASA Astrophysics Data System (ADS)

    Daniels, J. Michael

    2008-10-01

    Allogenic and autogenic mechanisms both cause changes in the bed elevation of rivers and thereby influence the characteristics of alluvial stratigraphic records (ASRs). Allogenic forcing mechanisms can be grouped into five categories whose relative influence varies with timescale: climate, tectonism, base level, land use/land cover and direct human modification of channels. Late Quaternary ASRs are influenced by the greatest range of allogenic forcing variables with climate among the most important. Autogenic mechanisms of bed elevation change are ubiquitous throughout fluvial systems and are always time-transgressive. Autogenic bed elevation change propagates through drainage networks at predictable rates and results in a time-space envelope within which its effects are capable of operating. ASRs that can be correlated over geographical areas large enough and time intervals small enough to exist outside this envelope most likely result from allogenic forcing. This formulation represents a quantitative and geographic set of threshold criteria for distinguishing between autogenic and allogenic mechanisms. Over late Quaternary timescales (10 2 to 10 5 years) in tectonically stable regions climate change is the dominant allogenic mechanism and, therefore, the first-order control on the morphology, sedimentology, pedologic characteristics and chronology of alluvial stratigraphic records that meet or exceed the threshold criteria for demonstrating allogenic causality.

  10. [Alleviation of palmoplantar pustulosis associated with adult T cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation].

    PubMed

    Akasaka, Hiroshi; Imaizumi, Kisako; Sakane, Emiko; Tsunemine, Hiroko; Ito, Kiminari; Kodaka, Taiichi; Matsumoto, Mayumi; Matsuoka, Masao; Takahashi, Takayuki

    2012-08-01

    A 68-year-old female with palmoplantar pustulosis was referred to our hospital in July, 2009 because of liver dysfunction, a positive test for HTLV-1, and circulating abnormal lymphocytes with irregularly shaped nuclei. A diagnosis of acute type adult T cell leukemia/lymphoma (ATLL) was made based on generalized lymph node swelling and high levels of serum LDH, in addition to the findings described above. The associated palmoplantar pustulosis responded to some extent to antibiotics, steroid ointment, and narrow band UBV light irradiation. For ATLL, she was serially treated with CHOP chemotherapy, an LSG 15 protocol, and CytaBOM protocol with consequent partial remission. These chemotherapies did not affect the palmoplantar pustulosis. For ATLL in partial remission, we performed allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from a related donor (HTLV-1-negative) with a conditioning regimen consisting of fludarabine, melphalan, and total body irradiation with 3 Gy in February, 2010. After the engraftment of donor hematopoietic cells, ATLL cells disappeared and the patient currently (as of April, 2012) remains in complete remission (CR). The residual palmoplantar pustulosis was further improved soon after allo-PBSCT and disappeared on Day 84 after transplantation. This refractory skin disease has also been in CR to date. PMID:22975820

  11. How Is Acute Lymphocytic Leukemia Classified?

    MedlinePlus

    ... How is acute lymphocytic leukemia treated? How is acute lymphocytic leukemia classified? Most types of cancers are assigned numbered ... ALL are now named as follows: B-cell ALL Early pre-B ALL (also called pro-B ...

  12. Targeted Therapy for Acute Lymphocytic Leukemia

    MedlinePlus

    ... Monoclonal antibodies to treat acute lymphocytic leukemia Targeted therapy for acute lymphocytic leukemia In recent years, new ... These drugs are often referred to as targeted therapy. Some of these drugs can be useful in ...

  13. Radionuclide labeled lymphocytes for therapeutic use

    DOEpatents

    Srivastava, Suresh C.; Fawwaz, Rashid A.; Richards, Powell

    1985-01-01

    Lymphocytes labelled with .beta.-emitting radionuclides are therapeutically useful, particularly for lymphoid ablation. They are prepared by incubation of the lymphocytes with the selected radionuclide-oxine complex.

  14. Radionuclide labeled lymphocytes for therapeutic use

    DOEpatents

    Srivastava, S.C.; Fawwaz, R.A.; Richards, P.

    1983-05-03

    Lymphocytes labelled with ..beta..-emitting radionuclides are therapeutically useful, particularly for lymphoid ablation. They are prepared by incubation of the lymphocytes with the selected radionuclide-oxine complex.

  15. Leukemia -- Chronic T-Cell Lymphocytic

    MedlinePlus

    ... Chronic T-Cell Lymphocytic: Overview Print to PDF Leukemia - Chronic T-Cell Lymphocytic: Overview Approved by the ... Platelets that help the blood to clot About leukemia Types of leukemia are named after the specific ...

  16. Antitumor immunomodulatory activity of allogenic bone marrow cells on TiNi scaffold

    NASA Astrophysics Data System (ADS)

    Kokorev, O. V.; Hodorenko, V. N.; Cherdyntseva, N. V.; Gunther, V. E.

    2016-08-01

    The present study was undertaken to evaluate the feasibility of modulation of anti-tumor response by allogenic bone marrow cell transplantation into porous TiNi-based scaffold. Transplantation of bone marrow cells into porous TiNi-based scaffold leads to antitumor (35%) and antimetastatic (55%) effects. The lifetime of tumor-bearing animals and implanted allogenic bone marrow cells in incubator of TiNi increases up to 60%. The possible mechanisms of the effect of allogenic cells on tumor process are the stimulation of endogenous effectors of antitumor immunity.

  17. A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies

    ClinicalTrials.gov

    2016-05-18

    Acute Leukemia; Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Biphenotypic Leukemia; Pre-leukemic Syndromes; Monosomy 7; Bone Marrow Clonal Malformations; Juvenile Myelomonocytic Leukemia; Myelodysplastic Syndromes; Chronic Myelogenous Leukemia

  18. Lymphocyte receptors for pertussis toxin

    SciTech Connect

    Clark, C.G.; Armstrong, G.D. )

    1990-12-01

    We have investigated human T-lymphocyte receptors for pertussis toxin by affinity isolation and photoaffinity labeling procedures. T lymphocytes were obtained from peripheral human blood, surface iodinated, and solubilized in Triton X-100. The iodinated mixture was then passed through pertussis toxin-agarose, and the fractions were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Autoradiography of the fixed, dried gels revealed several bands in the pertussis toxin-bound fraction that were not observed in fractions obtained from histone or fetuin-agarose. Further investigations employed a photoaffinity labeling reagent, sulfosuccinimidyl 2-(p-azido-salicylamido)-1,3'-dithiopropionate, to identify pertussis toxin receptors in freshly isolated peripheral blood monocytic cells, T lymphocytes, and Jurkat cells. In all three cell systems, the pertussis toxin affinity probe specifically labeled a single protein species with an apparent molecular weight of 70,000 that was not observed when the procedure was performed in the presence of excess unmodified pertussis toxin. A protein comparable in molecular weight to the one detected by the photoaffinity labeling technique was also observed among the species that bound to pertussis toxin-agarose. The results suggest that pertussis toxin may bind to a 70,000-Da receptor in human T lymphocytes.

  19. The course of lymphocytic hypophysitis.

    PubMed

    Bitton, R N; Slavin, M; Decker, R E; Zito, J; Schneider, B S

    1991-07-01

    A 27-year-old woman presented to our institution in her seventh month of pregnancy with complaints of headache and visual field disturbance. Workup revealed bitemporal hemianopia, a markedly enlarged pituitary gland on computed tomography scan, and biochemical evidence of partial hypopituitarism. At surgery, a biopsy specimen of the pituitary gland was taken revealing lymphocytic hypophysitis. The patient was treated with steroids and replacement doses of thyroid hormone. Visual fields improved postoperatively. A repeat computed tomography scan obtained 2 months after an uneventful pregnancy showed that her pituitary had regained normal size and contour. Over the next 9 months she had gradual recovery of all pituitary function. This case allowed us to follow and document the course of lymphocytic hypophysitis from its presentation as a macroadenoma with partial hypopituitarism to full recovery of both size and hormonal function of the pituitary. Lymphocytic hypophysitis should be considered in the differential diagnosis of a pituitary mass or pituitary dysfunction presenting in pregnancy. In patients with suspected lymphocytic hypophysitis and a pituitary mass, a trial of steroids may be therapeutic. PMID:2053072

  20. [Ultrastructure of blood lymphocytes in dairy cows with chronic lymphocytic leukemia].

    PubMed

    Cerný, L; Hajdu, I

    1982-03-01

    The morphology of blood lymphocytes was studied ultrastructurally in cows with chronical lymphocytic leucosis (CLL) and in healthy controls. A significantly higher occurrence of the so-called nuclear pockets in the leucaemic lymphocytes was found (13.8% v. 0.83% in healthy animals). The surfaces of lymphocytes were stained with ruthenium red; this showed the possibility of differentiating two distinct populations of lymphocytes in peripheral blood. In this way, a prevalence of B-lymphocytes, constituting 89.7% of all lymphocytes, was demonstrated in animals suffering from CLL. PMID:6179285

  1. Aiolos and Lymphocyte Mimicry in Lung Cancer

    PubMed Central

    Terada, Lance S; Liu, Zhe

    2014-01-01

    Aggressive carcinomas tend to adopt behaviors normally restricted to lymphocytes, including anchorage-independent mobilization, response to chemokines, and modulation of local inflammatory conditions. In a recent study we identified the lymphocyte-restricted chromatin regulator Aiolos as an epigenetic driver of lymphocyte mimicry in lung cancer that links immune cell development to metastatic behavior. PMID:27308319

  2. Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-03-28

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; T-Cell Large Granular Lymphocyte Leukemia

  3. Patterns and kinetics of T-cell chimerism after allo transplant with alemtuzumab-based conditioning: mixed chimerism protects from GVHD, but does not portend disease recurrence.

    PubMed

    van Besien, Koen; Dew, Alexander; Lin, Shang; Joseph, Loren; Godley, Lucy A; Larson, Richard A; Odenike, Toyosi; Rich, Elizabeth; Stock, Wendy; Wickrema, Amittha; Artz, Andrew S

    2009-11-01

    We analyzed the kinetics of CD3 chimerism in 120 consecutive allogeneic hematopoietic cell transplantation (HCT) recipients receiving alemtuzumab-based conditioning. Fifty-two received fludarabine/melphalan, 44 received fludarabine/busulfan, and 24 received clofarabine/melphalan in addition to alemtuzumab. Post-transplant GVHD prophylaxis consisted of tacrolimus. No prophylactic donor lymphocyte infusion or other interventions were used for mixed donor chimerism (MDC). Bone marrow (BM) and/or peripheral blood (PB) samples were obtained at 30 days, 100 days, 180 days, and 1 year following HCT. On Day 30, 15% of assessable patients had MDC in the CD3 compartment. This had increased to 50% by Day 100, and to 63% by Day 180. MDC predicted for a lower risk of acute (p = 0.08) and particularly of chronic GVHD (p = 0.01). MDC was not associated with subsequent relapse or TRM (p = 0.67 and 0.72, respectively). A decline of more than 15% in CD3 chimerism between Day 30 and Day 180 predicted for a 40% risk of subsequent disease recurrence. The observation of MDC after alemtuzumab conditioning does not by itself constitute a risk factor for relapse and should not be used to guide therapeutic intervention. By contrast, declining donor chimerism between Day 30 and Day 180 is associated with a somewhat increased risk of disease recurrence. The high incidence of MDC after alemtuzumab containing conditioning contributes to the low risk of acute and chronic GVHD. PMID:19821799

  4. Human CD4+ effector T lymphocytes generated upon TCR engagement with self-peptides respond defectively to IL-7 in their transition to memory cells

    PubMed Central

    González-Pérez, Gabriela; Segovia, Norma C; Rivas-Carvalho, Amaranta; Reyes, Diana P; Torres-Aguilar, Honorio; Aguilar-Ruiz, Sergio R; Irles, Claudine; Soldevila, Gloria; Sánchez-Torres, Carmen

    2013-01-01

    The peripheral repertoire of CD4+ T lymphocytes contains autoreactive cells that remain tolerant through several mechanisms. However, nonspecific CD4+ T cells can be activated in physiological conditions as in the course of an ongoing immune response, and their outcome is not yet fully understood. Here, we investigate the fate of human naive CD4+ lymphocytes activated by dendritic cells (DCs) presenting endogenous self-peptides in comparison with lymphocytes involved in alloresponses. We generated memory cells (Tmem) from primary effectors activated with mature autologous DCs plus interleukin (IL)-2 (Tmauto), simulating the circumstances of an active immune response, or allogeneic DCs (Tmallo). Tmem were generated from effector cells that were rested in the absence of antigenic stimuli, with or without IL-7. Tmem were less activated than effectors (demonstrated by CD25 downregulation) particularly with IL-7, suggesting that this cytokine may favour the transition to quiescence. Tmauto and Tmallo showed an effector memory phenotype, and responded similarly to polyclonal and antigen-specific stimuli. Biochemically, IL-7-treated Tmallo were closely related to conventional memory lymphocytes based on Erk-1/2 activation, whereas Tmauto were more similar to effectors. Autologous effectors exhibited lower responses to IL-7 than allogeneic cells, which were reflected in their reduced proliferation and higher cell death. This was not related to IL-7 receptor expression but rather to signalling deficiencies, according to STAT5 activation These results suggest that ineffective responses to IL-7 could impair the transition to memory cells of naive CD4+ T lymphocytes recognizing self-peptides in the setting of strong costimulation. PMID:23454917

  5. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    ClinicalTrials.gov

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  6. Ibrutinib or Idelalisib in Treating Patients With Persistent or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma After Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-04-08

    Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Small Lymphocytic Lymphoma

  7. Bullous pemphigoid after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kato, Keisuke; Koike, Kazutoshi; Kobayashi, Chie; Iijima, Shigeruko; Hashimoto, Takashi; Tsuchida, Masahiro

    2015-06-01

    Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated-donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft-versus-tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT. PMID:26113316

  8. Curative treatment for severe sickle cell disease: allogeneic transplantation.

    PubMed

    Oshrine, Benjamin; Talano, Julie-An

    2015-04-01

    Sickle cell disease is an inherited hematologic disorder that in its severe form can result in substantial morbidity and early mortality. Patients with this disorder can suffer from severe pain, lung disease, and strokes, resulting in chronic debilitating conditions, end organ dysfunction, and organ failure. The health care costs of caring for these chronically ill patients are substantial. Allogeneic transplantation is a modality that has the potential to cure these patients. To date, matched sibling donor transplantation is widely accepted as a standard of care for pediatric patients. Utilizing alternative donors for transplant is still under investigation, as is transplant for adult patients with sickle cell disease. This review focuses on the most recent data for hematopoietic cell transplantation for patients with sickle cell disease. PMID:26352583

  9. The host response to allogeneic and xenogeneic biological scaffold materials.

    PubMed

    Keane, Timothy J; Badylak, Stephen F

    2015-05-01

    The clinical use of biological scaffold materials has become commonplace. Such scaffolds are composed of extracellular matrix (ECM), or components of ECM, derived from allogeneic or xenogeneic tissues. Such scaffold materials vary widely in their source tissue, processing methods and sterilization methods. The success or failure of an ECM scaffold for a given application is dependent on the host response following implantation; a response that is largely mediated by the innate immune system and which is influenced by a numerous factors, including the processing methods used in the preparation of biological scaffolds. The present paper reviews various aspects of the host response to biological scaffolds and factors that affect this response. In addition, some of the logistical, regulatory and reconstructive implications associated with the use of biological scaffolds are discussed. PMID:24668694

  10. ALLOGENEIC STEM CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION

    PubMed Central

    Oran, Betul; Weisdorf, Daniel J.

    2016-01-01

    Purpose of review The optimal post-remission therapy of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. This review summarizes the recent developments in the clinical research and therapeutic applications defining the role of allogeneic hematopoietic stem cell transplantation (allo-HCT) in CR1. Recent findings Molecular markers in combinations with cytogenetics have improved the risk stratification and informed decision-making in patients with AML in CR1. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allo-HCT for a larger number of patients. Summary The progress in risk stratification and transplant technology dictate that early donor identification search should be initiated for all eligible AML patients in CR1. PMID:21912256

  11. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation

    PubMed Central

    Gilbert, Ethel S.; Rizzo, J. Douglas; Socié, Gérard; Banks, Peter M.; Sobocinski, Kathleen A.; Horowitz, Mary M.; Jaffe, Elaine S.; Kingma, Douglas W.; Travis, Lois B.; Flowers, Mary E.; Martin, Paul J.; Deeg, H. Joachim; Curtis, Rochelle E.

    2009-01-01

    We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial. PMID:19264919

  12. Allogeneic versus xenogeneic immune reaction to bioengineered skin grafts.

    PubMed

    Erdag, Gulsun; Morgan, Jeffrey R

    2004-01-01

    There are conflicting reports on the survival and immune reaction to allografts and xenografts of cultured skin substitutes (CSS). In this study, we investigated the allogeneic and xenogeneic responses to CSS of human keratinocytes and genetically engineered CSS expressing keratinocyte growth factor (KGF) that forms a hyperproliferative epidermis. CSS (control and KGF modified) and neonatal human foreskins were evaluated by immunohistochemistry for the expression of MHC class I and II. To study allograft rejection, grafts were transplanted to human peripheral blood mononuclear cell (huPBMC)-reconstituted SCID mice. To study xenograft rejection, grafts were transplanted to immunocompetent mice. Graft survival and immune reaction were assessed visually and microscopically. After transplantation, control CSS formed a normal differentiated epidermis, whereas KGF CSS formed a hyperproliferative epidermis. Control and KGF CSS expressed class I similar to neonatal foreskin, but did not express class II. In the allograft model, rejection of neonatal foreskins was between 5 and 9 days. In contrast, neither control nor KGF CSS was rejected by huPBMC-SCID mice. Histology showed dense mononuclear cell infiltration in human foreskins, with few, if any, mononuclear cells in control or KGF CSS. In contrast to the allogeneic reaction, CSS (control and KGF) were rejected in the xenograft model, but rejection was delayed (9-21 days) compared with neonatal skin (5-8 days). Humanized SCID mice rejected allografts of human neonatal foreskins, but did not reject control CSS or KGF CSS, even though the KGF CSS formed a hyperproliferative epidermis. Rejection of control and KGF CSS by immunocompetent mice in a xenograft model was comparable and their survival was significantly prolonged compared with neonatal skin. These results demonstrate that control CSS and hyperproliferative KGF CSS are less immunogenic than normal human skin and that sustained hyperproliferation of the epidermis

  13. Toll like receptor polymorphisms in allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2014-01-01

    To assess the impact of the genetic variation in toll-like receptors (TLR) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT) we have investigated 29 single nucleotide polymorphisms (SNP) across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni corrected level P≤0.001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease free survival (DFS) (hazard ratio (HR) 1.47 (95% confidence interval (CI) 1.16–1.85); P=0.001). Further analysis stratified by donor sex due to confounding by sex, was suggestive for associations with overall survival (male donor: HR 1.41 (95% CI 1.09–1.83), P=0.010); female donor: (HR 2.78 (95% CI 1.43–5.41), P=0.003), DFS (male donor: HR 1.45 (95% CI 1.12–1.87), P=0.005; female donor: HR 2.34 (95% CI 1.18–4.65), P=0.015) and treatment related mortality (male donor: HR 1.49 (95% CI 1.09–2.04), P=0.012; female donor: HR 3.12 (95% CI 1.44–6.74), P=0.004). In conclusion our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT. PMID:25464115

  14. Serotonin Uptake Is Largely Mediated by Platelets versus Lymphocytes in Peripheral Blood Cells

    PubMed Central

    2012-01-01

    The serotonin transporter (SERT), a primary target for many antidepressants, is expressed in the brain and also in peripheral blood cells. Although platelet SERT function is well accepted, lymphocyte SERT function has not been definitively characterized. Due to their small size, platelets often are found in peripheral blood mononuclear cell preparations aimed at isolating lymphocytes, monocytes, and macrophages. The presence of different cells makes it difficult to assign SERT expression and function to specific cell types. Here, we use flow cytometry and IDT307, a monoamine transporter substrate that fluoresces after uptake into cells, to investigate SERT function in lymphocyte and platelet populations independently, as well as simultaneously without prior isolation. We find that murine lymphocytes exhibit temperature-dependent IDT307 transport but uptake is independent of SERT. Lack of measurable SERT function in lymphocytes was corroborated by chronoamperometry using serotonin as a substrate. When we examined rhesus and human mixed blood cell populations, we found that platelets, and not lymphocytes, were primary contributors to SERT function. Overall, these findings indicate that lymphocyte SERT function is minimal. Moreover, flow cytometry, in conjunction with the fluorescent transporter substrate IDT307, can be widely applied to investigate SERT in platelets from populations of clinical significance. PMID:23336055

  15. Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia

    PubMed Central

    Ossenkoppele, Gert J.; Janssen, Jeroen J.W.M.; van de Loosdrecht, Arjan A.

    2016-01-01

    Acute myeloid leukemia is a clonal neoplasm derived from myeloid progenitor cells with a varying outcome. The initial goal of treatment is the achievement of complete remission, defined for over 40 years by morphology. However, without additional post-remission treatment the majority of patients relapse. In many cases of acute myeloid leukemia, allogeneic stem cell transplantation offers the best prospects of cure. In 2013, 5608 stem cell transplantations in acute myeloid leukemia were performed in Europe (5228 allogeneic and 380 autologous stem cell transplantations). Most stem cell transplantations are performed in first complete remission. However, despite a considerable reduction in the chance of relapse, in most studies, overall survival benefit of allogeneic stem cell transplantation is modest due to substantial non-relapse mortality. Here we discuss the many factors related to the risk of relapse after allogeneic stem cell transplantation. PMID:26721801

  16. The Use of Cultured Allogenic Keratinocyte Grafting in a Patient with Epidermolysis Bullosa Simplex

    PubMed Central

    Shin, Kee Cheol; Park, Bo Young; Kim, Woo Seob; Bae, Tae Hui

    2011-01-01

    Epidermolysis bullosa (EB) is a rare genetic disease that is known for continuous skin blistering caused by minor trauma. The skin blisters and bullae that develop often cause skin defects. There is no definitive treatment for EB, only symptomatic relief. We report our experience with cultured allogenic keratinocyte grafting in a newborn patient with EB simplex who had unhealed raw surfaces and was not a skin grafting candidate. The skin lesions of the patient were covered with cultured allogenic keratinocyte grafts and re-epithelialized quickly with no scarring. Allogenic keratinocyte grafting reduced pain and produced noticeable improvements in the unhealed wounds. We think that allogenic keratinocyte grafting can play an important role in the management of patients with EB simplex. PMID:22346287

  17. Suppression of Antigen-Specific Lymphocyte Activation in Simulated Microgravity

    NASA Technical Reports Server (NTRS)

    Cooper, David; Pride, Michael W.; Brown, Eric L.; Risin, Diana; Pellis, Neal R.

    1999-01-01

    Various parameters of immune suppression are observed in astronauts during and after spaceflight, and in isolated immune cells in true and simulated microgravity. Specifically, polyclonal activation of T cells is severely suppressed in true and simulated microgravity. These recent findings with various polyclonal activators suggests a suppression of oligoclonal lymphocyte activation in microgravity. We utilized rotating wall vessel (RWV) bioreactors that simulate aspects of microgravity for cell cultures to analyze three models of antigen-specific activation. A mixed-lymphocyte reaction (MLR), as a model for a primary immune response; a tetanus toxoid (TT) response and a B. burgdorferi (Bb) response, as models of a secondary immune response, were all suppressed in the RWV bioreactor. Our findings confirm that the suppression of activation observed with polyclonal models also encompasses oligoclonal antigen-specific activation.

  18. Chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor promotes sciatic nerve repair

    PubMed Central

    Zhang, Yanru; Zhang, Hui; Katiella, Kaka; Huang, Wenhua

    2014-01-01

    A chemically extracted acellular allogeneic nerve graft can reduce postoperative immune rejection, similar to an autologous nerve graft, and can guide neural regeneration. However, it remains poorly understood whether a chemically extracted acellular allogeneic nerve graft combined with neurotrophic factors provides a good local environment for neural regeneration. This study investigated the repair of injured rat sciatic nerve using a chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor. An autologous nerve anastomosis group and a chemical acellular allogeneic nerve bridging group were prepared as controls. At 8 weeks after repair, sciatic functional index, evoked potential amplitude of the soleus muscle, triceps wet weight recovery rate, total number of myelinated nerve fibers and myelin sheath thickness were measured. For these indices, values in the three groups showed the autologous nerve anastomosis group > chemically extracted acellular nerve graft + ciliary neurotrophic factor group > chemical acellular allogeneic nerve bridging group. These results suggest that chemically extracted acellular nerve grafts combined with ciliary neurotrophic factor can repair sciatic nerve defects, and that this repair is inferior to autologous nerve anastomosis, but superior to chemically extracted acellular allogeneic nerve bridging alone. PMID:25221592

  19. Chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor promotes sciatic nerve repair.

    PubMed

    Zhang, Yanru; Zhang, Hui; Katiella, Kaka; Huang, Wenhua

    2014-07-15

    A chemically extracted acellular allogeneic nerve graft can reduce postoperative immune rejection, similar to an autologous nerve graft, and can guide neural regeneration. However, it remains poorly understood whether a chemically extracted acellular allogeneic nerve graft combined with neurotrophic factors provides a good local environment for neural regeneration. This study investigated the repair of injured rat sciatic nerve using a chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor. An autologous nerve anastomosis group and a chemical acellular allogeneic nerve bridging group were prepared as controls. At 8 weeks after repair, sciatic functional index, evoked potential amplitude of the soleus muscle, triceps wet weight recovery rate, total number of myelinated nerve fibers and myelin sheath thickness were measured. For these indices, values in the three groups showed the autologous nerve anastomosis group > chemically extracted acellular nerve graft + ciliary neurotrophic factor group > chemical acellular allogeneic nerve bridging group. These results suggest that chemically extracted acellular nerve grafts combined with ciliary neurotrophic factor can repair sciatic nerve defects, and that this repair is inferior to autologous nerve anastomosis, but superior to chemically extracted acellular allogeneic nerve bridging alone. PMID:25221592

  20. Clinical evaluation of allogeneic cultured dermal substitutes for intractable skin ulcers after tumor resection.

    PubMed

    Moroi, Yoichi; Fujita, Shohei; Fukagawa, Shuji; Mashino, Toshihiko; Goto, Takako; Masuda, Teiichi; Urabe, Kazunori; Kubo, Kentaro; Matsui, Hiromichi; Kagawa, Shizuko; Kuroyanagi, Yoshimitsu; Furue, Masutaka

    2004-01-01

    Clinical research on allogeneic cultured dermal substitute (CDS), which was newly developed at the R&D Center for Artificial Skin of Kitasato University, has been carried out in medical centers across Japan with the support of the Millennium Project of the Ministry of Health, Labor and Welfare of Japan. Allogeneic CDS was prepared by cultivation of fibroblasts on a two-layered spongy matrix of hyaluronic acid and atelo-collagen. This paper reports the clinical results of application of allogeneic CDS in 12 patients with full-thickness skin defects after surgical resection of skin tumors. In 9 of 10 patients, healthy granulation tissue developed immediately, allowing us to perform split-thickness skin grafts at an early stage. In two cases, allogeneic CDS was used to cover an expanded mesh skin graft that had been applied to treat a large ulcer, and rapid epithelization was observed. No patient developed local infection nor local tumor recurrence after treatment with CDS. The spongy matrix itself as well as the vascular endothelial growth factor (VEGF) released by the allogeneic CDS seemed to be beneficial for the treatment of intractable skin ulcers. Allogeneic CDS functions as an excellent biological dressing, and could dramatically change the treatment of intractable skin ulcers. PMID:15246944

  1. Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study

    PubMed Central

    Bejanyan, Nelli; Weisdorf, Daniel J.; Logan, Brent R.; Wang, Hai-Lin; Devine, Steven M.; de Lima, Marcos; Bunjes, Donald W.; Zhang, Mei-Jie

    2015-01-01

    Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990–2010) during first or second complete remission (CR) to identify factors associated with longer post-relapse survival. Median time of post HCT relapse was 7 months (mo; range, 1–177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy (CT) alone (n=660), donor lymphocyte infusion (DLI)±CT (n=202; %), or 2nd alloHCT±CT ±DLI (n=369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 mo (range, <1–193). Survival for all patients was 23% at 1 year post-relapse; however, 3-yr overall survival correlated with time from HCT to relapse (4% for relapse during 1–6 mo period, 12% during 6 mo-2 yr, 26% during 2–3 yr, and 38% for ≥3 yr). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (RR 0.55 for 6 mo-2 yr, RR 0.39 for 2–3 yr, and RR 0.28 for ≥3 yr; p<0.0001) and a 1st HCT using reduced-intensity conditioning (RR=0.77; 95% CI 0.66–0.88, p=0.0002). In contrast, inferior survival was associated with age >40 yr (RR=1.42, 95% CI 1.24–1.64; p<0.0001), active GVHD at relapse (RR=1.25, 95% CI 1.13–1.39; p<0.0001), adverse cytogenetics (RR=1.37, 95% CI 1.09–1.71; p=0.0062), mismatched URD (RR=1.61, 95% CI 1.22–2.13; p=0.0008), and use of cord blood for 1st HCT (RR=1.23, 95% CI 1.06–1.42; p=0.0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 mo after their initial alloHCT had better survival and may benefit from intensive therapy such as 2nd alloHCT±DLI. PMID:25460355

  2. Obatoclax, Fludarabine, and Rituximab in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2013-09-27

    B-cell Chronic Lymphocytic Leukemia; Leukemia; Prolymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia

  3. Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    ClinicalTrials.gov

    2016-09-13

    Anemia; Fever, Sweat, and Hot Flashes; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; Weight Change

  4. The pyrimidin analogue cyclopentenyl cytosine induces alloantigen-specific non-responsiveness of human T lymphocytes

    PubMed Central

    Nikolaeva, N; Bemelman, F J; Yong, S-L; Verschuur, A; van Lier, R A W; ten Berge, I J M

    2008-01-01

    Cyclopentenyl cytosine (CPEC) has been shown to induce apoptosis in human T lymphoblastic cell lines and T cells from leukaemia patients. In this study we have addressed the question of whether CPEC is able to decrease proliferation and effector functions of human alloresponsive T lymphocytes and induce T cell anergy. The proliferative capacity of human peripheral blood mononuclear cells in response to allogeneic stimulation was measured by 5,6-carboxy-succinimidyl-diacetate-fluorescein-ester staining. Flow cytometric analysis was performed using surface CD4, CD8, CD25, CD103 and intracellular perforin, granzyme A, granzyme B, caspase-3 and forkhead box P3 (FoxP3) markers. The in vivo immunosuppressive capacity was tested in a murine skin graft model. Addition of CPEC at a concentration of 20 nM strongly decreased the expansion and cytotoxicity of alloreactive T cells. Specific restimulation in the absence of CPEC showed that the cells became anergic. The drug induced caspase-dependent apoptosis of alloreactive T lymphocytes. Finally, CPEC increased the percentage of CD25high FoxP3+ CD4+ and CD103+ CD8+ T cells, and potentiated the effect of rapamycin in increasing the numbers of alloreactive regulatory T cells. Treatment with CPEC of CBA/CA mice transplanted with B10/Br skin grafts significantly prolonged graft survival. We conclude that CPEC inhibits proliferation and cytotoxicity of human alloreactive T cells and induces alloantigen non-responsiveness in vitro. PMID:18062797

  5. CCI-779 in Treating Patients With Recurrent or Refractory B-Cell Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia

    ClinicalTrials.gov

    2014-05-07

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Malignant Neoplasm; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  6. Reconstruction of Beagle Hemi-Mandibular Defects with Allogenic Mandibular Scaffolds and Autologous Mesenchymal Stem Cells

    PubMed Central

    Luo, JinChao; Liu, HuaWei; Hu, Min; Yue, Wen

    2014-01-01

    Objective Massive bone allografts are frequently used in orthopedic reconstructive surgery, but carry a high failure rate of approximately 25%. We tested whether treatment of graft with mesenchymal stem cells (MSCs) can increase the integration of massive allografts (hemi-mandible) in a large animal model. Methods Thirty beagle dogs received surgical left-sided hemi-mandibular defects, and then divided into two equal groups. Bony defects of the control group were reconstructed using allografts only. Those of the experimental group were reconstructed using allogenic mandibular scaffold-loaded autologous MSCs. Beagles from each group were killed at4 (n = 4), 12 (n = 4), 24 (n = 4) or 48 weeks (n = 3) postoperatively. CT and micro-CT scans, histological analyses and the bone mineral density (BMD) of transplants were used to evaluate defect reconstruction outcomes. Results Gross and CT examinations showed that the autologous bone grafts had healed in both groups. At 48 weeks, the allogenic mandibular scaffolds of the experimental group had been completely replaced by new bone, which has a smaller surface area to that of the original allogenic scaffold, whereas the scaffold in control dogs remained the same size as the original allogenic scaffold throughout. At 12 weeks, the BMD of the experimental group was significantly higher than the control group (p<0.05), and all micro-architectural parameters were significantly different between groups (p<0.05). Histological analyses showed almost all transplanted allogeneic bone was replaced by new bone, principally fibrous ossification, in the experimental group, which differed from the control group where little new bone formed. Conclusions Our study demonstrated the feasibility of MSC-loaded allogenic mandibular scaffolds for the reconstruction of hemi-mandibular defects. Further studies are needed to test whether these results can be surpassed by the use of allogenic mandibular scaffolds loaded with a

  7. Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

    PubMed

    Maddocks, Kami; Jones, Jeffrey A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. PMID:27040703

  8. Selective T-cell Ablation with Bismuth-213 Labeled Anti-TCR Alpha Beta as Nonmyeloablative Conditionaing for Allogeneic Canine Marrow Transplantion

    SciTech Connect

    Bethge, W. A.; Wilbur, D. Scott; Storb, R.; Hamlin, Donald K.; Santos, E. B.; Brechbiel, M. W.; Fisher, Darrell R.; Sandmaier, B. M.

    2003-06-15

    Two major immunological barriers, the host versus graft (HVG) and the graft versus host (GVH) reaction, must be overcome for successful allogeneic hematopoietic stem cell transplantation. T-cells are involved in these barriers in the major histocompatibility complex-identical settings. We hypothesized that selective ablation of T-cells using radioimmunotherapy, together with postgrafting immunosuppression, would ensure stable allogeneic engraftment. We developed a canine model of nonmyeloablative marrow transplantation in which host immune reactions are impaired by a single dose of 2 Gy total body irradiation (TBI), and where both GVH and residual HVG reactions are controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We substituted the alpha-emitter bismuth-213 linked to a monoclonal antibody against TCR(alpha,beta)using the metal-binding chelate CHX-A”-DTPA, for 2 Gy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen and liver. In a dosimetry study, 4 dogs were treated with 0.13-0.46 mg/kg TCR mAb labeled with 3.7-5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantion of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Therapy was well tolerated except for elevations of transaminases, which were transient in all but one dog. No other organ toxicities or signs of graft-versus-host-disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5-55 % with >30 weeks follow up.

  9. Stimulation of human tonsillar lymphocytes in vitro

    PubMed Central

    Oettgen, H. F.; Silber, R.; Miescher, P. A.; Hirschhorn, K.

    1966-01-01

    We have studied the in vitro behaviour of cultured human tonsillar lymphocytes. In comparison with peripheral blood lymphocytes these cells show a higher degree of formation of large cells and mitoses in control cultures without any additive. They behave in a manner similar to peripheral blood lymphocytes when cultured with phytohaemagglutinin (PHA), streptolysin S (SLS) and specific antigens. The only exception is a lack of response to streptolysin O (SLO). PMID:5916348

  10. Increased transendothelial migration of scleroderma lymphocytes

    PubMed Central

    Stummvoll, G; Aringer, M; Grisar, J; Steiner, C; Smolen, J; Knobler, R; Graninger, W

    2004-01-01

    Background: CD4+ T lymphocytes play an important part in the pathogenesis of scleroderma (systemic sclerosis, SSc) and predominate in perivascular SSc skin lesions. Both soluble and membrane bound adhesion molecules are overexpressed in SSc, possibly influencing lymphocyte/endothelial cell (EC) contact. Objective: To assess the transendothelial migration capacity of peripheral lymphocytes in vitro. Patients and methods: Collagen was covered with human umbilical vein endothelial cells (HUVEC), and peripheral blood mononuclear cells (PBMC) of patients and matched healthy controls (HC) were added in parallel experiments. Before and after fractionated harvest of non-adherent, bound, and migrated lymphocytes, the CD4/CD8 ratio and the lymphocytic expression of activation markers and adhesion molecules were analysed by fluorocytometry. Results: 13 (SD 12)% of the SSc PBMC migrated compared with only 5 (5)% HC PBMC (p<0.0002); this increase was primarily due to the migration of CD3+ T lymphocytes and mainly to a larger proportion of CD4+ cells within this CD3+ fraction (71 (SD 14)% for SSc v 56 (14)% for HC, p<0.03), leading to an increased CD4/CD8 ratio among migrated SSc lymphocytes in comparison with controls (3.3 (1.5) v 1.62 (0.93), p<0.006). Among migrated SSc CD4+ T lymphocytes, the frequency of HLA-DR+ cells was increased; migrated lymphocytes highly expressed the adhesion molecules CD11a, CD49d, CD29, and CD44. Conclusion: Transendothelial migration of CD4+ T lymphocytes is enhanced in SSc, and migrating cells exhibit an activated phenotype. The data suggest that activated CD3+CD4+ lymphocytes as found in SSc peripheral blood are prone to transvascular migration, thus contributing to the formation of typical perivascular lymphocytic infiltrates. PMID:15082489

  11. Modulation of GvHD by suicide-gene transduced donor T lymphocytes: clinical applications in mismatched transplantation.

    PubMed

    Ciceri, F; Bonini, C; Gallo-Stampino, C; Bordignon, C

    2005-01-01

    In allogeneic hematopoietic cell transplantation (allo-HCT), donor lymphocytes play a central therapeutic role in both GvL and immune reconstitution. However, the full exploitation of these therapeutic properties is limited by the occurrence of GvHD. Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GvHD. The genetic engineering of donor lymphocytes with the herpes simplex virus-thymidine kinase (HSV-TK) suicide gene confers the ability to modulate GvHD by invivo ganciclovir-induced elimination of the transduced cells. The suicide-gene strategy has applications in both donor lymphocyte infusion (DLI) for disease relapse and in add-back infusions after T-cell depleted allo-HCT. TK cell DLI resulted in anti-tumor activity in a relevant proportion of treated patients. Haplo-identical stem cell transplantation (haplo-HCT) is a promising therapeutic option for patients with high risk hematologic malignancies lacking an HLA-matched donor. However, the profound T-cell depletion required to overcome the risk of lethal GvHD has been associated with a marked delayed T-cell recovery with a prolonged risk of post-transplant viral, fungal and other opportunistic infections. TK cell add-backs efficiently promote early immune reconstitution after haplo-HCT and prevent disease relapse, providing a unique tool for the control of GvHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allo-HCT. PMID:16040393

  12. Sexual function 1-year after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Noerskov, K H; Schjødt, I; Syrjala, K L; Jarden, M

    2016-06-01

    Treatment with allogeneic hematopoietic stem cell transplantation (HSCT) is associated with short and long-term toxicities that can result in alterations in sexual functioning. The aims of this prospective evaluation were to determine: (1) associations between HSCT and increased sexual dysfunction 1 year after treatment; and (2) associations between sexual dysfunction, body image, anxiety and depression. This controlled prospective cohort study was conducted from October 2010 to November 2013. Patients completed assessments 2-3 weeks before HSCT (N=124) and 1 year after treatment (N=63). Assessment included descriptive data, Sexual Functioning Questionnaire, Body Image Scale and Hospital Anxiety and Depression Scale. The results showed a significant decline in overall sexual function in both men and women (P=<0.001, P=0.010, respectively), although men generally scored higher than women. Forty-seven percent of men and 60% of women reported at least one physical sexual problem 1 year after HSCT. Patients with chronic GVHD trended toward reporting lower levels of sexual function. Finally, women with chronic GVHD scored lower than those without chronic GVHD on the sexual function problem subscale (P=0.008). Sexual dysfunction remains a major problem for men and women 1 year after HSCT and requires routine evaluation and treatment after HSCT. PMID:26878660

  13. Allogenic banking of dental pulp stem cells for innovative therapeutics

    PubMed Central

    Collart-Dutilleul, Pierre-Yves; Chaubron, Franck; De Vos, John; Cuisinier, Frédéric J

    2015-01-01

    Medical research in regenerative medicine and cell-based therapy has brought encouraging perspectives for the use of stem cells in clinical trials. Multiple types of stem cells, from progenitors to pluripotent stem cells, have been investigated. Among these, dental pulp stem cells (DPSCs) are mesenchymal multipotent cells coming from the dental pulp, which is the soft tissue within teeth. They represent an interesting adult stem cell source because they are recovered in large amount in dental pulps with non-invasive techniques compared to other adult stem cell sources. DPSCs can be obtained from discarded teeth, especially wisdom teeth extracted for orthodontic reasons. To shift from promising preclinical results to therapeutic applications to human, DPSCs must be prepared in clinical grade lots and transformed into advanced therapy medicinal products (ATMP). As the production of patient-specific stem cells is costly and time-consuming, allogenic biobanking of clinical grade human leukocyte antigen (HLA)-typed DPSC lines provides efficient innovative therapeutic products. DPSC biobanks represent industrial and therapeutic innovations by using discarded biological tissues (dental pulps) as a source of mesenchymal stem cells to produce and store, in good manufacturing practice (GMP) conditions, DPSC therapeutic batches. In this review, we discuss about the challenges to transfer biological samples from a donor to HLA-typed DPSC therapeutic lots, following regulations, GMP guidelines and ethical principles. We also present some clinical applications, for which there is no efficient therapeutics so far, but that DPSCs-based ATMP could potentially treat. PMID:26328017

  14. [Human Herpesvirus-6 Encephalitis in Allogeneic Hematopoietic Stem Cell Transplantation].

    PubMed

    Ogata, Masao

    2015-07-01

    The reactivation of human herpesvirus-6B (HHV-6B) is common after allogeneic hematopoietic cell transplantation (allo-HCT), and it is sporadically associated with the development of HHV-6 encephalitis. HHV-6 encephalitis typically develops around 2-6 weeks after allo-HCT, and it is characterized by short-term memory loss. Magnetic resonance imaging typically shows bilateral signal abnormalities in the limbic system. The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation. The mortality of HHV-6 encephalitis is high, and survivors are often left with serious sequelae. Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis, but the efficacy of the currently available treatment is insufficient once HHV-6 encephalitis has developed. The elucidation of the pathogenesis of HHV-6 encephalitis and the establishment of preventative therapy are needed to overcome this disease. PMID:26160819

  15. Allogeneic anorectal transplantation in rats: technical considerations and preliminary results.

    PubMed

    Galvão, Flavio H F; Waisberg, Daniel R; Seid, Victor E; Costa, Anderson C L; Chaib, Eleazar; Baptista, Rachel Rossini; Capelozzi, Vera Luiza; Lanchotte, Cinthia; Cruz, Ruy J; Araki, Jun; D'Albuquerque, Luiz Carneiro

    2016-01-01

    Fecal incontinence is a challenging condition with numerous available treatment modalities. Success rates vary across these modalities, and permanent colostomy is often indicated when they fail. For these cases, a novel potential therapeutic strategy is anorectal transplantation (ATx). We performed four isogeneic (Lewis-to-Lewis) and seven allogeneic (Wistar-to-Lewis) ATx procedures. The anorectum was retrieved with a vascular pedicle containing the aorta in continuity with the inferior mesenteric artery and portal vein in continuity with the inferior mesenteric vein. In the recipient, the native anorectal segment was removed and the graft was transplanted by end-to-side aorta-aorta and porto-cava anastomoses and end-to-end colorectal anastomosis. Recipients were sacrificed at the experimental endpoint on postoperative day 30. Surviving animals resumed normal body weight gain and clinical performance within 5 days of surgery. Isografts and 42.9% of allografts achieved normal clinical evolution up to the experimental endpoint. In 57.1% of allografts, signs of immunological rejection (abdominal distention, diarrhea, and anal mucosa inflammation) were observed three weeks after transplantation. Histology revealed moderate to severe rejection in allografts and no signs of rejection in isografts. We describe a feasible model of ATx in rats, which may allow further physiological and immunologic studies. PMID:27488366

  16. Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma.

    PubMed

    Bhatt, Vijaya Raj

    2016-06-01

    Observational studies indicate a similar or higher probability of disease control, higher risk of non-relapse mortality (NRM), and similar overall survival (OS) with allogeneic stem cell transplantation (alloSCT), compared to autologous SCT, in relapsed or refractory non-Hodgkin lymphoma. Careful patient selection and utilization of reduced intensity conditioning (RIC) alloSCT may allow reduction in NRM. The optimal conditioning regimen and the roles of radioimmunotherapy, T cell depletion, and tandem SCT continue to be explored. Recent studies highlight comparable results with haploidentical SCT and cord blood SCT, thus providing alternate donor sources. Disease relapse and late effects continue to be major problems. Optimization of SCT techniques (e.g., improved graft-versus-host disease prophylaxis), post-transplant monitoring of minimal residual disease, and post-transplant maintenance, or pre-emptive therapy (e.g., with novel therapies) are emerging strategies to reduce the risk of relapse. Survivorship management using a multidisciplinary care approach, adoption of healthy lifestyle, and socioeconomic counseling are integral parts of a high-quality transplant program. PMID:26983957

  17. Neutrophil function in children following allogeneic hematopoietic stem cell transplant.

    PubMed

    Kent, Michael W; Kelher, Marguerite R; Silliman, Christopher C; Quinones, Ralph

    2016-08-01

    HSCT is a lifesaving procedure for children with malignant and non-malignant conditions. The conditioning regimen renders the patient severely immunocompromised and recovery starts with neutrophil (PMN) engraftment. We hypothesize that children demonstrate minimal PMN dysfunction at engraftment and beyond, which is influenced by the stem cell source and the conditioning regimen. Peripheral blood was serially collected from children at 1 to 12 months following allogeneic HSCT. PMN superoxide (O2-) production, degranulation (elastase), CD11b surface expression, and phagocytosis were assessed. Twenty-five patients, mean age of 10.5 yr with 65% males, comprised the study and transplant types included: 14 unrelated cord blood stem cells (cords), seven matched related bone marrow donors, three matched unrelated bone marrow donors, and one peripheral blood progenitor cells. Engraftment occurred at 24 days. There were no significant differences between controls and patients in PMN O2- production, phagocytosis, CD11b surface expression, and total PMN elastase. Elastase release was significantly decreased <6 months vs. controls (p < 0.05) and showed normalization by six months for cords only. The conditioning regimen did not affect PMN function. PMN function returns with engraftment, save elastase release, which occurs later related to the graft source utilized, and its clinical significance is unknown. PMID:27114335

  18. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Maffini, Enrico; Giaccone, Luisa; Festuccia, Moreno; Brunello, Lucia; Busca, Alessandro; Bruno, Benedetto

    2016-06-01

    Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation. PMID:27043241

  19. Reduced-intensity conditioned allogeneic SCT in adults with AML.

    PubMed

    Reshef, R; Porter, D L

    2015-06-01

    AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. PMID:25730186

  20. Allogeneic anorectal transplantation in rats: technical considerations and preliminary results

    PubMed Central

    Galvão, Flavio H. F.; Waisberg, Daniel R.; Seid, Victor E.; Costa, Anderson C. L.; Chaib, Eleazar; Baptista, Rachel Rossini; Capelozzi, Vera Luiza; Lanchotte, Cinthia; Cruz, Ruy J.; Araki, Jun; D’Albuquerque, Luiz Carneiro

    2016-01-01

    Fecal incontinence is a challenging condition with numerous available treatment modalities. Success rates vary across these modalities, and permanent colostomy is often indicated when they fail. For these cases, a novel potential therapeutic strategy is anorectal transplantation (ATx). We performed four isogeneic (Lewis-to-Lewis) and seven allogeneic (Wistar-to-Lewis) ATx procedures. The anorectum was retrieved with a vascular pedicle containing the aorta in continuity with the inferior mesenteric artery and portal vein in continuity with the inferior mesenteric vein. In the recipient, the native anorectal segment was removed and the graft was transplanted by end-to-side aorta-aorta and porto-cava anastomoses and end-to-end colorectal anastomosis. Recipients were sacrificed at the experimental endpoint on postoperative day 30. Surviving animals resumed normal body weight gain and clinical performance within 5 days of surgery. Isografts and 42.9% of allografts achieved normal clinical evolution up to the experimental endpoint. In 57.1% of allografts, signs of immunological rejection (abdominal distention, diarrhea, and anal mucosa inflammation) were observed three weeks after transplantation. Histology revealed moderate to severe rejection in allografts and no signs of rejection in isografts. We describe a feasible model of ATx in rats, which may allow further physiological and immunologic studies. PMID:27488366

  1. Suppression of antigen-specific lymphocyte activation in modeled microgravity

    NASA Technical Reports Server (NTRS)

    Cooper, D.; Pride, M. W.; Brown, E. L.; Risin, D.; Pellis, N. R.; McIntire, L. V. (Principal Investigator)

    2001-01-01

    Various parameters of immune suppression are observed in lymphocytes from astronauts during and after a space flight. It is difficult to ascribe this suppression to microgravity effects on immune cells in crew specimens, due to the complex physiological response to space flight and the resultant effect on in vitro immune performance. Use of isolated immune cells in true and modeled microgravity in immune performance tests, suggests a direct effect of microgravity on in vitro cellular function. Specifically, polyclonal activation of T-cells is severely suppressed in true and modeled microgravity. These recent findings suggest a potential suppression of oligoclonal antigen-specific lymphocyte activation in microgravity. We utilized rotating wall vessel (RWV) bioreactors as an analog of microgravity for cell cultures to analyze three models of antigen-specific activation. A mixed-lymphocyte reaction, as a model for a primary immune response, a tetanus toxoid response and a Borrelia burgdorferi response, as models of a secondary immune response, were all suppressed in the RWV bioreactor. Our findings confirm that the suppression of activation observed with polyclonal models also encompasses oligoclonal antigen-specific activation.

  2. Wilms Tumor 1 Expression and Pre-emptive Immunotherapy in Patients with Acute Myeloid Leukemia Undergoing an Allogeneic Hemopoietic Stem Cell Transplantation.

    PubMed

    Di Grazia, Carmen; Pozzi, Sarah; Geroldi, Simona; Grasso, Raffaella; Miglino, Maurizio; Colombo, Nicoletta; Tedone, Elisabetta; Luchetti, Silvia; Lamparelli, Teresa; Gualandi, Francesca; Ibatici, Adalberto; Bregante, Stefania; Van Lint, Maria Teresa; Raiola, Anna Maria; Dominietto, Alida; Varaldo, Riccardo; Galaverna, Federica; Ghiso, Anna; Sica, Simona; Bacigalupo, Andrea

    2016-07-01

    Minimal residual disease (MRD) was monitored by Wilms tumor 1 (WT1) expression in 207 patients with acute myeloid leukemia (AML) after an allogeneic hemopoietic stem cell transplantation (HSCT) as a trigger to initiate pre-emptive immunotherapy (IT) with cyclosporin discontinuation and/or donor lymphocyte infusion. The trigger for IT was WT1 ≥ 180 copies/10(4) Abelson cells in marrow cells in the first group of 122 patients (WT1-180) and ≥ 100 copies in a subsequent group of 85 patients (WT1-100). Forty patients received IT. The cumulative incidence (CI) of relapse was 76% in WT1-180 (n = 17) versus 29% in WT1-100 patients (n = 23) receiving IT (P = .006); the leukemia-free survival from MRD positivity was 23% versus 74%, respectively (P = .003). We then looked at the entire AML patient population (n = 207). WT1-180 and WT1-100 patients were comparable for disease phase and age. The overall 4-year CI of transplantation-related mortality was 13% in both groups; the CI of leukemia relapse was 38% in the WT1-180 and 28% in the WT1-100 patients (P = .05) and leukemia-free survival was 56% versus 48%, respectively (P = .07). In conclusion, we suggests that WT1-based pre-emptive immunotherapy is feasible in patients with undergoing an allogeneic HSCT. The protective effect on relapse is greater when IT is triggered at lower levels of WT1. PMID:26970379

  3. Different immune reconstitution in multiple myeloma, chronic myeloid leukemia and acute myeloid leukemia patients after allogeneic transplantation of peripheral blood stem cells.

    PubMed

    Rondelli, D; Re, F; Bandini, G; Raspadori, D; Arpinati, M; Senese, B; Stanzani, M; Bonifazi, F; Falcioni, S; Chirumbolo, G; Tura, S

    2000-12-01

    In this study we compared the lymphocyte reconstitution in 13 multiple myeloma (MM), nine acute myeloid leukemia (AML) and 10 chronic myeloid leukemia (CML) patients after allogeneic G-CSF-mobilized PBSC transplantation from HLA-identical siblings. Conditioning regimens included standard total body irradiation + cyclophosphamide (CY), or busulphan + CY, whereas VP-16 was added in patients with advanced disease. Overall comparable numbers of mononuclear cells, CD34+ cells and CD3+ T cells were infused in each group. A significantly higher CD3+ T cell number was observed in MM and AML than in CML patients 1 month after transplant. However, MM patients showed a faster and better recovery of CD4+ T cells than both AML and CML patients at 3 months (P = 0.01 and P = 0.01, respectively) and 12 months (P = 0.01 vs AML, while P = NS vs CML) after transplant, and had a CD4:CD8 ratio > 1 with a median CD4+ T cell value > 400/microl 1 year after transplant. Development of acute graft-versus-host disease (GVHD) did not affect CD4:CD8 ratios but patients who experienced acute GVHD > grade I had lower CD4+ and CD8+ T cell numbers at all time points. However, after excluding patients with GVHD > grade I, MM patients still showed a significantly higher CD4+ T cell value than patients with myeloproliferative diseases 1 year after transplant. These findings suggest that although allogeneic PBSC transplantation induces rapid immune reconstitution, different kinetics may occur among patients with hematological malignancies. In particular, the rapid reconstitution of CD4+ T cells in MM patients may contribute to the low transplant-related mortality achieved in this disease. PMID:11223973

  4. Interferon-α: A Potentially Effective Treatment for Minimal Residual Disease in Acute Leukemia/Myelodysplastic Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mo, Xiao-Dong; Zhang, Xiao-Hui; Xu, Lan-Ping; Wang, Yu; Yan, Chen-Hua; Chen, Huan; Chen, Yu-Hong; Han, Wei; Wang, Feng-Rong; Wang, Jing-Zhi; Liu, Kai-Yan; Huang, Xiao-Jun

    2015-11-01

    In this prospective clinical study, the safety and efficacy of preemptive interferon-α (IFN-α) treatment were investigated and compared with preemptive donor lymphocyte infusion (DLI) in patients who were minimal residual disease (MRD)-positive after allogeneic hematopoietic stem cell transplantation (HSCT). Patients undergoing allogeneic HSCT were eligible if they had acute leukemia or myelodysplastic syndrome and were MRD-positive after HSCT. Patients who were able to receive DLI were assigned to a preemptive DLI group (n = 45); patients who could not or did not agree to receive DLI after HSCT received preemptive IFN-α. A total of 22 patients received preemptive IFN-α; the median treatment duration was 35 days (range, 4 to 180 days). Seven patients relapsed, and 1 patient died from severe pneumonia. The 1-year cumulative incidence of chronic graft-versus-host disease (cGVHD) after intervention was 90.9% for the IFN-α group and 62.9% for the DLI group (P < .001). MRD status after preemptive intervention was comparable in the 2 groups, and the 1-year cumulative incidence of relapse after intervention was 27.3% for the IFN-α group and 35.6% for the DLI group (P = .514). The 1-year cumulative incidence of nonrelapse mortality after intervention was 4.5% for the IFN-α group and 4.4% for the DLI group (P = .985). The 1-year probability of disease-free survival after intervention was 68.2% for the IFN-α group and 60.0% for the DLI group (P = .517). In multivariate analysis, early-onset MRD, persistent MRD after intervention, and absence of cGVHD after intervention were significantly associated with poorer clinical outcomes. Thus, preemptive IFN-α may be a potential alternative for MRD-positive patients who cannot receive preemptive DLI after HSCT. PMID:26116088

  5. The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation.

    PubMed

    Mohamed, Yehia S; Bashawri, Layla A; Vatte, Chittibabu; Abu-Rish, Eman Y; Cyrus, Cyril; Khalaf, Wafaa S; Browning, Michael J

    2016-09-01

    Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft-versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA-expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201(+) hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-γ release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235-243, hTERT615-624 or PRAME100-108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting. PMID:27490939

  6. Assessment of genotoxicity of Lannate-90® and its plant and animal metabolites in human lymphocyte cultures.

    PubMed

    Valencia-Quintana, Rafael; Gómez-Arroyo, Sandra; Sánchez-Alarcón, Juana; Milić, Mirta; Olivares, José Luis Gómez; Waliszewski, Stefan M; Cortés-Eslava, Josefina; Villalobos-Pietrini, Rafael; Calderón-Segura, María Elena

    2016-06-01

    This study evaluated direct and metabolic genotoxic effects caused by Lannate-90®, a methomyl-based formulation (90 % active ingredient), in human lymphocyte cultures using sister chromatid exchange assay (SCE). Two processes were used for the plant promutagens evaluation: in vivo activation, applying the insecticide systemically in plants for 4 h and subsequently adding plant metabolites containing extracts to lymphocyte cultures; and in vitro activation, where the insecticide was incubated with Vicia faba S10 mix plus human lymphocyte culture. Direct treatment with the insecticide significantly increased SCE frequency in human lymphocytes (250-750 mgL-1), with cellular death observed at 1000 mgL-1 concentration. Using the extracts of Vicia faba treated with Lannate-90® to treat human lymphocytes, a dose-response relationship was observed. In lymphocyte cultures treated directly with the insecticide for 2 h, a negative response was obtained. When S10 mix was added, SCE frequency did not change significantly. Meanwhile, a mixture of S9 mammalian metabolic mix and Lannate-90® increased the SCE frequency, with an observed concentration-dependent response. Although Lannate-90® induced cellular death at the highest concentrations, it did not cause a delay in cell proliferation in any of the treatments, confirming its genotoxic action. This study is one of the first to evaluate and compare the direct effect of Lannate-90® in two bioassays, animal and vegetal, and the effect of plant and animal metabolism on its genotoxic potential. PMID:27331299

  7. Lymphocytic panniculitis: an algorithmic approach to lymphocytes in subcutaneous tissue.

    PubMed

    Shiau, Carolyn J; Abi Daoud, Marie S; Wong, Se Mang; Crawford, Richard I

    2015-12-01

    The diagnosis of panniculitis is a relatively rare occurrence for many practising pathologists. The smaller subset of lymphocyte-predominant panniculitis is further complicated by the diagnostic consideration of T cell lymphoma involving the subcutaneous tissue, mimicking inflammatory causes of panniculitis. Accurate classification of the panniculitis is crucial to direct clinical management as treatment options may vary from non-medical therapy to immunosuppressive agents to aggressive chemotherapy. Many diseases show significant overlap in clinical and histological features, making the process of determining a specific diagnosis very challenging. However, with an adequate biopsy including skin and deep subcutaneous tissue, a collaborative effort between clinician and pathologist can often lead to a specific diagnosis. This review provides an algorithmic approach to the diagnosis of lymphocyte-predominant panniculitis, including entities of septal-predominant pattern panniculitis (erythema nodosum, deep necrobiosis lipoidica, morphea profunda and sclerosing panniculitis) and lobular-predominant pattern panniculitis (lupus erythematous panniculitis/lupus profundus, subcutaneous panniculitis-like T cell lymphoma, cutaneous γ-δ T cell lymphoma, Borrelia infection and cold panniculitis). PMID:26602413

  8. Effects of Anti-CD45RB Monoclonal Antibody for T Lymphocyte Subsets in Mice Heart Transplantation Model.

    PubMed

    Deng, C-Y; Wang, X-F; Qi, H; Li, F-R

    2016-08-01

    Anti-CD45RB monoclonal antibody (anti-CD45RBmAb), as a new immune tolerance inducer, may inhibit T cell proliferation and induce immune tolerance through competitive combination with CD45RB on the T cell surface, which blocks the conduction of activation signals. However, how anti-CD45RBmAb plays its role on T lymphocyte subsets during immunosuppression remains unclear. In this work, we investigate the effects of anti-CD45RBmAb on CD3(+) T lymphocyte both in vitro and in allogeneic heart transplant model in vivo. Interestingly, anti-CD45RBmAb could inhibit the proliferation of T cells, promote the transformation of T lymphocyte to Treg and Th2 cells, suppress the transformation to Th17 and Th1 cells, increase the number of Ts cells, decrease the number of Tm cells and thus play a role in immune inhibition and induction of immune tolerance. PMID:27146476

  9. Lymphocytic thrombophilic arteritis: an enigma.

    PubMed

    Kalegowda, Inchara Yeliur; Tirumalae, Rajalakshmi; Murthy, K Srinivasa; Rout, Pritilata

    2014-09-01

    A 55-year-old woman presented with a 5-year history of livedo racemosa on her limbs. Histology showed vasculitis of medium-sized arteries with a circumferential, hyalinised, intraluminal fibrin ring. Her laboratory investigations did not indicate any underlying systemic disease. The findings were consistent with lymphocytic thrombophilic arteritis (LTA), alias macular arteritis, which is a recently described entity. The importance of LTA lies in the fact that it is a close clinical and microscopic mimic of polyarteritis nodosa (PAN). LTA is believed to be a distinct entity by some and as a form of PAN by others. We have discussed this case in our report. PMID:25284860

  10. Lymphocytic Thrombophilic Arteritis: An Enigma

    PubMed Central

    Kalegowda, Inchara Yeliur; Tirumalae, Rajalakshmi; Murthy, K Srinivasa; Rout, Pritilata

    2014-01-01

    A 55-year-old woman presented with a 5-year history of livedo racemosa on her limbs. Histology showed vasculitis of medium-sized arteries with a circumferential, hyalinised, intraluminal fibrin ring. Her laboratory investigations did not indicate any underlying systemic disease. The findings were consistent with lymphocytic thrombophilic arteritis (LTA), alias macular arteritis, which is a recently described entity. The importance of LTA lies in the fact that it is a close clinical and microscopic mimic of polyarteritis nodosa (PAN). LTA is believed to be a distinct entity by some and as a form of PAN by others. We have discussed this case in our report. PMID:25284860

  11. Allogenic Blood Transfusion Following Total Hip Arthroplasty: Results from the Nationwide Inpatient Sample, 2000 to 2009

    PubMed Central

    Saleh, Anas; Small, Travis; Chandran Pillai, Aiswarya Lekshmi Pillai; Schiltz, Nicholas K.; Klika, Alison K.; Barsoum, Wael K.

    2014-01-01

    Background: The large-scale utilization of allogenic blood transfusion and its associated outcomes have been described in critically ill patients and those undergoing high-risk cardiac surgery but not in patients undergoing elective total hip arthroplasty. The objective of this study was to determine the trends in utilization and outcomes of allogenic blood transfusion in patients undergoing primary total hip arthroplasty in the United States from 2000 to 2009. Methods: An observational cohort of 2,087,423 patients who underwent primary total hip arthroplasty from 2000 to 2009 was identified in the Nationwide Inpatient Sample. International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes 99.03 and 99.04 were used to identify patients who received allogenic blood products during their hospital stay. Risk factors for allogenic transfusions were identified with use of multivariable logistic regression models. We used propensity score matching to estimate the adjusted association between transfusion and surgical outcomes. Results: The rate of allogenic blood transfusion increased from 11.8% in 2000 to 19.0% in 2009. Patient-related risk factors for receiving an allogenic blood transfusion include an older age, female sex, black race, and Medicaid insurance. Hospital-related risk factors include rural location, smaller size, and non-academic status. After adjusting for confounders, allogenic blood transfusion was associated with a longer hospital stay (0.58 ± 0.02 day; p < 0.001), increased costs ($1731 ± $49 [in 2009 U.S. dollars]; p < 0.001), increased rate of discharge to an inpatient facility (odds ratio, 1.28; 95% confidence interval, 1.26 to 1.31), and worse surgical and medical outcomes. In-hospital mortality was not affected by allogenic blood transfusion (odds ratio, 0.97; 95% confidence interval, 0.77 to 1.21). Conclusions: The increase in allogenic blood transfusion among total hip arthroplasty patients is concerning

  12. Autologous and allogeneic hematopoietic stem cell transplantation for Multiple Sclerosis: perspective on mechanisms of action.

    PubMed

    Van Wijmeersch, Bart; Sprangers, Ben; Dubois, Bénédicte; Waer, Mark; Billiau, An D

    2008-07-15

    Multiple Sclerosis (MS) is a frequent demyelinating immune-mediated disease of the central nervous system (CNS) that affects principally young adults and leads to severe physical and cognitive impairment. The current standard treatment makes use of the immune modulators beta-interferon, glatiramer acetate and natalizumab, or immunosuppressants such as mitoxantrone. However, these agents are only partially effective and in a number of patients fail to achieve satisfactory disease control. Autologous hematopoietic stem cell transplantation (HSCT) is being explored in the treatment of severe MS as a means of delivering high-dose immunosuppression followed by 'rescue' of the immuno-hematopoietic system with autologous HSC. The potential therapeutic benefit is based on the concept of so-called 'resetting' the immune system. The use of allogeneic HSCT as a possible therapeutic approach for severe MS is inspired by case reports of MS patients that underwent allogeneic HSCT for a concomitant hematological malignancy, and subsequently is supported by data from rodent models of MS. Allogeneic HSCT may offer specific therapeutic effects, such as the replacement of the autoreactive immune compartment by healthy allogeneic cells and the development of a graft-versus-autoimmunity (GVA) effect. Here, we review the currently available experimental and clinical evidence to support the role of autologous and allogeneic HSCT in MS. PMID:18541311

  13. Allogeneic T cell responses are regulated by a specific miRNA-mRNA network

    PubMed Central

    Sun, Yaping; Tawara, Isao; Zhao, Meng; Qin, Zhaohui S.; Toubai, Tomomi; Mathewson, Nathan; Tamaki, Hiroya; Nieves, Evelyn; Chinnaiyan, Arul M.; Reddy, Pavan

    2013-01-01

    Donor T cells that respond to host alloantigens following allogeneic bone marrow transplantation (BMT) induce graft-versus-host (GVH) responses, but their molecular landscape is not well understood. MicroRNAs (miRNAs) regulate gene (mRNA) expression and fine-tune the molecular responses of T cells. We stimulated naive T cells with either allogeneic or nonspecific stimuli and used argonaute cross-linked immunoprecipitation (CLIP) with subsequent ChIP microarray analyses to profile miR responses and their direct mRNA targets. We identified a unique expression pattern of miRs and mRNAs following the allostimulation of T cells and a high correlation between the expression of the identified miRs and a reduction of their mRNA targets. miRs and mRNAs that were predicted to be differentially regulated in allogeneic T cells compared with nonspecifically stimulated T cells were validated in vitro. These analyses identified wings apart-like homolog (Wapal) and synaptojanin 1 (Synj1) as potential regulators of allogeneic T cell responses. The expression of these molecular targets in vivo was confirmed in MHC-mismatched experimental BMT. Targeted silencing of either Wapal or Synj1 prevented the development of GVH response, confirming a role for these regulators in allogeneic T cell responses. Thus, this genome-wide analysis of miRNA-mRNA interactions identifies previously unrecognized molecular regulators of T cell responses. PMID:24216511

  14. Allogeneic Transplantation for Patients With Acute Leukemia or Chronic Myelogenous Leukemia (CML)

    ClinicalTrials.gov

    2016-06-14

    Leukemia, Lymphocytic, Acute; Leukemia; Leukemia Acute Promyelocytic Leukemia (APL); Leukemia Acute Lymphoid Leukemia (ALL); Leukemia Chronic Myelogenous Leukemia (CML); Leukemia Acute Myeloid Leukemia (AML); Leukemia Chronic Lymphocytic Leukemia (CLL)

  15. Lymphocyte apoptosis in murine Pneumocystis pneumonia

    PubMed Central

    Shi, Xin; LeCapitaine, Nicole J; Rudner, Xiaowen L; Ruan, Sanbao; Shellito, Judd E

    2009-01-01

    Background Apoptosis of lymphocytes is important in the termination of an immune response to infection but has also been shown to have detrimental effects in animal models of systemic infection and sepsis. We sought to characterize lymphocyte apoptosis in an animal model of pneumonia due to Pneumocystis murina, an infection localized to the lungs. Methods Control mice and mice depleted of CD4+ lymphocytes were inoculated with Pneumocystis. Apoptosis of lung and spleen lymphocytes was assayed by flow cytometry and PCR assay of apoptotic proteins. Results In control mice, apoptosis of lung lymphocytes was maximal just after the infection was cleared from lung tissue and then declined. However, in CD4-depleted mice, apoptosis was also upregulated in recruited lymphocytes in spite of progressive infection. In splenic lymphocytes, apoptosis was observed early at 1 week after inoculation and then declined. Apoptosis of lung lymphocytes in control mice was associated with a decrease in mRNA for Bcl-2 and an increase in mRNA for Bim. In CD4-depleted mice, lavaged CD8+ cells did change intracellular Bcl-2 but showed increased mRNA for Bim. Conclusion Apoptosis of both pulmonary and extrapulmonary lymphocytes is part of the normal host response to Pneumocystis but is also triggered in CD4-deficient animals with progressive infection. In normal mice apoptosis of pulmonary lymphocytes may serve to terminate the immune response in lung tissue. Apoptosis of lung lymphocytes takes place via both the intrinsic and extrinsic apoptotic pathways and is associated with changes in both pro- and anti-apoptotic proteins. PMID:19558669

  16. Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation

    SciTech Connect

    Ikehara, S.; Yasumizu, R.; Inaba, M.; Izui, S.; Hayakawa, K.; Sekita, K.; Toki, J.; Sugiura, K.; Iwai, H.; Nakamura, T. )

    1989-05-01

    Long-term effects of allogeneic bone marrow transplantation (ABMT) across major histocompatibility complex barriers were studied in (NZB x NZW)F1 (B/W), BXSB, and MRL/Mr-lpr-lpr (MRL/lpr) mice with established autoimmune disease at the time of ABMT. In the BXSB or B/W mice, ABMT cured all aspects of autoimmune disease. Glomerular damage, revealed by histological study was dramatically improved. Serological abnormalities and immunologic functions also were normalized. Correction of autoimmune disease and advanced renal disease in BXSB and B/W mice regularly lasted greater than 5-6 mo and even 1 yr after ABMT. In the MRL/lpr mice, however, autoimmune and renal disease at first improved but then recurred after ABMT, apparently because of intolerance of mice for high doses of irradiation and a high degree of resistance of recipient stem cells to irradiation. In this model, H-2 typing revealed that by the time of relapse, immunocompetent cells of the chimeric mice had been replaced by host (MRL/lpr; H-2k) cells. B220+ Ly-1+ cells, present in increased numbers in untreated MRL/lpr mice, initially returned to normal levels after ABMT but then reappeared in the MRL/lpr mice that had received marrow from donors having few such lymphocytes. Thus, our results show that MRL/lpr mice possess abnormal radioresistant stem cells and provide impressive evidence that the origin of autoimmune diseases in this strain, as in the several other strains studied, resids in abnormalities present in stem cells.

  17. Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

    SciTech Connect

    Torpey, D.J. III

    1987-01-01

    Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with /sup 51/Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant.

  18. Long-Term Outcomes of Patients with Persistent Indolent B-cell Malignancies Undergoing Nonmyeloablative Allogeneic Transplantation

    PubMed Central

    Cassaday, Ryan D.; Storer, Barry E.; Sorror, Mohamed L.; Sandmaier, Brenda M.; Guthrie, Katherine A.; Maloney, David G.; Rajendran, Joseph G.; Pagel, John M.; Flowers, Mary E.; Green, Damian J.; Rezvani, Andrew R.; Storb, Rainer F.; Press, Oliver W.; Gopal, Ajay K.

    2015-01-01

    Relapse is least common in patients with indolent B-cell malignancies (iB-NHL) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR prior to NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia (CLL) treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease prior to NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small lymphocytic lymphoma/CLL (N = 62) and follicular lymphoma (N = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 (20%), who more frequently had chemoresistant disease (81% vs 39%, P = 0.003), disease bulk >5 cm (61% vs 15%, P <0.001), thrombocytopenia <25k/µL (33% vs 7%, P = 0.002), and Hematopoietic Cell Transplant Comorbidity Index scores of ≥3 (72% vs 37%, P = 0.006). After adjusting for these imbalances, RIT-treated patients had improved PFS (HR = 0.4, 95% CI: 0.2–0.9, P = 0.02) and OS (HR = 0.3, 95% CI: 0.1–0.8, P = 0.008) compared to the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87%, vs 44% and 59% (respectively). The use of RIT was the only factor independently associated with improved PFS and OS. Rates of non-relapse mortality and graft-versus-host disease (GVHD) were similar between the two groups, though over 70% of patients developed clinically-significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT. PMID:25445025

  19. What Are the Key Statistics about Acute Lymphocytic Leukemia?

    MedlinePlus

    ... lymphocytic leukemia? What are the key statistics about acute lymphocytic leukemia? The American Cancer Society’s estimates for acute lymphocytic leukemia (ALL) in the United States for 2016 (including ...

  20. What's New in Chronic Lymphocytic Leukemia Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for chronic lymphocytic leukemia What`s new in chronic lymphocytic leukemia research and treatment? Many ... person's outlook and whether they will need treatment. New drugs for chronic lymphocytic leukemia Dozens of new ...

  1. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation

    PubMed Central

    Dhakal, B.; D'Souza, A.; Pasquini, M.; Saber, W.; Fenske, T. S.; Moss, R. B.; Drobyski, W. R.; Hari, P.; Abidi, M. Z.

    2016-01-01

    Parainfluenza virus (PIV) may cause life-threatening pneumonia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Currently, there are no proven effective therapies. We report the use of inhaled DAS181, a novel sialidase fusion protein, for treatment of PIV type 3 pneumonia in two allogeneic hematopoietic SCT recipients with respiratory failure. PMID:26941799

  2. Ultraviolet irradiation of platelet concentrate abrogates lymphocyte activation without affecting platelet function in vitro

    SciTech Connect

    Kahn, R.A.; Duffy, B.F.; Rodey, G.G.

    1985-11-01

    We studied the effect of ultraviolet (UV) radiation on platelet concentrates. Samples irradiated at 310 mm for 30 minutes at a dose of 1782 J per m2 showed no loss of platelet function in vitro as determined by adenosine diphosphate, collagen, or ristocetin-induced aggregation. Lymphocytes isolated from irradiated units were unable to act as responders or stimulators in a mixed-lymphocyte reaction. These data suggest that UV radiation of platelet concentrates may result in a cell suspension that is unable to evoke an immunological response.

  3. Percutaneous Vertebroplasty Using Fresh Frozen Allogeneic Bone Chips as Filler

    PubMed Central

    Lee, Song; Kim, Dae Geun; Shin, Won Sik

    2014-01-01

    Background Vertebroplasty is not free from cement related complications. If an allograft is used as a filler, most of them can be averted. Methods Forty consecutive cases of osteoporotic vertebral fracture were divided into two groups by self-selection. The study and the control groups underwent vertebroplasty with fresh frozen allogeneic bone chips and bone cement, respectively. Clinical results were assessed at preoperation, postoperative day 1 and months 3, 6, and 12 by 10-grade visual analog scale (VAS), and radiological results were assessed at the same time by vertebral kyphotic angle (VKA) and local kyphotic angle (LKA). The results were compared within and between the groups. Survival function was analyzed. The criteria of an event were clinical or radiological deterioration versus pre-index surgery state. Results VAS was improved in the study group from 8.4 ± 0.8 to 5.2 ± 1.4, 6.4 ± 1.2, 5.5 ± 2.7, and 3.7 ± 1.4 at postoperative day 1 and months 3, 6, and 12, respectively, and in the control group from 8.4 ± 1.2 to 3.2 ± 1.1, 3.2 ± 1.7, 3.2 ± 2.7, and 2.5 ± 1.7, respectively (within group, p < 0.001; between groups, p < 0.001). VKA was improved in the study group from 18.9° ± 8.0° to 15.2° ± 6.1° (p = 0.046) and in the control group from 14.7° ± 5.2° to 10.3° ± 4.7° (p < 0.001) at postoperative day 1. LKA was not improved in the study group but was improved in the control group from 16.8° ± 11.7° to 14.3° ± 9.6° (p = 0.015). Correction angle was 2.7° ± 4.6°, -7.9° ± 5.3°, -7.2° ± 5.2°, and -7.4° ± 6.3° at postoperative day 1 and months 3, 6, and 12, respectively, in the study group and 4.3° ± 3.7°, 0.7° ± 3.6°, 0.7° ± 4.2°, and 0.1° ± 4.4°, respectively, in the control group. Correction loss was significant in both groups (p < 0.001) and more serious in the study group (p < 0.001). The 6-month survival rate was 16.7% in the study group and 64.3% in the control group (p = 0.003; odds ratio, 5

  4. Alternative procedures for reducing allogeneic blood transfusion in elective orthopedic surgery.

    PubMed

    Kleinert, Kathrin; Theusinger, Oliver M; Nuernberg, Johannes; Werner, Clément M L

    2010-09-01

    Perioperative blood loss is a major problem in elective orthopedic surgery. Allogeneic transfusion is the standard treatment for perioperative blood loss resulting in low postoperative hemoglobin, but it has a number of well-recognized risks, complications, and costs. Alternatives to allogeneic blood transfusion include preoperative autologous donation and intraoperative salvage with postoperative autotransfusion. Orthopedic surgeons are often unaware of the different pre- and intraoperative possibilities of reducing blood loss and leave the management of coagulation and use of blood products completely to the anesthesiologists. The goal of this review is to compare alternatives to allogeneic blood transfusion from an orthopedic and anesthesia point of view focusing on estimated costs and acceptance by both parties. PMID:21886535

  5. Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go?

    PubMed

    Mamidi, Murali Krishna; Dutta, Susmita; Bhonde, Ramesh; Das, Anjan Kumar; Pal, Rajarshi

    2014-12-01

    Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue. PMID:25456787

  6. Allogenic sedimentary components of Bear Lake, Utah and Idaho

    USGS Publications Warehouse

    Rosenbaum, J.G.; Dean, W.E.; Reynolds, R.L.; Reheis, M.C.

    2009-01-01

    Bear Lake is a long-lived lake filling a tectonic depression between the Bear River Range to the west and the Bear River Plateau to the east, and straddling the border between Utah and Idaho. Mineralogy, elemental geochemistry, and magnetic properties provide information about variations in provenance of allogenic lithic material in last-glacial-age, quartz-rich sediment in Bear Lake. Grain-size data from the siliciclastic fraction of late-glacial to Holocene carbonate-rich sediments provide information about variations in lake level. For the quartz-rich lower unit, which was deposited while the Bear River fl owed into and out of the lake, four source areas are recognized on the basis of modern fluvial samples with contrasting properties that reflect differences in bedrock geology and in magnetite content from dust. One of these areas is underlain by hematite-rich Uinta Mountain Group rocks in the headwaters of the Bear River. Although Uinta Mountain Group rocks make up a small fraction of the catchment, hematite-rich material from this area is an important component of the lower unit. This material is interpreted to be glacial fl our. Variations in the input of glacial flour are interpreted as having caused quasi-cyclical variations in mineralogical and elemental concentrations, and in magnetic properties within the lower unit. The carbonate-rich younger unit was deposited under conditions similar to those of the modern lake, with the Bear River largely bypassing the lake. For two cores taken in more than 30 m of water, median grain sizes in this unit range from ???6 ??m to more than 30 ??m, with the coarsest grain sizes associated with beach or shallow-water deposits. Similar grain-size variations are observed as a function of water depth in the modern lake and provide the basis for interpreting the core grain-size data in terms of lake level. Copyright ?? 2009 The Geological Society of America.

  7. Intravenous Tranexamic Acid Decreases Allogeneic Transfusion Requirements in Periacetabular Osteotomy.

    PubMed

    Bryan, Andrew J; Sanders, Thomas L; Trousdale, Robert T; Sierra, Rafael J

    2016-01-01

    Bernese (Ganz) periacetabular osteotomy is associated with significant blood loss and the need for perioperative transfusion. Tranexamic acid decreases blood loss and minimizes transfusion rates in total joint arthroplasty. However, no reports have described its use in patients undergoing Bernese periacetabular osteotomy. This study reports the use of intravenous tranexamic acid in these patients. The study included 137 patients (150 hips) who underwent isolated periacetabular osteotomy at a single institution between 2003 and 2014. Of these, 68 patients (75 hips) received intravenous tranexamic acid 1 g at the time of incision and 1 g at the time of closure. A group of 69 patients (75 hips) served as control subjects who underwent periacetabular osteotomy without administration of intravenous tranexamic acid. Thromboembolic disease was defined as deep venous thrombosis or pulmonary embolism occurring within 6 weeks of surgery. Outcomes measured included transfusion requirements, pre- and postoperative hemoglobin values, operative times, and thromboembolic disease rates. Aspirin was used as the thromboembolic prophylactic regimen in 95% of patients. The rate of allogeneic transfusion was 0 in the tranexamic acid group compared with 21% in the control group (P=.0001). No significant difference was found in the autologous cell salvage requirement (.96 vs 1.01; P=.43) or the thromboembolic disease rate between the tranexamic acid group and the control group (2.67% vs 1.33%; P=.31). The use of intravenous tranexamic acid led to a decreased transfusion requirement with no increased risk of thromboembolic disease in this contemporary cohort of patients undergoing periacetabular osteotomy. PMID:26726988

  8. Intrasplenic transplantation of allogeneic hepatocytes prolongs survival in anhepatic rats.

    PubMed

    Arkadopoulos, N; Lilja, H; Suh, K S; Demetriou, A A; Rozga, J

    1998-11-01

    To examine whether hepatocytes transplanted in the spleen can function as an ectopic liver, we performed hepatocyte transplantation in rats that were rendered anhepatic. Total hepatectomy was performed by using a novel single-stage technique. Following hepatectomy, Group 1 rats (n = 16) were monitored until death to determine survival time without prior intervention. Group 2 anhepatic rats (n = 20) were sacrificed at various times to measure blood hepatocyte growth factor (HGF) and transforming growth factor beta1 (TGF-beta1) levels. Group 3 (n = 16) rats received intrasplenic injection of isolated hepatocytes (2.5 x 10(7) cells/rat) followed by total hepatectomy after 3 days. Group 4 (n = 12) sham-transplanted rats received intrasplenic saline infusion, and after 3 days they were rendered anhepatic. Group 2, 3, and 4 rats were maintained on daily Cyclosporine A (10 mg/kg; intramuscularly). Group 1 anhepatic rats survived for 22.4 +/- 5.2 hours (standard deviation). The anhepatic state was associated with a progressive and statistically significant rise in blood HGF and TGF-beta1 levels. Rats that received hepatocyte transplantation before total hepatectomy had a significantly longer survival time than sham-transplanted anhepatic controls (34.1 +/- 8.5 vs. 15.5 +/- 4.8 hrs, P < .01). Additionally, at 12 hours post-hepatectomy, transplanted rats had significantly lower blood ammonia, prothrombin time, international normalized ratio, and TGF-beta1 levels when compared with sham-transplanted controls. In conclusion, intrasplenic transplantation of allogeneic hepatocytes prolonged survival, improved blood chemistry, and lowered blood TGF-beta1 levels in rats rendered anhepatic. PMID:9794923

  9. Immune Reconstitution after Allogeneic Hematopoietic Cell Transplantation in Children.

    PubMed

    de Koning, Coco; Plantinga, Maud; Besseling, Paul; Boelens, Jaap Jan; Nierkens, Stefan

    2016-02-01

    Allogeneic (allo) hematopoietic cell transplantation (HCT) has evolved into a potent curative treatment option for a variety of malignant and nonmalignant diseases. The occurrence of complications and mortality after allo-HCT is, however, still high and is strongly associated with immune reconstitution (IR). Therefore, detailed information on IR through immunomonitoring is crucial to improve survival chances after HCT. To date, information about the reconstituting immune system after allo-HCT in pediatric patients is mostly derived from routine standard-of-care measurements. More profound knowledge on IR may provide tools to better predict and modulate adverse reactions and, subsequently, improve survival chances. Here, we provide an overview of IR (eg, immune cell subsets and circulating chemokines/cytokines) after allo-HCT in children, taking into account different cell sources and serotherapy, and discuss strategies to enhance immunomonitoring. We conclude that available IR data after allo-HCT contain limited information on immune cell families (mostly only generic T, B, and NK cells), which would improve with more detailed information on reconstituting cell subsets or effector cell functionality at earlier time points (<1 month). In addition, secretome data (eg, multiplex cytokine/chemokine profiles) could add to the understanding of IR mechanisms and cell functionality and may even provide (early) biomarkers for individual disease outcome, such as viral reactivity, graft-versus-host disease, or graft-versus-leukemia. The present data and suggestions for more detailed, standardized, and harmonized immunomonitoring in future (pediatric) allo-HCT studies will pave the path to "precision transplantation:" an individualized HCT approach (including conditioning), based on detailed information on IR and biomarkers, aiming to reduce transplantation related mortality and relapse, and subsequently improve survival chances. PMID:26341398

  10. Other Malignancies in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

    PubMed Central

    Tsimberidou, Apostolia-Maria; Wen, Sijin; McLaughlin, Peter; O'Brien, Susan; Wierda, William G.; Lerner, Susan; Strom, Sara; Freireich, Emil J; Medeiros, L. Jeffrey; Kantarjian, Hagop M.; Keating, Michael J.

    2009-01-01

    Purpose Other malignancies have been reported to occur with increased frequency in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The aim of this study was to determine the frequency, outcomes, and factors associated with other cancers in patients with CLL/SLL. Patients and Methods We reviewed the records of consecutive patients with previously untreated CLL/SLL seen at The University of Texas M. D. Anderson Cancer Center from 1985 to 2005. The number of second cancers observed was compared with the number expected from the Surveillance, Epidemiology, and End Results database. Results Among 2,028 patients, 324 (16%) had a history of other cancers and 227 (11.2%) developed other malignancies during the follow-up period. Overall, 625 cancers were observed in 551 patients, including skin (30%), prostate (13%), breast (9%), melanoma (8%), lymphoma (8%), gastrointestinal (9%), lung (6%), and other cancers (17%). The risk of a second cancer was 2.2 times higher than the expected risk. The response rates in patients with and without a history of other cancers were 86% and 92%, respectively (P = .04), and the 5-year survival rates were 70% and 82%, respectively (P < .001). In Cox analysis, independent factors predicting development of new cancers were older age, male sex, and elevated levels of β2-microglobulin, lactate dehydrogenase, and creatinine. In patients who were treated for CLL/SLL, the treatment regimen did not affect the risk of subsequent cancer (P = .49). Conclusion Patients with CLL/SLL have more than twice the risk of developing a second cancer and an increased frequency of certain cancer types. Awareness of risk factors could permit early detection. PMID:19114699

  11. Splenic lymphoma with circulating villous lymphocytes.

    PubMed Central

    Imbing, F; Kumar, D; Kumar, S; Yuoh, G; Gardner, F

    1995-01-01

    This report describes the occurrence of splenic lymphoma with villous lymphocytes (SLVL) in a 56 year old white female with a family history of chronic lymphocytic leukaemia. Other unusual features included a marked lymphocytosis with counts up to 224 x 10(9)/l and marked clumping of lymphocytes in EDTA anticoagulated blood. The neoplastic cells were CD19+, CD20+, CD22+, CD22+, IgM+, lambda+, kappa-, CD5-, and CD10-. The spleen had nodular infiltrates of B lymphocytes in the region of the white pulp with minimal red pulp involvement. Electron microscopy of peripheral blood lymphocytes revealed cells with polar cytoplasmic processes. This report underlines the need for detailed analysis, including morphology and immunophenotyping, for each patient with a small B cell lymphoproliferative disorder. Images PMID:7665709

  12. Risk Factors for the Postoperative Transfusion of Allogeneic Blood in Orthopedics Patients With Intraoperative Blood Salvage

    PubMed Central

    Tang, Jia-Hua; Lyu, Yi; Cheng, Li-Ming; Li, Ying-Chuan; Gou, Da-Ming

    2016-01-01

    Abstract The purpose of this study is to explore the risk factors affecting the postoperative transfusion of allogeneic blood in patients undergoing orthopedics surgery with intraoperative blood salvage (IBS). A retrospective study of 279 patients undergoing orthopedic surgeries with IBS from May 2013 to May 2015 was enrolled. The binary logistic regression was used to find out the risk factors associated with postoperative transfusion of allogeneic blood in orthopedics patients with IBS, and then receiver operating characteristic (ROC) curve was drawn to determine the optimal threshold of the regression model. Single factor analysis showed that age, American Society of Anesthesiologists (ASA) grade, preoperative hemoglobin, operation time, received autologous blood, the laying time of autologous blood, bleeding volume, and postoperative drainage volume had significant effects on postoperative allogeneic blood transfusion. In binary logistic regression analysis, the independent factors predicting orthopedic patients with IBS need to transfuse allogeneic blood after surgeries were age (odds ratio [OR] = 0.415, P = 0.006), ASA grade (OR = 2.393, P = 0.035), preoperative hemoglobin (OR = 0.532, P = 0.022), and postoperative drainage volume (OR = 4.279, P = 0.000). The area under ROC curve was 0.79 and the predicted accuracy rate of the model was 81.58%. After operation, the orthopedic patients with IBS still have a high allogeneic blood transfusion rate, and IBS is not a perfect blood protection method. The logistic regression model of our study provides a reliable prediction for postoperative transfusion of allogeneic blood in orthopedic patients with IBS, which have a certain reference value. PMID:26937919

  13. Nivolumab and Urelumab Enhance Antitumor Activity of Human T Lymphocytes Engrafted in Rag2-/-IL2Rγnull Immunodeficient Mice.

    PubMed

    Sanmamed, Miguel F; Rodriguez, Inmaculada; Schalper, Kurt A; Oñate, Carmen; Azpilikueta, Arantza; Rodriguez-Ruiz, Maria E; Morales-Kastresana, Aizea; Labiano, Sara; Pérez-Gracia, Jose L; Martín-Algarra, Salvador; Alfaro, Carlos; Mazzolini, Guillermo; Sarno, Francesca; Hidalgo, Manuel; Korman, Alan J; Jure-Kunkel, Maria; Melero, Ignacio

    2015-09-01

    A current pressing need in cancer immunology is the development of preclinical model systems that are immunocompetent for the study of human tumors. Here, we report the development of a humanized murine model that can be used to analyze the pharmacodynamics and antitumor properties of immunostimulatory monoclonal antibodies (mAb) in settings where the receptors targeted by the mAbs are expressed. Human lymphocytes transferred into immunodeficient mice underwent activation and redistribution to murine organs, where they exhibited cell-surface expression of hCD137 and hPD-1. Systemic lymphocyte infiltrations resulted in a lethal CD4(+) T cell-mediated disease (xenograft-versus-host disease), which was aggravated when murine subjects were administered clinical-grade anti-hCD137 (urelumab) and anti-hPD-1 (nivolumab). In mice engrafted with human colorectal HT-29 carcinoma cells and allogeneic human peripheral blood mononuclear cells (PBMC), or with a patient-derived gastric carcinoma and PBMCs from the same patient, we found that coadministration of urelumab and nivolumab was sufficient to significantly slow tumor growth. Correlated with this result were increased numbers of activated human T lymphocytes producing IFNγ and decreased numbers of human regulatory T lymphocytes in the tumor xenografts, possibly explaining the efficacy of the therapeutic regimen. Our results offer a proof of concept for the use of humanized mouse models for surrogate efficacy and histology investigations of immune checkpoint drugs and their combinations. PMID:26113085

  14. I-131-Metaiodobenzylguanidine therapy with allogeneic cord blood stem cell transplantation for recurrent neuroblastoma.

    PubMed

    Sato, Yuya; Kurosawa, Hidemitsu; Fukushima, Keitaro; Okuya, Mayuko; Hagisawa, Susumu; Sugita, Kenichi; Arisaka, Osamu; Inaki, Anri; Wakabayashi, Hiroshi; Nakamura, Ayane; Fukuoka, Makoto; Kayano, Daiki; Kinuya, Seigo

    2012-01-01

    Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible. PMID:23067429

  15. Autologous is Superior to Allogeneic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission

    PubMed Central

    Chakrabarty, Jennifer L. Holter; Rubinger, Morel; Le-Rademacher, Jennifer; Wang, Hai-Lin; Grigg, Andrew; Selby, George B.; Szer, Jeffrey; Rowe, Jacob M.; Weisdorf, Daniel J.; Tallman, Martin S.

    2014-01-01

    PURPOSE To identify favored choice of transplantation in patients with acute promyelocytic leukemia in second complete remission. PATIENTS We studied 294 acute promyelocytic leukemia (APL) patients receiving allogeneic (n=232) or autologous (62) hematopoietic cell transplantation (HCT) in second complete remission (CR2) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006 including pre-HCT PML/RAR∝ status in 155 (49% of allogeneic and 66% of autologous). METHODS Patient characteristics and transplant characteristics including treatment related mortality, overall survival, and disease free survival were collected and analyzed for both univariate and multivariate outcomes. RESULTS With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous 63% (49-75%) compared to allogeneic 50% (44-57%) (p=0.10) and overall survival (OS) 75% (63-85%) vs. 54% (48-61%) (p=.002) Multivariate analysis showed significantly worse DFS after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011) and age >40 years (HR=2.30, 95% CI 1.44-3.67, p=0.0005). OS was significantly worse after allogeneic HCT (HR=2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and CR1<12 months (HR=1.56 95% CI 1.07-2.26, p=0.021). Positive pre-HCT PML-RAR∝ status in 17/114 allogeneic and 6/41 autologous transplants did not influence relapse, treatment failure or survival in either group. The survival advantage for autografting was attributable to increased 3 years TRM: allogeneic 30%; autologous 2%, and GVHD. CONCLUSION We conclude that autologous HCT yields superior overall survival for APL in CR2. Long term DFS in autologous recipients, even with MRD+ grafts remains an important subject for further study. PMID:24691221

  16. Mesenchymal Stromal Cells Protect Endothelial Cells from Cytotoxic T Lymphocyte-Induced Lysis.

    PubMed

    Cahill, E F; Sax, T; Hartmann, I; Haffner, S; Holler, E; Holler, B; Huss, R; Günther, C; Parolini, O; Kolch, W; Eissner, G

    2016-09-01

    The integrity of the vasculature plays an important role in the success of allogeneic organ and haematopoietic stem cell transplantation. Endothelial cells (EC) have previously been shown to be the target of activated cytotoxic T lymphocytes (CTL) resulting in extensive cell lysis. Mesenchymal stromal cells (MSC) are multipotent cells which can be isolated from multiple sites, each demonstrating immunomodulatory capabilities. They are explored herein for their potential to protect EC from CTL-targeted lysis. CD8(+) T cells isolated from human PBMC were stimulated with mitotically inactive cells of a human microvascular endothelial cell line (CDC/EU.HMEC-1, further referred to as HMEC) for 7 days. Target HMEC were cultured in the presence or absence of MSC for 24 h before exposure to activated allogeneic CTL for 4 h. EC were then analysed for cytotoxic lysis by flow cytometry. Culture of HMEC with MSC in the efferent immune phase (24 h before the assay) led to a decrease in HMEC lysis. This lysis was determined to be MHC Class I restricted linked and further analysis suggested that MSC contact is important in abrogation of lysis, as protection is reduced where MSC are separated in transwell experiments. The efficacy of multiple sources of MSC was also confirmed, and the collaborative effect of MSC and the endothelium protective drug defibrotide were determined, with defibrotide enhancing the protection provided by MSC. These results support the use of MSC as an adjuvant cellular therapeutic in transplant medicine, alone or in conjunction with EC protective agents such as defibrotide. PMID:27384426

  17. Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation.

    PubMed

    Davis, Zachary B; Cooley, Sarah A; Cichocki, Frank; Felices, Martin; Wangen, Rose; Luo, Xianghua; DeFor, Todd E; Bryceson, Yenan T; Diamond, Don J; Brunstein, Claudio; Blazar, Bruce R; Wagner, John E; Weisdorf, Daniel J; Horowitz, Amir; Guethlein, Lisbeth A; Parham, Peter; Verneris, Michael R; Miller, Jeffrey S

    2015-09-01

    Cytomegalovirus (CMV) reactivates in >30% of CMV-seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of natural killer (NK) cells expressing NKG2C, CD57, and inhibitory killer cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation after HCT. These NK cells persist after the resolution of infection and display "adaptive" or memory properties. Despite these findings, the differential impact of persistent/inactive versus reactivated CMV on NK versus T cell maturation after HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pretransplantation CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an adaptive phenotype (NKG2C(+)CD57(+)). Compared with CMV-seronegative recipients, those who reactivated CMV had the highest adaptive cell frequencies, whereas intermediate frequencies were observed in CMV-seropositive recipients harboring persistent/nonreplicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV-seropositive recipients of sibling but not UCB grafts and were correlated with lower rates of CMV reactivation (sibling 33% versus UCB 51%; P < .01). These data suggest that persistent/nonreplicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. PMID:26055301

  18. Different deoxyribonucleases in human lymphocytes

    PubMed Central

    Zöllner, E.Jürgen; Helm, Wolfgang; Zahn, Rudolf K.; Beck, Jörn; Reltz, Manfred

    1974-01-01

    The distribution pattern of deoxyribonuclease activities in human lymphocytes has been examined by micro-disc-electrophoresis. Four groups of deoxyribonuclease activities, differing in their electrophoretic mobility, in the nature of their optimal substrate and in their optimal incubation conditions, are characterized. There are two alkaline DNase-activities. One corresponds to DNase I (EC 3.1.4.5), the other having pH optimum of about pH 9.0, prefers denatured DNA as substrate and is not dependent on divalent cations. The fractions with an acid pH optimum can be subdivided into two groups, which differ in their activity towards native DNA, towards denatured DNA, in their activity when succinate is present and in their pH optimum. PMID:10793736

  19. Subpopulations of mouse spleen lymphocytes

    PubMed Central

    Mugraby, Lea; Gery, I.; Sulitzeanu, D.

    1974-01-01

    Fractionation on bovine serum albumin (BSA) continuous gradients or passage through anti-immunoglobulin-coated (RaMIg) columns were used to separate the populations of mouse spleen cells which react against mitogens specific for B (E. coli lipopolysaccharide (LPS)) or T cells (concanavalin A (Con A) or phytohaemagglutinin (PHA)). These manipulations could distinguish the subsets of T cells reacting toward PHA or Con A. Fractionation on BSA gradients yielded two fractions, one light and the other dense, with high reactivity toward Con A; the cells reactive to LPS were concentrated in a fraction located between these two fractions, whereas the response to PHA was distributed irregularly throughout the gradient, without any apparent correlation with the response against Con A. Lymphocytes eluted from the RaMIg columns did not react to LPS, showed increased reactivity to PHA and decreased response to Con A, as compared to the unfractionated cells. PMID:4605183

  20. Chronic Lymphocytic Leukemia: Current Concepts.

    PubMed

    Yu, Eun-Mi; Kittai, Adam; Tabbara, Imad A

    2015-10-01

    Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults, and while in early, asymptomatic stages treatment is not indicated, the threat to the quality of life and increased mortality of patients posed by more advanced-stage disease necessitate therapeutic intervention. Guidelines of when and how to treat are not well-established because CLL is a disease of the elderly and it is important to balance preservation of functional status and control of the disease. Advances in molecular and genetic profiling has led to the ability to identify sub-groups of patients with CLL whose disease may respond to selected therapy. This review discusses current standard therapies in the major sub-groups of CLL based on age and functional status, in both the front-line and relapsed/refractory settings. It also provides a concise review of novel agents that have shown considerable efficacy in CLL. PMID:26408673

  1. Early lymphocyte recovery after intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells

    PubMed Central

    Kanakry, Christopher G.; Gocke, Christopher D.; Thoburn, Christopher; Kos, Ferdynand; Meyer, Christian; Briel, Janet; Luznik, Leo; Smith, B. Douglas; Levitsky, Hyam; Karp, Judith E.

    2011-01-01

    Few published studies characterize early lymphocyte recovery after intensive chemotherapy for acute myelogenous leukemia (AML). To test the hypothesis that lymphocyte recovery mirrors ontogeny, we characterized early lymphocyte recovery in 20 consecutive patients undergoing induction timed sequential chemotherapy for newly diagnosed AML. Recovering T lymphocytes were predominantly CD4+ and included a greatly expanded population of CD3+CD4+CD25+Foxp3+ T cells. Recovering CD3+CD4+CD25+Foxp3+ T cells were phenotypically activated regulatory T cells and showed suppressive activity on cytokine production in a mixed lymphocyte reaction. Despite an initial burst of thymopoiesis, most recovering regulatory T cells were peripherally derived. Furthermore, regulatory T cells showed marked oligoclonal skewing, suggesting that their peripheral expansion was antigen-driven. Overall, lymphocyte recovery after chemotherapy differs from ontogeny, specifically identifying a peripherally expanded oligoclonal population of activated regulatory T lymphocytes. These differences suggest a stereotyped immunologic recovery shared by patients with newly diagnosed AML after induction timed sequential chemotherapy. Further insight into this oligoclonal regulatory T-cell population will be fundamental toward developing effective immunomodulatory techniques to improve survival for patients with AML. PMID:20935254

  2. Age associated oxidative damage in lymphocytes

    PubMed Central

    Gautam, Nandeslu; Das, Subhasis; Mahapatra, Santanu Kar; Chakraborty, Subhankari Prasad; Kundu, Pratip Kumar

    2010-01-01

    Lymphocytes are an important immunological cell and have been played a significant role in acquired immune system; hence, may play in pivotal role in immunosenescence. Oxidative stress has been reported to increase in elderly subjects, possibly arising from an uncontrolled production of free radicals with aging and decreased antioxidant defenses. This study was aimed to evaluate the level of lipid-protein damage and antioxidant status in lymphocytes of healthy individuals to correlate between oxidative damage with the aging process. Twenty healthy individuals of each age group (11–20; 21–30; 31–40; 41–50; and 51–60 years) were selected randomly. Blood samples were drawn by medical practitioner and lymphocytes were isolated from blood samples. Malondialdehyde (MDA), protein carbonyls (PC) level were evaluated to determine the lipid and protein damage in lymphocytes. Superoxide dismutase (SOD), catalase (CAT), glutathione and glutathione dependent enzymes were estimated to evaluate the antioxidant status in the lymphocytes. Increased MDA and PC levels strongly support the increased oxidative damage in elderly subject than young subjects. The results indicated that, balance of oxidant and antioxidant systems in lymphocytes shifts in favor of accelerated oxidative damage during aging. Thus oxidative stress in lymphocytes may particular interest in aging and may play important role in immunosenescence. PMID:20972374

  3. Multi-state analysis illustrates treatment success after stem cell transplantation for acute myeloid leukemia followed by donor lymphocyte infusion.

    PubMed

    Eefting, Matthias; de Wreede, Liesbeth C; Halkes, Constantijn J M; von dem Borne, Peter A; Kersting, Sabina; Marijt, Erik W A; Veelken, Hendrik; Putter, Hein; Schetelig, Johannes; Falkenburg, J H Frederik

    2016-04-01

    In the field of hematopoietic stem cell transplantation, the common approach is to focus outcome analyses on time to relapse and death, without assessing the impact of post-transplant interventions. We investigated whether a multi-state model would give insight into the events after transplantation in a cohort of patients who were transplanted using a strategy including scheduled donor lymphocyte infusions. Seventy-eight consecutive patients who underwent myeloablative T-cell depleted allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome were studied. We constructed a multi-state model to analyze the impact of donor lymphocyte infusion and graft-versus-host disease on the probabilities of relapse and non-relapse mortality over time. Based on this model we introduced a new measure for outcome after transplantation which we called 'treatment success': being alive without relapse and immunosuppression for graft-versus-host disease. All relevant clinical events were implemented into the multi-state model and were denoted treatment success or failure (either transient or permanent). Both relapse and non-relapse mortality were causes of failure of comparable magnitude. Whereas relapse was the dominant cause of failure from the transplantation state, its rate was reduced after graft-versus-host disease, and especially after donor lymphocyte infusion. The long-term probability of treatment success was approximately 40%. This probability was increased after donor lymphocyte infusion. Our multi-state model helps to interpret the impact of post-transplantation interventions and clinical events on failure and treatment success, thus extracting more information from observational data. PMID:26802054

  4. Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant

    ClinicalTrials.gov

    2016-01-21

    Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia; Relapsed/Refractory Chronic Lymphocytic Leukemia; Relapsed/Refractory Non Hodgkin's Lymphoma; Hodgkins Disease; Relapsed Refractory Multiple Myeloma

  5. Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy.

    PubMed

    Shima, Tomoko; Inada, Kumiko; Nakashima, Akitoshi; Ushijima, Akemi; Ito, Mika; Yoshino, Osamu; Saito, Shigeru

    2015-04-01

    Paternal antigen-specific regulatory T (PA-specific Treg) cells play an important role in feto-maternal tolerance. To detect the PA-specific Tregs, female BALB/c mice were mated with male DBA/2 mice. Mls Ia antigen on DBA/2 mice is recognized by the T-cell receptor Vβ6; thus, CD4(+)Foxp3(+)Vβ6(+) cells are recognized as PA-specific Treg cells. CD4(+)CD25(+)Vβ6(+) cells effectively suppressed the allo-reactive proliferation of lymphocytes compared with that of CD4(+)CD25(+)Vβ6(-) cells. Vβ6(+) PA-specific Treg cells expressed CCR4 and CCR5 on their surface. The frequency of Ki67(+) PA-specific Treg cells among Treg cells was significantly increased in draining lymph nodes on day 3.5 post-coitus (pc; 6.8±1.1%, p<0.05) and day 5.5 pc (7.2±1.1%, p<0.05) in allogeneic pregnant mice compared with that in nonpregnant mice (2.7±0.2%). The frequency of Ki67(+) PA-specific Treg cells in the uterus increased significantly after day 5.5 pc in allogeneic pregnant mice compared with that in nonpregnant mice (8.8±2.8% vs. 1.2±1.3%, p<0.05). However, Ki67(-)PA-specific Tregs did not change during pregnancy. To analyze the role of seminal fluid or sperm in Treg expansion, female BALB/c mice were mated with vasectomized DBA/2 male mice (VAS) or seminal vesicle-excised DBA/2 male mice (SVX). The frequency of Ki67(+) PA-specific Treg cells did not increase in draining lymph nodes or uterus in BALB/c×DBA/2 (SVX) allogeneic mating mice. These findings suggest that the priming by seminal fluid is important for the induction of proliferating PA-specific Tregs in uterine-draining lymph nodes just before implantation and pregnant uterus after implantation, resulting in successful implantation and the maintenance of allogeneic pregnancy. PMID:25817463

  6. Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome

    PubMed Central

    Radujkovic, Aleksandar; Becker, Natalia; Benner, Axel; Penack, Olaf; Platzbecker, Uwe; Stölzel, Friedrich; Bornhäuser, Martin; Hegenbart, Ute; Ho, Anthony D.; Dreger, Peter; Luft, Thomas

    2015-01-01

    Allogeneic stem cell transplantation (alloSCT) represents a curative therapeutic option for patients with myelodysplastic syndrome (MDS), but relapse and non-relapse mortality (NRM) limit treatment efficacy. Based on our previous observation in acute myeloid leukemia we investigated the impact of pre-transplant weight loss on post-transplant outcome in MDS patients. A total of 111 patients diagnosed with MDS according to WHO criteria transplanted between 2000 and 2012 in three different transplant centers were included into the analysis. Data on weight loss were collected from medical records prior to conditioning therapy and 3–6 months earlier. Patient, disease and transplant characteristics did not differ between patients with weight loss (2–5%, n = 17; > 5%, n = 17) and those without (n = 77). In a mixed effect model, weight loss was associated with higher risk MDS (p = 0.046). In multivariable analyses, pre-transplant weight loss exceeding 5% was associated with a higher incidence of relapse (p < 0.001) and NRM (p = 0.007). Pre-transplant weight loss of 2–5% and > 5% were independent predictors of worse disease-free (p = 0.023 and p < 0.001, respectively) and overall survival (p = 0.043 and p < 0.001, respectively). Our retrospective study suggests that MDS patients losing weight prior to alloSCT have an inferior outcome after transplantation. Prospective studies addressing pre-transplant nutritional interventions are highly warranted. PMID:26360778

  7. Scalded Skin of Rat Treated by Using Fibrin Glue Combined with Allogeneic Bone Marrow Mesenchymal Stem Cells

    PubMed Central

    Yang, Yadong; Li, Ying; Fang, Guojian; Zhang, Keji

    2014-01-01

    Background It is difficult to achieve satisfactory results with the traditional treatment of large-area skin defects and deep burns. Objective To test the treatment effect of an active dressing film made of a mixture of fibrin glue and bone marrow mesenchymal stem cells (BMSCs) for repairing burn wounds on the skin of rats. Methods Two scald wounds were made on the back of each rat. A total of 30 scald wounds were randomly divided into 3 groups, with 10 wounds in each group. In the experimental treatment group, the scald wounds were covered with the fibrin glue and BMSC mixture. The wounds of the experimental control group were covered with fibrin glue only. No intervention was administered to the blank control group. Thirty days after treatment, pathological sections were cut from the scalded local tissues of all rats from the 3 groups and observed with a microscope. Results The speed of scald wound healing in the experimental treatment group was faster than the other 2 groups. In the experimental treatment group, histopathological analysis revealed that the sebaceous glands showed obviously proliferous at the edge of the new tissue and gradually extended to the deep dermal layer of the new tissue. Conclusion BMSCs may have an active role in promoting skin tissue repair and generating skin appendages. Allogeneic BMSCs mixed with fibrin glue can contribute to the quick formation of a film-like gel over the scald wounds, which might be of significance for emergency treatment and skin-grafting operations. PMID:24966626

  8. Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in children with sickle cell disease.

    PubMed

    Strocchio, Luisa; Zecca, Marco; Comoli, Patrizia; Mina, Tommaso; Giorgiani, Giovanna; Giraldi, Eugenia; Vinti, Luciana; Merli, Pietro; Regazzi, Mario; Locatelli, Franco

    2015-06-01

    Although allogeneic haematopoietic stem cell transplantation (HSCT) still represents the only consolidated possibility of cure for sickle cell disease (SCD) patients, its use has been limited by the risk of morbidity and mortality associated with conventional myeloablative therapy. The introduction of treosulfan to replace busulfan in conditioning regimens has recently been explored by virtue of its lower toxicity profile. We report our experience with a treosulfan/thiotepa/fludarabine conditioning for human leucocyte antigen (HLA)-matched sibling or unrelated donor-HSCT in 15 children with SCD, and compare patient outcomes with those of a historical cohort (15 patients) given a busulfan-based regimen. Engraftment was achieved in 28 out of 30 patients (93%), with one case of graft failure in either group. The conditioning regimen was well tolerated in both groups, with no cases of grade III-IV regimen-related toxicity. The 7-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 100% and 93%, respectively, with a 93% DFS in both busulfan and treosulfan groups. No SCD-related adverse events occurred after engraftment in patients with complete or mixed donor chimerism. This retrospective analysis suggests that a treosulfan-based conditioning regimen is able to ensure engraftment with excellent OS/DFS and low regimen-related toxicity in patients with SCD. PMID:25818248

  9. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits

    PubMed Central

    Chiang, En-Rung; Ma, Hsiao-Li; Wang, Jung-Pan; Liu, Chien-Lin; Chen, Tain-Hsiung; Hung, Shih-Chieh

    2016-01-01

    Mesenchymal stem cell (MSC)-based therapies may aid in the repair of articular cartilage defects. The purpose of this study was to investigate the effects of intraarticular injection of allogeneic MSCs in an in vivo anterior cruciate ligament transection (ACLT) model of osteoarthritis in rabbits. Allogeneic bone marrow-derived MSCs were isolated and cultured under hypoxia (1% O2). After 8 weeks following ACLT, MSCs suspended in hyaluronic acid (HA) were injected into the knees, and the contralateral knees were injected with HA alone. Additional controls consisted of a sham operation group as well as an untreated osteoarthritis group. The tissues were analyzed by macroscopic examination as well as histologic and immunohistochemical methods at 6 and 12 weeks post-transplantation. At 6 and 12 weeks, the joint surface showed less cartilage loss and surface abrasion after MSC injection as compared to the tissues receiving HA injection alone. Significantly better histological scores and cartilage content were observed with the MSC transplantation. Furthermore, engraftment of allogenic MSCs were evident in surface cartilage. Thus, injection of the allogeneic MSCs reduced the progression of osteoarthritis in vivo. PMID:26915044

  10. Apoptosis of ileal crypt epithelia after allogeneic bone marrow transplantation without graft-versus-host disease

    PubMed Central

    Kreft, Andreas; Russo, Alexandra; Lux, Steffi; Waiz, Lioudmila; Seidmann, Larissa; Faber, Jörg; Kirkpatrick, Charles J

    2015-01-01

    Key Clinical Message Intestinal crypt cell apoptosis may occur after allogeneic bone marrow transplantation without clinically overt graft-versus-host disease. We describe this phenomenon in a case of a 12-year-old girl who had segments of the ileum resected because of a relapse of acute lymphoblastic leukemia. The diagnostic difficulties are discussed. PMID:25984309

  11. No evidence of plasticity in hair follicles of recipients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Rovó, Alicia; Meyer-Monard, Sandrine; Heim, Dominik; Arber, Caroline; Passweg, Jakob R; Gratwohl, Alois; Tichelli, André

    2005-08-01

    Here we show in a prospective quantitative study of 115 patients after allogeneic hematopoietic stem cell transplantation that hair follicles remain exclusively of recipient type despite full whole blood donor-type chimerism. Our data indicate that unmanipulated hematopoietic donor stem cells do not contribute directly to reconstitution even in an organ at highest need for repair. PMID:16038783

  12. A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation.

    PubMed

    Brennan, Yvonne; Gottlieb, David J; Baewer, David; Blyth, Emily

    2015-11-01

    Human herpesvirus 6 (HHV-6) is an ubiquitous virus that can reactivate in immunocompromised hosts, resulting in diverse clinical sequelae. We describe a case of fatal acute HHV-6 myocarditis in a patient who underwent allogeneic haemopoietic stem cell transplantation (HSCT). To our knowledge, this is the first reported case of biopsy proven HHV-6 myocarditis post-HSCT. PMID:26465970

  13. Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome

    PubMed Central

    Alessandrino, Emilio Paolo; Porta, Matteo G Della; Malcovati, Luca; Jackson, Christopher H; Pascutto, Cristiana; Bacigalupo, Andrea; Teresa van Lint, Maria; Falda, Michele; Bernardi, Massimo; Onida, Francesco; Guidi, Stefano; Iori, Anna Paola; Cerretti, Raffaella; Marenco, Paola; Pioltelli, Pietro; Angelucci, Emanuele; Oneto, Rosi; Ripamonti, Francesco; Rambaldi, Alessandro; Bosi, Alberto; Cazzola, Mario

    2013-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc. PMID:23606215

  14. Elimination of allogeneic multipotent stromal cells by host macrophages in different models of regeneration

    PubMed Central

    Arutyunyan, Irina; Elchaninov, Andrey; Fatkhudinov, Timur; Makarov, Andrey; Kananykhina, Evgeniya; Usman, Natalia; Bolshakova, Galina; Glinkina, Valeria; Goldshtein, Dmitry; Sukhikh, Gennady

    2015-01-01

    Allogeneic multipotent stromal cells were previously thought to be poorly recognized by host immune system; the prolonged survival in host environments was explained by their immune privileged status. As long as the concept is currently reconsidered, the routes of elimination of allogeneic multipotent stromal cells by host immunity must be taken into account. This is necessary for correct comprehension of their therapeutic action. The study was focused upon survival of umbilical cord-derived allogeneic multipotent stromal cells in different rat models of tissue regeneration induced by partial hepatectomy or by critical limb ischemia. The observations were carried out by means of vital labeling of the cells with PKH26 prior to injection, in combination with differential immunostaining of host macrophages with anti-CD68 antibody. According to the results, allogeneic multipotent stromal cells are specifically eliminated by host immune system; the efficacy can reach 100%. Massive clearance of transplanted cells by host macrophages is accompanied by appropriation of the label by the latter, and this is a pronounced case of misleading presentation of exogenous label by host cells. The study emphasizes the role of macrophages in host response and also the need of additional criteria for correct data interpretation. PMID:26191137

  15. Elimination of allogeneic multipotent stromal cells by host macrophages in different models of regeneration.

    PubMed

    Arutyunyan, Irina; Elchaninov, Andrey; Fatkhudinov, Timur; Makarov, Andrey; Kananykhina, Evgeniya; Usman, Natalia; Bolshakova, Galina; Glinkina, Valeria; Goldshtein, Dmitry; Sukhikh, Gennady

    2015-01-01

    Allogeneic multipotent stromal cells were previously thought to be poorly recognized by host immune system; the prolonged survival in host environments was explained by their immune privileged status. As long as the concept is currently reconsidered, the routes of elimination of allogeneic multipotent stromal cells by host immunity must be taken into account. This is necessary for correct comprehension of their therapeutic action. The study was focused upon survival of umbilical cord-derived allogeneic multipotent stromal cells in different rat models of tissue regeneration induced by partial hepatectomy or by critical limb ischemia. The observations were carried out by means of vital labeling of the cells with PKH26 prior to injection, in combination with differential immunostaining of host macrophages with anti-CD68 antibody. According to the results, allogeneic multipotent stromal cells are specifically eliminated by host immune system; the efficacy can reach 100%. Massive clearance of transplanted cells by host macrophages is accompanied by appropriation of the label by the latter, and this is a pronounced case of misleading presentation of exogenous label by host cells. The study emphasizes the role of macrophages in host response and also the need of additional criteria for correct data interpretation. PMID:26191137

  16. Progress in the prevention of cytomegalovirus infection after allogeneic bone marrow transplantation.

    PubMed

    Devergie, A; Traineau, R; Esperou-Bourdeau, H; Ribaud, P; Socié, G; Richard, P; Selimi, F; Hirsch, I; Gluckman, E

    1994-01-01

    There has been substantial progress in preventing and treating CMV infection. Prophylaxis with CMV screened blood products, IVIG and antiviral drugs (high dose acyclovir and/or Ganciclovir) considerably reduce the incidence of CMV disease and nearly eliminate CMV pneumonia after allogeneic BMT. PMID:8177726

  17. Porcine Intervertebral Disc Repair Using Allogeneic Juvenile Articular Chondrocytes or Mesenchymal Stem Cells

    PubMed Central

    Acosta, Frank L.; Metz, Lionel; Adkisson, Huston Davis; Liu, Jane; Carruthers-Liebenberg, Ellen; Milliman, Curt; Maloney, Michael

    2011-01-01

    Tissue engineering strategies for intervertebral disc repair have focused on the use of autologous disc-derived chondrocytes. Difficulties with graft procurement, harvest site morbidity, and functionality, however, may limit the utility of this cell source. We used an in vivo porcine model to investigate allogeneic non-disc-derived chondrocytes and allogeneic mesenchymal stem cells (MSCs) for disc repair. After denucleation, lumbar discs were injected with either fibrin carrier alone, allogeneic juvenile chondrocytes (JCs), or allogeneic MSCs. Discs were harvested at 3, 6, and 12 months, and cell viability and functionality were assessed qualitatively and quantitatively. JC-treated discs demonstrated abundant cartilage formation at 3 months, and to a lesser extent at 6 and 12 months. For the carrier and MSC-treated groups, however, there was little evidence of proteoglycan matrix or residual notochordal/chondrocyte cells, but rather a type I/II collagen-enriched scar tissue. By contrast, JCs produced a type II collagen-rich matrix that was largely absent of type I collagen. Viable JCs were observed at all time points, whereas no evidence of viable MSCs was found. These data support the premise that committed chondrocytes are more appropriate for use in disc repair, as they are uniquely suited for survival in the ischemic disc microenvironment. PMID:21910592

  18. Geriatric assessment to predict survival in older allogeneic hematopoietic cell transplantation recipients

    PubMed Central

    Muffly, Lori S.; Kocherginsky, Masha; Stock, Wendy; Chu, Quynh; Bishop, Michael R.; Godley, Lucy A.; Kline, Justin; Liu, Hongtao; Odenike, Olatoyosi M.; Larson, Richard A.; van Besien, Koen; Artz, Andrew S.

    2014-01-01

    Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients aged 50 years and over. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. A total of 203 patients completed geriatric assessment and underwent transplant. Median age was 58 years (range 50–73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95%CI: 1.59–3.56; P<0.001), slow walk speed (HR 1.80, 95%CI: 1.14–2.83; P=0.01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95%CI: 1.07–2.28; P=0.02), low mental health by short-form-36 mental component summary (HR 1.67, 95%CI: 1.13–2.48; P=0.01), and elevated serum C-reactive protein (HR 2.51, 95%CI: 1.54–4.09; P<0.001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and over. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid appropriate selection of older adults. PMID:24816237

  19. Treatment of faecal incontinence using allogeneic-adipose-derived mesenchymal stem cells: a study protocol for a pilot randomised controlled trial

    PubMed Central

    Park, Eun Jung; Kang, Jeonghyun; Baik, Seung Hyuk

    2016-01-01

    Introduction Faecal incontinence is a distressing condition with recurrent uncontrolled passage of faecal material. Although faecal incontinence may cause psychological depression and social isolation, previous treatments have been limited. Recently, regenerative treatment has been developed using mesenchymal stem cells. Especially, there are possibilities that adipose-tissue-derived stem cells can be effective to treat a degenerated anal sphincter that is causing faecal incontinence. Therefore, this study aimed to investigate the safety and efficacy of using allogeneic-adipose-derived mesenchymal stem cells in the treatment of the anal sphincter of patients with faecal incontinence. Methods and analysis This study is a randomised, prospective, dose escalation, placebo-controlled, single-blinded, single-centre trial with two parallel groups. The safety test is performed by an injection of allogeneic-adipose-derived mesenchymal stem cells (ALLO-ASCs) into the anal sphincter with dose escalation (3×107, 6×107 and 9×107 cells, sequentially). After confirming the safety of the stem cells, an efficacy test is performed by this dose in the experimental group. The experimental group will receive ALLO-ASCs mixed with fibrin glue into the anal sphincter, and the placebo group will receive 0.9% normal saline injection mixed with fibrin glue. The primary end point is to assess the safety of ALLO-ASCs after the injection into the anal sphincter, and the secondary end point is to compare the efficacy of ALLO-ASC injection with fibrin glue in patients with faecal incontinence. Ethics and dissemination The study protocol was approved by the Ministry of Food and Drug Safety and the Ministry of Health & Welfare, in the Republic of Korea. The informed consent form was approved by the institutional review board of Gangnam Severance Hospital (IRB approval number 3-2014-0271). Dissemination of the results will be presented at a conference and in peer-reviewed publications. Trial

  20. Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation

    PubMed Central

    Eisfeld, Ann-Kathrin; Krahl, Rainer; Jaekel, Nadja; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

    2012-01-01

    Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of

  1. The PD-1 Axis Enforces an Anatomical Segregation of CTL Activity that Creates Tumor Niches after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Michonneau, David; Sagoo, Pervinder; Breart, Béatrice; Garcia, Zacarias; Celli, Susanna; Bousso, Philippe

    2016-01-19

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a curative treatment for hematologic malignancies, relies on donor cytotoxic T lymphocyte (CTL)-mediated graft-versus-leukemia (GVL) effect. Major complications of HSCT are graft-versus-host disease (GVHD) that targets specific tissues and tumor relapses. However, the mechanisms dictating the anatomical features of GVHD and GVL remain unclear. Here, we show that after HSCT, CTLs exhibited different killing activity in distinct tissues, being highest in the liver and lowest in lymph nodes. Differences were imposed by the microenvironment, partly through differential PD-1 ligand expression, which was strongly elevated in lymph nodes. Two-photon imaging revealed that PD-1 blockade restored CTL sensitivity to antigen and killing in lymph nodes. Weak CTL activity in lymph nodes promoted local tumor escape but could be reversed by anti-PD-1 treatment. Our results uncover a mechanism generating an anatomical segregation of CTL activity that might dictate sites of GVHD and create niches for tumor escape. PMID:26795248

  2. Generation of a cord blood-derived Wilms Tumor 1 dendritic cell vaccine for AML patients treated with allogeneic cord blood transplantation

    PubMed Central

    de Haar, Colin; Plantinga, Maud; Blokland, Nina JG; van Til, Niek P; Flinsenberg, Thijs WH; Van Tendeloo, Viggo F; Smits, Evelien L; Boon, Louis; Spel, Lotte; Boes, Marianne; Boelens, Jaap Jan; Nierkens, Stefan

    2015-01-01

    The poor survival rates of refractory/relapsed acute myeloid leukemia (AML) patients after haematopoietic cell transplantation (HCT) requires the development of additional immune therapeutic strategies. As the elicitation of tumor-antigen specific cytotoxic T lymphocytes (CTLs) is associated with reduced relapses and enhanced survival, enhanced priming of these CTLs using an anti-AML vaccine may result in long-term immunity against AML. Cord blood (CB), as allogeneic HCT source, may provide a unique setting for such post-HCT vaccination, considering its enhanced graft-versus-leukemia (GvL) effects and population of highly responsive naïve T cells. It is our goal to develop a powerful and safe immune therapeutic strategy composed of CB-HCT followed by vaccination with CB CD34+-derived dendritic cells (DCs) presenting the oncoprotein Wilms Tumor-1 (WT1), which is expressed in AML-blasts in the majority of patients. Here, we describe the optimization of a clinically applicable DC culture protocol. This two-step protocol consisting of an expansion phase followed by the differentiation toward DCs, enables us to generate sufficient cord blood-derived DCs (CBDCs) in the clinical setting. At the end of the culture, the CBDCs exhibit a mature surface phenotype, are able to migrate, express tumor antigen (WT1) after electroporation with mRNA encoding the full-length WT1 protein, and stimulate WT1-specific T cells. PMID:26451309

  3. Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection

    SciTech Connect

    Ely, Lauren K.; Green, Katherine J.; Beddoe, Travis; Clements, Craig S.; Miles, John J.; Bottomley, Stephen P.; Zernich, Danielle; Kjer-Nielsen, Lars; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R.

    2010-06-30

    Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801{sup +} individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801{sup FLRGRAYGL}. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 {micro}M, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

  4. Umbilical cord blood-derived mesenchymal stem cells ameliorate graft-versus-host disease following allogeneic hematopoietic stem cell transplantation through multiple immunoregulations.

    PubMed

    Wu, Qiu-Ling; Liu, Xiao-Yun; Nie, Di-Min; Zhu, Xia-Xia; Fang, Jun; You, Yong; Zhong, Zhao-Dong; Xia, Ling-Hui; Hong, Mei

    2015-08-01

    Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK cells, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4(+) and CD8(+) Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations. PMID:26223913

  5. Risk factors for invasive aspergillosis and related mortality in recipients of allogeneic SCT from alternative donors: an analysis of 306 patients.

    PubMed

    Mikulska, M; Raiola, A M; Bruno, B; Furfaro, E; Van Lint, M T; Bregante, S; Ibatici, A; Del Bono, V; Bacigalupo, A; Viscoli, C

    2009-09-01

    Invasive aspergillosis (IA) is a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT), particularly from donors other than HLA-identical sibling. All 306 patients who underwent alternative donor HSCT between 01 January 1999 and 31 December 2006 were studied. Late IA was defined as occurring >or=40 days after HSCT. The median follow-up was 284 days (range, 1-2709). Donors were matched unrelated (n=185), mismatched related (n=69), mismatched unrelated (n=35) and unrelated cord blood (n=17). According to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, 2 patients already had IA at HSCT, 23 had early IA and 20 had late IA (IA incidence 15%). Eight patients had proven and 37 probable IA. Multivariate analyses showed that significant predictors of IA were delayed neutrophil engraftment, extensive chronic GVHD (cGVHD), secondary neutropenia and relapse after transplant. Early IA was associated with active malignancy at HSCT, CMV reactivation and delayed lymphocyte engraftment. Late IA was predicted by cGVHD, steroid therapy, secondary neutropenia and relapse after HSCT. IA-related mortality among IA patients was 67% and was influenced by use of anti-thymocyte globulin, steroids, higher levels of creatinine, and lower levels of IgA and platelets. The outcome of IA depends on the severity of immunodeficiency and the status of the underlying disease. PMID:19308042

  6. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders.

    PubMed

    Laport, Ginna G; Sandmaier, Brenda M; Storer, Barry E; Scott, Bart L; Stuart, Monic J; Lange, Thoralf; Maris, Michael B; Agura, Edward D; Chauncey, Thomas R; Wong, Ruby M; Forman, Stephen J; Petersen, Finn B; Wade, James C; Epner, Elliot; Bruno, Benedetto; Bethge, Wolfgang A; Curtin, Peter T; Maloney, David G; Blume, Karl G; Storb, Rainer F

    2008-02-01

    Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m(2)/day on days -4 to -2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of

  7. The Pathogenesis of Chronic Lymphocytic Leukemia

    PubMed Central

    Galton, D. A. G.

    1966-01-01

    The pathogenesis of chronic lymphocytic leukemia was examined in a series of 88 cases observed during a 15-year period. In untreated cases the trend of the absolute lymphocyte counts followed two main patterns. In the type I trend, the counts rose throughout the observation period; in the type II trend, the tendency to rise ceased and the counts stabilized above and below a mean value, the stationary trend being maintained for months or years. The type II trend was associated with relatively benign disease. The development of lymphocytosis was correlated with the progression of lymphadenopathy. It is suggested that lymphocytosis may result from the physiological process of recirculation and that the accumulation of lymphocytes may result from the proliferation of a single slightly abnormal cell-line. The abnormal cells might survive an unusually long time because they are unable to respond to stimuli which cause normal lymphocytes to transform. PMID:4952384

  8. Microangiectasias: Structural regulators of lymphocyte transmigration

    PubMed Central

    Secomb, Timothy W.; Konerding, Moritz A.; West, Charles A.; Su, Mei; Young, Alan J.; Mentzer, Steven J.

    2003-01-01

    The migration of lymphocytes into inflammatory tissue requires the migrating cell to overcome mechanical forces produced by blood flow. A generally accepted hypothesis is that these forces are overcome by a multistep sequence of adhesive interactions between lymphocytes and endothelial cells. This hypothesis has been recently challenged by results demonstrating wall shear stress on the order of 20 dyn/cm2 in vivo and infrequent lymphocyte–endothelial adhesion at wall shear stress >1–2 dyn/cm2 in vitro. Here, we show that lymphocyte slowing and transmigration in the skin is associated with microangiectasias, i.e., focal structural dilatations of microvessel segments. Microangiectasias are inducible within 4 days of the onset of inflammation and lead to a greater than 10-fold local reduction in wall shear stress. These findings support the hypothesis that a preparatory step to lymphocyte transmigration involves structural adaptations in the inflammatory microcirculation. PMID:12782790

  9. Lymphocytes and ischemia-reperfusion injury.

    PubMed

    Linfert, Douglas; Chowdhry, Tayseer; Rabb, Hamid

    2009-01-01

    Ischemia reperfusion injury (IRI) is a common and important clinical problem in many different organ systems, including kidney, brain, heart, liver, lung, and intestine. IRI occurs during all deceased donor organ transplants. IRI is a highly complex cascade of events that includes interactions between vascular endothelium, interstitial compartments, circulating cells, and numerous biochemical entities. It is well established that the innate immune system, such as complement, neutrophils, cytokines, chemokines, and macrophages participate in IRI. Recent data demonstrates an important role for lymphocytes, particularly T cells but also B cells in IRI. Lymphocytes not only participate in augmenting injury responses after IRI, but could also be playing a protective role depending on the cell type and stage of injury. Furthermore, lymphocytes appear to be participating in the healing response from IRI. These new data open the possibility for lymphocyte targeted therapeutics to improve the short and long term outcomes from IRI. PMID:19027612

  10. Ontogeny of Innate T Lymphocytes – Some Innate Lymphocytes are More Innate than Others

    PubMed Central

    Vermijlen, David; Prinz, Immo

    2014-01-01

    Innate lymphocytes have recently received a lot of attention. However, there are different ideas about the definition of what is “innate” in lymphocytes. Lymphocytes without V(D)J-rearranged antigen receptors are now termed innate lymphoid cells (ILCs) and include cells formerly known as natural killer (NK) cells. Also, lymphocytes that are innate should be able to recognize microbial or stress-induced patterns and react rapidly without prior sensitization, as opposed to adaptive immune responses. Formally, genuine innate lymphocytes would be present before or at birth. Here, we review the ontogeny of human and mouse innate T lymphocyte populations. We focus on γδ T cells, which are prototype lymphocytes that often use their V(D)J rearrangement machinery to generate genetically encoded predetermined recombinations of antigen receptors. We make parallels between the development of γδ T cells with that of innate αβ T cells [invariant (i)NKT and mucosa-associated invariant T cells] and compare this with the ontogeny of innate B cells and ILCs (including NK cells). We conclude that some subsets are more innate than others, i.e., innate lymphocytes that are made primarily early in utero during gestation while others are made after birth. In practice, a ranking of innateness by ontogeny has implications for the reconstitution of innate lymphocyte subsets after hematopoietic stem cell transplantation. PMID:25346734

  11. Chemotaxis of large granular lymphocytes

    SciTech Connect

    Pohajdak, B.; Gomez, J.; Orr, F.W.; Khalil, N.; Talgoy, M.; Greenberg, A.H.

    1986-01-01

    The hypothesis that large granular lymphocytes (LGL) are capable of directed locomotion (chemotaxis) was tested. A population of LGL isolated from discontinuous Percoll gradients migrated along concentration gradients of N-formyl-methionyl-leucyl-phenylalanine (f-MLP), casein, and C5a, well known chemoattractants for polymorphonuclear leukocytes and monocytes, as well as interferon-..beta.. and colony-stimulating factor. Interleukin 2, tuftsin, platelet-derived growth factor, and fibronectin were inactive. Migratory responses were greater in Percoll fractions with the highest lytic activity and HNK-1/sup +/ cells. The chemotactic response to f-MLP, casein, and C5a was always greater when the chemoattractant was present in greater concentration in the lower compartment of the Boyden chamber. Optimum chemotaxis was observed after a 1 hr incubation that made use of 12 ..mu..m nitrocellulose filters. LGL exhibited a high degree of nondirected locomotion when allowed to migrate for longer periods (> 2 hr), and when cultured in vitro for 24 to 72 hr in the presence or absence of IL 2 containing phytohemagluttinin-conditioned medium. LGL chemotaxis to f-MLP could be inhibited in a dose-dependent manner by the inactive structural analog CBZ-phe-met, and the RNK tumor line specifically bound f-ML(/sup 3/H)P, suggesting that LGL bear receptors for the chemotactic peptide.

  12. T and B lymphocytes in myasthenia gravis.

    PubMed Central

    Itoyama, Y; Kawanami, S; Goto, I; Kuroiwa, Y

    1979-01-01

    Peripheral blood lymphocytes from seventeen non-thymectomized and nine thymectomized patients with myasthenia gravis (MG) and thirteen healthy controls were examined for the presence of surface markers characteristic of T and B lymphocytes by rosette formation with sheep red blood cells (SRBC). T cells were identified by their capacity to spontaneously form rosettes with SRBCs. The percentage of B lymphocytes was determined by the erythrocyte antibody complement (EAC) rosette-forming test. The EAC complex was prepared with either whole rabbit anti-SRBC serum or with the IgM fraction of rabbit anti-SRBC serum. The two kind of erythrocyte complement rosette-forming cells (EAC-RFC) are designated erythrocyte-haemolysin-complement RFC (EA(H)C-RFC), and erythrocyte-IgM-complement RFC (EA(M)C-RFC). The percentage of total lymphocytes and T cells was not altered in MG patients. The percentage of 'active' T cells, which have been considered to be more actively involved in cellular immunity, was also similar in MG patients and controls. A significant increase in EA(H)C-RFC occurred in both thymectomized and non-thymectomized MG patients, while in B cells detected by EA(M)C-RFC no alterations were found. The increase in EA(H)C-RFC in lymphocytes from MG patients may be due to an increase in the 19S antibody-forming B lymphocytes or to an increase in T cells which have Fc receptors on their surface. PMID:315844

  13. Effects of isolation on various lymphocyte activities

    SciTech Connect

    Jessop, J.J.

    1986-01-01

    Prolonged exposure of Sprague Dawley male rats to isolation, water scheduling, or their combination resulted in an enhanced lymphocyte proliferative response to mitogen. Time course studies of effects of isolation on mitogenic response of splenic and/or blood T and B lymphocytes and splenic NK cell activity demonstrated a suppression with short term exposure followed by an enhancement with prolonged exposure. Use of immunoperoxidase staining techniques to identify splenic T or T helper cells revealed that prolonged exposure to isolation had no significant effect on the proportion of these cell populations in the spleen. Examination of the data by Lineweaver-Burke plot and plot of the data as % maximum response showed that prolonged exposure to isolation did not alter the sensitivity of the lymphocytes to mitogen. Involvement of corticosteroids and opioid peptides in mediation of the effects of exposure to isolation on lymphocyte activity was assessed by measurement of plasma corticosterone by radioimmunoassay and by examination of the ability of the opioid antagonist naltrexone to alter the effects of isolation on lymphocyte proliferative response to mitogen. Attempts were made to mimic the effects of short-term isolation on lymphocyte activity by morphine sulfate administration.

  14. Regulation of Lymphocyte Function by Adenosine

    PubMed Central

    Linden, Joel; Cekic, Caglar

    2014-01-01

    Adenosine regulates the interaction between lymphocytes and the vasculature and is important for controlling lymphocyte trafficking in response to tissue injury or infection. Adenosine can blunt the effects of T cell receptor (TCR) activation primarily by activating adenosine A2A receptors (A2AR) and signaling via cyclic AMP and protein kinase A (PKA). PKA reduces proximal TCR signaling by phosphorylation of C-terminal Src kinase (Csk), nuclear factor of activated T cells (NF-AT) and cyclic AMP response element binding protein (CREB). PKA activation can either enhance or inhibit the survival of T cells depending on the strength and duration of signaling. Inducible enzymes such as CD73 and CD39 regulate adenosine formation and degradation in vivo. The extravasation of lymphocytes through blood vessels is influenced by A2AR-mediated suppression of Intercellular Adhesion Molecule 1 (ICAM) expression on lymphocytes and diminished production of IFNγ and IFNγ-inducible chemokines that are chemotactic to activated lymphocytes. Adenosine also decreases the barrier function of vascular endothelium by activating A2BRs. In sum, adenosine signaling is influenced by tissue inflammation and injury through induction of receptors and enzymes and has generally inhibitory effects on lymphocyte migration into inflamed tissues due to PKA-mediated effects on adhesion molecules, IFNγ production and endothelial barrier function. PMID:22772752

  15. Setting the clock for recirculating lymphocytes.

    PubMed

    Eichner, Alexander; Sixt, Michael

    2011-01-01

    In their search for antigens, lymphocytes continuously shuttle among blood vessels, lymph vessels, and lymphatic tissues. Chemokines mediate entry of lymphocytes into lymphatic tissues, and sphingosine 1-phosphate (S1P) promotes localization of lymphocytes to the vasculature. Both signals are sensed through G protein-coupled receptors (GPCRs). Most GPCRs undergo ligand-dependent homologous receptor desensitization, a process that decreases their signaling output after previous exposure to high ligand concentration. Such desensitization can explain why lymphocytes do not take an intermediate position between two signals but rather oscillate between them. The desensitization of S1P receptor 1 (S1PR1) is mediated by GPCR kinase 2 (GRK2). Deletion of GRK2 in lymphocytes compromises desensitization by high vascular S1P concentrations, thereby reducing responsiveness to the chemokine signal and trapping the cells in the vascular compartment. The desensitization kinetics of S1PR1 allows lymphocytes to dynamically shuttle between vasculature and lymphatic tissue, although the positional information in both compartments is static. PMID:22067458

  16. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    ClinicalTrials.gov

    2016-09-09

    Adult Mixed Glioma; Adult Pineal Gland Astrocytoma; Adult Solid Neoplasm; AIDS Related Immunoblastic Lymphoma; AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Diffuse Mixed Cell Lymphoma; AIDS-Related Diffuse Small Cleaved Cell Lymphoma; AIDS-Related Hodgkin Lymphoma; AIDS-Related Lymphoblastic Lymphoma; AIDS-Related Lymphoma; AIDS-Related Primary Central Nervous System Lymphoma; Glioma; Lymphoma; Recurrent Adult Brain Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma

  17. Ipilimumab After Allogeneic Stem Cell Transplant in Treating Patients With Persistent or Progressive Cancer

    ClinicalTrials.gov

    2013-03-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Childhood Myelodysplastic Syndromes; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Disseminated Neuroblastoma; Malignant Neoplasm; Ovarian Choriocarcinoma; Ovarian Embryonal Carcinoma; Ovarian Immature Teratoma; Ovarian Mature Teratoma; Ovarian Mixed Germ Cell Tumor; Ovarian Monodermal and Highly Specialized Teratoma; Ovarian Polyembryoma; Ovarian Yolk Sac Tumor; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Malignant Testicular Germ Cell Tumor; Recurrent Mantle Cell Lymphoma; Recurrent Neuroblastoma; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Stage I Multiple Myeloma; Stage II Multiple Myeloma; Stage II Ovarian Epithelial Cancer; Stage III Malignant Testicular Germ Cell Tumor; Stage III Multiple Myeloma; Stage III Ovarian Epithelial Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Ovarian Epithelial Cancer; Testicular Choriocarcinoma; Testicular Choriocarcinoma and Embryonal Carcinoma; Testicular Choriocarcinoma and Seminoma; Testicular Choriocarcinoma and Teratoma; Testicular Choriocarcinoma and Yolk Sac Tumor; Testicular Embryonal Carcinoma; Testicular

  18. T-Cell Depleted Allogeneic Stem Cell Transplantation for Patients With Hematologic Malignancies

    ClinicalTrials.gov

    2015-10-05

    Acute Myelogenous Leukemia; Lymphoid Leukemia; Chronic Myelogenous Leukemia; Malignant Lymphoma; Hodgkin's Disease; Chronic Lymphocytic Leukemia; Myeloproliferative Disorder; Anemia, Aplastic; Myelodysplastic Syndromes

  19. Potentiation of lymphocyte proliferative responses by nickel sulfide

    NASA Technical Reports Server (NTRS)

    Jaramillo, A.; Sonnenfeld, G.

    1992-01-01

    Crystalline nickel sulfide (NiS) induced a spleen cell proliferation that resembles a mixed lymphocyte reaction (MLR). It depended on cell-cell interaction, induced high levels of interleukin-1 (IL-1) and interleukin-2 (IL-2) and the responding cell subpopulation was composed of CD4+ T lymphocytes. Furthermore, the proliferation was inhibited in a dose-dependent manner by magnesium. Crystalline NiS also increased significantly the spleen cell proliferative response to concanavalin A (Con A) and lipopolysaccharide (LPS) with magnesium potentiating the combined effects of crystalline NiS and mitogens. Interestingly, crystalline NiS did not show any effect on the induction of IL-2 by Con A. The results described herein suggest that crystalline NiS can potentiate both antigenic (MLR) and mitogenic (Con A and LPS) proliferative responses in vitro. Crystalline NiS appears to potentiate these responses by acting in the form of ionic nickel on several intracellular targets for which magnesium ions have different noncompetitive interactions. The effects of magnesium on the potentiating action of crystalline NiS are different depending upon the type of primary stimulatory signal for proliferation (mitogenic or antigenic).

  20. Abnormal immune responses of Bloom's syndrome lymphocytes in vitro.

    PubMed Central

    Hütteroth, T H; Litwin, S D; German, J

    1975-01-01

    Bloom's syndrome is a rare autosmal recessive disorder, first characterized by growth retardation and asum-sensitive facial telangiectasia and more recently demonstarted to have increased chromosome instability, a predisposition to malignancy, and increased susecptibitily to infection. The present report ocncern the immune function of Bloom's syndrom lymphoctes in vitro. Four affected homozgotes and five heterozygotes were studied. An abnormal serum concentartion of at least one class of immunoglobin was present in three out of four homozgotes. Affected homozgotes were shown capable of both a humoral and cellular response after antigenic challenge, the responses in general being weak but detectable. Blood lymphocytes from Bloom's syndrome individuals were cultured in impaired proliferavite response and synthesized less immunoglobulin at the end of 5 days than did normal controls. In contrast, they had a normal proliferative response to phytohemagglutinin except at highest concentrations of the mitogen. In the mixed lymphocte culture, Bloom's syndrome lymphocytes proved to be poor responder cells but normal stimulator cells. Lmyphoctes from the heterozgotes produced normal responses in these three systems. Distrubed immunity appears to be on of several major consequences of homozygosity for the Bloom's syndrome gene. Although the explanation for this pleiotropism is at present obscure, the idea was advanced that the aberrant immune function is, along with the major clincial feature-small body size, amanifestation of defect in cellular proliferation. PMID:124745

  1. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  2. PD-L1 expression is associated with massive lymphocyte infiltration and histology in gastric cancer.

    PubMed

    Li, Zhongwu; Lai, Yumei; Sun, Li; Zhang, Xiaotian; Liu, Ruping; Feng, Guoshuang; Zhou, Lixin; Jia, Lin; Huang, Xiaozheng; Kang, Qiang; Lin, Dongmei; Gao, Jing; Shen, Lin

    2016-09-01

    The mechanism of carcinogenesis of gastric cancer (GC) is still unclear now. This study aimed to explore the correlations among PD-L1, Epstein-Barr virus (EBV) infection, lymphocyte infiltration, HER2 expression, HER2 gene status, histology, and other clinicopathological factors in GC. A total of 44 GC patients with massive lymphocyte infiltration (GC-MLI) and 93 GC patients without massive lymphocyte infiltration were involved in this study. Immunohistochemical analysis was used to test the expression levels of PD-L1 and HER2. Fluorescence in situ hybridization was used on HER2-positive cases with a score of 2+ to test the HER2 gene status. EBV-encoded RNA was used to test for EBV infection. In univariate analysis, PD-L1 expression was significantly associated with GC-MLI (P<.001), lower age (P=.019), EBV infection (P<.001), lower HER2 expression (P=.011), and diffuse/mixed type of histology (P=.022). EBV-encoded RNA-positive cases were significantly associated with GC-MLI (P<.001), lower age (P=.016), diffuse/mixed type of histology (P=.011), and lower HER2 expression (P=.032). In the multivariate logistic regression model, GC-MLI and the diffuse/mixed type histology were identified as 2 independent factors that affected PD-L1 expression (P<.001). Furthermore, PD-L1-positive cases have worse overall survival than do PD-L1-negative cases (P=.011). These results suggest that massive lymphocyte infiltration and the diffuse/mixed type histology of GC should be taken into consideration to select the appropriate patients for PD-L1 inhibitory treatment in the future. PMID:27260946

  3. Selective Blockade of Herpesvirus Entry Mediator–B and T Lymphocyte Attenuator Pathway Ameliorates Acute Graft-versus-Host Reaction

    PubMed Central

    del Rio, Maria-Luisa; Jones, Nick D.; Buhler, Leo; Norris, Paula; Shintani, Yasushi; Ware, Carl F.; Rodriguez-Barbosa, Jose-Ignacio

    2013-01-01

    The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F1 transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases. PMID:22490863

  4. Mixed Dementia

    MedlinePlus

    ... bodies , What Is Alzheimer's? NIA-Funded Memory & Aging Project Reveals Mixed Dementia Common Data from the first ... disease. For example, in the Memory and Aging Project study involving long-term cognitive assessments followed by ...

  5. Technical modifications in hyperfractionated total body irradiation for T-lymphocyte deplete bone marrow transplant

    SciTech Connect

    Lawton, C.A.; Barber-Derus, S.; Murray, K.J.; Casper, J.T.; Ash, R.C.; Gillin, M.T.; Wilson, J.F. )

    1989-08-01

    The Medical College of Wisconsin implemented a major bone marrow transplant (BMT) program in July 1985. The type of transplants to be focused on were allogeneic T-lymphocyte deplete. Total body irradiation (TBI) was initially patterned after the Memorial method. Patients received total body irradiation in a sitting position at a dose rate of 20-25 cGy/minute with 50% attenuation lung blocks used both anterior/posterior and posterior/anterior. Electron boosting was utilized for the ribs beneath the lung blocks. Occasionally, lower extremity boosting was required because of the sitting position. A dose of 14 Gy was chosen since T-lymphocyte deplete bone marrow transplant data suggest the need for higher total doses to consistently obtain engraftment. This dose was given in 3 equal daily fractions over 3 days following conditioning chemotherapy. Six of 11 patients treated in this manner developed lethal pulmonary events. In response to the pulmonary toxicity, partial lung shielding was increased to 60% attenuation. In the next 107 patients receiving this program of total body irradiation there was a reduced incidence of fatal pulmonary events (10 cases of fatal idiopathic interstitial pneumonitis and 12 cases of fatal pulmonary infections) after a median follow-up of 9 months. This was an obvious improvement over the initial group. A significant level of hepato-renal toxicity was also observed with 14 Gy total body irradiation when no liver or kidney blocking was used. Of the first 20 patients treated, three cases of fatal veno-occlusive disease resulted. Subsequently, a 10% attenuation right sided liver block was added. Five of 98 patients treated with this block have developed fatal hepatic dysfunction, (median follow-up of 7.2 months).

  6. Metabolic dysfunction in lymphocytes promotes postoperative morbidity.

    PubMed

    Edwards, Mark R; Sultan, Pervez; del Arroyo, Ana Gutierrez; Whittle, John; Karmali, Shamir N; Moonesinghe, S Ramani; Haddad, Fares S; Mythen, Michael G; Singer, Mervyn; Ackland, Gareth L

    2015-09-01

    Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction is an important mechanism underlying lymphopenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417 and 328, respectively), we confirmed prospectively that preoperative lymphopenia (≤1.3 x 10(9)·l(-1); <20% white cell count; prevalence 15-18%) was associated with infectious complications (relative risk 1.5 (95% confidence interval 1.1-2.0); P=0.008) and prolonged hospital stay. Lymphocyte respirometry, mitochondrial bioenergetics and function were assessed (n=93 patients). Postoperative lymphocytes showed a median 43% fall (range: 26-65%; P=0.029; n=13 patients) in spare respiratory capacity, the extra capacity available to produce energy in response to stress. This was accompanied by reduced glycolytic capacity. A similar hypometabolic phenotype was observed in lymphocytes sampled preoperatively from chronically lymphopenic patients (n=21). This hypometabolic phenotype was associated with functional lymphocyte impairment including reduced T-cell proliferation, lower intracellular cytokine production and excess apoptosis induced by a range of common stressors. Glucocorticoids, which are ubiquitously elevated for a prolonged period postoperatively, generated increased levels of mitochondrial reactive oxygen species, activated caspase-1 and mature interleukin (IL)-1β in human lymphocytes, suggesting inflammasome activation. mRNA transcription of the NLRP1 inflammasome was increased in lymphocytes postoperatively. Genetic ablation of the murine NLRP3 inflammasome failed to prevent glucocorticoid-induced lymphocyte apoptosis and caspase-1 activity, but increased NLRP1 protein expression. Our findings suggest that the hypometabolic phenotype observed in chronically lymphopenic

  7. Activation of human lymphocytes by supernatants from human thymic epithelium.

    PubMed Central

    Goust, J M; Vesole, D H; Fudenberg, H H

    1979-01-01

    Supernatants from human thymic epithelial cells (TS) were found to have a mitogenic effect on cultured human peripheral blood mononuclear cells and to potentiate their responses to lectins. This was not observed with culture supernatants from the human cell lines AV-3 and HeLa or from the murine cell line L-929. The maximum potentiating effects were observed with pokeweed mitogen (PWM) and phytohaemagglutinin (PHA), whereas the response to concanavalin A (Con A) was only slightly enhanced. TS also potentiated the mixed lymphocyte culture (MLC) response of normal T cells and thymocytes cultured with mitomycin C-treated B lymphoid cell lines. The mitogenic effect of TS was time-dependent and paralleled the appearance of lymphoid colonies in semi-solid agar. Chromatographical separation of concentrated serum-free TS on Sephadex G-100 yielded an active fraction of molecular weight 15,000--25,000 which had all the activities of unseparated TS. PMID:160851

  8. Activation of human lymphocytes by supernatants from human thymic epithelium.

    PubMed

    Goust, J M; Vesole, D H; Fudenberg, H H

    1979-11-01

    Supernatants from human thymic epithelial cells (TS) were found to have a mitogenic effect on cultured human peripheral blood mononuclear cells and to potentiate their responses to lectins. This was not observed with culture supernatants from the human cell lines AV-3 and HeLa or from the murine cell line L-929. The maximum potentiating effects were observed with pokeweed mitogen (PWM) and phytohaemagglutinin (PHA), whereas the response to concanavalin A (Con A) was only slightly enhanced. TS also potentiated the mixed lymphocyte culture (MLC) response of normal T cells and thymocytes cultured with mitomycin C-treated B lymphoid cell lines. The mitogenic effect of TS was time-dependent and paralleled the appearance of lymphoid colonies in semi-solid agar. Chromatographical separation of concentrated serum-free TS on Sephadex G-100 yielded an active fraction of molecular weight 15,000--25,000 which had all the activities of unseparated TS. PMID:160851

  9. Differentiation and activation phenotypes of lung T lymphocytes differ from those of circulating T lymphocytes.

    PubMed Central

    Davidson, B L; Faust, J; Pessano, S; Daniele, R P; Rovera, G

    1985-01-01

    We used dual laser two-color flow cytometry to compare the expression of surface markers associated with activation and with differentiation in lung and peripheral blood T lymphocytes from normal subjects. T cell subsets, defined based on their reactivity with monoclonal antibodies (MAb) OKT3, OKT4, and OKT8, were analyzed for expression of activation antigens as detected by MAbs to the interleukin-2 receptor, the transferrin receptor, and HLA-DR determinants. Whereas circulating T lymphocytes expressed the three activation antigens at low levels, and the total of T4+ and T8+ cells always approximated the number of T3+ cells, lung T lymphocytes of the T3+, T4+, and T8+ populations expressed the activation antigens at variable levels in combinations not seen in circulating lymphocytes, and the sum of T4+ and T8+ cells always exceeded the T3+ total. A proportion of T4+T8+ cells was detected in lung lymphocytes. PMID:3926821

  10. Characterization of the atypical lymphocytes in African swine fever

    PubMed Central

    Karalyan, Z. A.; Ter-Pogossyan, Z. R.; Abroyan, L. O.; Hakobyan, L. H.; Avetisyan, A. S.; Karalyan, N. Yu; Karalova, E. M.

    2016-01-01

    Aim: Atypical lymphocytes usually described as lymphocytes with altered shape, increased DNA amount, and larger size. For analysis of cause of genesis and source of atypical lymphocytes during African swine fever virus (ASFV) infection, bone marrow, peripheral blood, and in vitro model were investigated. Materials and Methods: Atypical lymphocytes under the influence of ASFV were studied for morphologic, cytophotometric, and membrane surface marker characteristics and were used in vivo and in vitro models. Results: This study indicated the increased size, high metabolic activity, and the presence of additional DNA amount in atypical lymphocytes caused by ASFV infection. Furthermore, in atypical lymphocytes, nuclear-cytoplasmic ratio usually decreased, compared to normal lymphocytes. In morphology, they looking like lymphocytes transformed into blasts by exposure to mitogens or antigens in vitro. They vary in morphologic detail, but most of them are CD2 positive. Conclusions: Our data suggest that atypical lymphocytes may represent an unusual and specific cellular response to ASFV infection. PMID:27536044

  11. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?

    PubMed

    Goldman, John; Gordon, Myrtle

    2006-01-01

    It is generally accepted that allogeneic stem cell transplantation can 'cure' chronic myelogenous leukemia (CML), although occasional patients relapse more than 10 years after the transplant procedure. Such cures presumably result from the combined effects of leukemia stem cells (LSCs) of the conditioning regimen and the graft-vs.-leukemia (GvL) effect mediated by donor-derived T lymphocytes. The advent of imatinib has revolutionized the management of patients with CML, but much evidence suggests that it does not eradicate all LSCs, which theoretically remain a potential source of relapse to chronic phase or advanced phase disease. Moreover, sub-clones of Philadelphia-positive cells bearing mutations that code for amino-acid substitutions in the Bcr-Abl kinase domain can be identified in patients receiving treatment with imatinib and are associated with varying degrees of resistance to this agent. In the present review, we postulate that LSCs, similar to their normal counterparts, may alternate between cycling and quiescent modes. In the cycling mode, they may express Bcr-Abl protein and be susceptible to the acquisition of additional mutations, whereas, in the quiescent mode, they may express little or no Bcr-Abl oncoprotein, cannot acquire additional mutations and are unaffected by imatinib. Thus, a patient who starts treatment early in the natural history of CML, and who responds to imatinib clinically, may not have had the opportunity to acquire additional mutations in LSCs. In this case, the persistence long-term of quiescent 'non-mutated' LSCs despite imatinib treatment might be consistent with freedom from relapse to chronic or advanced phase disease, provided that they remain vulnerable to imatinib when they are recruited into cycle. Conversely, when imatinib resistant Philadelphia-positive sub-clones predominate, this is likely to be due to the recruitment to hematopoiesis of quiescent stem cells that had been in cycle before administration of imatinib and

  12. Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations

    PubMed Central

    Fingerson, Stephanie; Albrecht, Mark; Maiers, Martin; Kalaycio, Matt; Hill, Brian T.

    2014-01-01

    Chronic lymphocytic leukemia (CLL) displays remarkable ethnic predisposition for whites, with relative sparing of African-American and Asian populations. In addition, CLL displays among the highest familial predispositions of all hematologic malignancies, yet the genetic basis for these differences is not clearly defined. The highly polymorphic HLA genes of the major histocompatibility complex play a central role in immune surveillance and confer risk for autoimmune and infectious diseases and several different cancers, the role for which in the development of CLL has not been extensively investigated. The National Marrow Donor Program/Be The Match has collected HLA typing from CLL patients in need of allogeneic hematopoietic stem cell transplant and has recruited millions of volunteers to potentially donate hematopoietic stem cells. HLA genotypes for 3491 US white, 397 African-American, and 90 Hispanic CLL patients were compared with 50 000 controls per population from the donor registry. We identified several HLA alleles associated with CLL susceptibility in each population, reconfirming predisposing roles of HLA-A*02:01 and HLA-DRB4*01:01 in whites. Associations for haplotype DRB4*01:01∼DRB1*07:01∼DQB1*03:03 were replicated across all 3 populations. These findings provide a comprehensive assessment of the role of HLA in the development of severe CLL. PMID:25232063

  13. Pitting new treatments for chronic lymphocytic leukemia against old ones: how do they fare?

    PubMed

    Shvidel, Lev; Berrebi, Alain

    2016-03-01

    Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) patients during the last two decades. In this review we present a personal case study for discussion on contemporary management in CLL. Presently immunochemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) is the standard upfront regimen for physically fit patients requiring treatment. Patients older than 65 years can be treated with modified doses of FCR, bendamustine, or chlorambucil combined with anti-CD20 antibody. This treatment can be repeated at relapse when the duration of response is over 2 years. Patients at high risk (with 17p deletion or early relapse) need alternative treatment with novel agents, e.g. ibrutinib or idelalisib. However, the optimal use of the novel agents in terms of duration, combinations, and long-term adverse effects is unknown. In selected eligible patients at high risk, allogeneic transplantation should be considered. Clinical trials in all stages of treatment are encouraged. PMID:26613391

  14. B lymphocytes: how they develop and function

    PubMed Central

    2008-01-01

    The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries. PMID:18725575

  15. SHARPIN Regulates Uropod Detachment in Migrating Lymphocytes

    PubMed Central

    Rantakari, Pia; Auvinen, Kaisa; Karikoski, Marika; Mattila, Elina; Potter, Christopher; Sundberg, John P.; Hogg, Nancy; Gahmberg, Carl G.

    2013-01-01

    SUMMARY Sharpin-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization and migration. We found that SHARPIN localizes to the trailing edges (uropods) of both mouse and human chemokine-activated lymphocytes migrating on ICAM-1, which is one of the major endothelial ligands for migrating leukocytes. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration and uropod defects in SHARPIN deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically we show that SHARPIN interacts directly with LFA-1, a leukocyte counter-receptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells. PMID:24210817

  16. How do I manage hyperglycemia/post-transplant diabetes mellitus after allogeneic HSCT.

    PubMed

    Fuji, S; Rovó, A; Ohashi, K; Griffith, M; Einsele, H; Kapp, M; Mohty, M; Majhail, N S; Engelhardt, B G; Tichelli, A; Savani, B N

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients frequently develop glucose intolerance and post-transplant diabetes mellitus (PTDM). The clinical importance of PTDM and its detrimental impact on HSCT outcomes are under-recognized. After allo-HSCT, various mechanisms can contribute to the development of PTDM. Here we review information about hyperglycemia and PTDM after allo-HSCT as well as PTDM after solid organ transplantation and describe ways to manage hyperglycemia/PTDM after allogeneic HSCT. Taking into consideration a lack of well-established evidence in the field of allo-HSCT, more studies should be conducted in the future, which will require closer multidisciplinary collaboration between hematologists, endocrinologists and nutritionists. PMID:27042848

  17. Immune responses to an encapsulated allogeneic islet {beta}-cell line in diabetic NOD mice

    SciTech Connect

    Black, Sasha P. . E-mail: Sasha.Black@ca.crl.com; Constantinidis, Ioannis; Cui, Hong; Tucker-Burden, Carol; Weber, Collin J.; Safley, Susan A.

    2006-02-03

    Our goal is to develop effective islet grafts for treating type 1 diabetes. Since human islets are scarce, we evaluated the efficacy of a microencapsulated insulin-secreting conditionally transformed allogeneic {beta}-cell line ({beta}TC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of {beta}TC-tet cells without inhibiting effective control of hyperglycemia in recipients. There was no significant host cellular reaction to the allografts or host cell adherence to microcapsules, and host cytokine levels were similar to those of sham-operated controls. We conclude that encapsulated allogeneic {beta}-cell lines may be clinically relevant, because they effectively restore euglycemia and do not elicit a strong cellular immune response following transplantation. To our knowledge, this is First extensive characterization of the kinetics of host cellular and cytokine responses to an encapsulated islet cell line in an animal model of type 1 diabetes.

  18. Optimal graft source for allogeneic hematopoietic stem cell transplant: bone marrow or peripheral blood?

    PubMed

    Adhikari, Janak; Sharma, Priyadarshani; Bhatt, Vijaya Raj

    2016-08-01

    Peripheral blood (PB), compared with bone marrow graft, has higher stem cell content, leads to faster engraftment and is more convenient for collection. Consequently, the use of PB graft has significantly increased in recent years. Although the use of PB graft is acceptable or even preferred to bone marrow graft in matched related donor allogeneic transplant due to a possibility of improved survival, PB graft increases the risk of chronic graft-versus-host disease and associated long-term toxicities in the setting of matched unrelated donor allogeneic transplant. In haploidentical transplant, mitigation of graft-versus-host disease with the use of post-transplant cyclophosphamide is a hypothesis-generating possibility; however, available studies have significant limitations to draw any definite conclusion. PMID:27168462

  19. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors

    PubMed Central

    Zakrzewski, Johannes L; Suh, David; Markley, John C; Smith, Odette M; King, Christopher; Goldberg, Gabrielle L; Jenq, Robert; Holland, Amanda M; Grubin, Jeremy; Cabrera-Perez, Javier; Brentjens, Renier J; Lu, Sydney X; Rizzuto, Gabrielle; Sant’Angelo, Derek B; Riviere, Isabelle; Sadelain, Michel; Heller, Glenn; Zúñiga-Pflücker, Juan Carlos; Lu, Chen; van den Brink, Marcel R M

    2009-01-01

    We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for ‘off-the-shelf’ immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy. PMID:18376399

  20. The Role of Allogeneic Stem Cell Transplantation in Relapsed/Refractory Hodgkin's Lymphoma Patients

    PubMed Central

    Klyuchnikov, Evgeny; Bacher, Ulrike; Kröger, Nicolaus; Kazantsev, Ilya; Zabelina, Tatjana; Ayuk, Francis; Zander, Axel Rolf

    2011-01-01

    Despite the favorable prognosis of most patients with Hodgkin's Lymphoma (HL), 15–20% of patients remain refractory to chemoradiotherapy, and 20–40% experience relapses following autologous stem cell transplantation (SCT) being used as salvage approach in this situation. Long-term survival of only 20% was reported for patients who failed this option. As some authors suggested the presence of a graft versus HL effect, allogeneic SCT was introduced as a further option. Myeloablative strategies were reported to be able to achieve cure in some younger patients, but high nonrelapse mortality remains a problem. Reduced intensity conditioning, in turn, was found to be associated with high posttransplant relapse rates. As there is currently no standard in the management of HL patients who failed autologous SCT, we here review the literature on allogeneic stem cell transplantation in HL patients with a special focus on the outcomes and risk factors being reported in the largest studies. PMID:20981158

  1. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation.

    PubMed

    Chen, Y; Scieux, C; Garrait, V; Socié, G; Rocha, V; Molina, J M; Thouvenot, D; Morfin, F; Hocqueloux, L; Garderet, L; Espérou, H; Sélimi, F; Devergie, A; Leleu, G; Aymard, M; Morinet, F; Gluckman, E; Ribaud, P

    2000-10-01

    Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period. Recipients of unrelated stem cell transplants were at higher risk. All patients received foscarnet; 8 subsequently received cidofovir. Strains were initially foscarnet-resistant in 3 patients and secondarily so in 4 patients. In vitro resistance to acyclovir or foscarnet was associated with clinical failure of these drugs; however, in vitro susceptibility to foscarnet was associated with complete response in only 5 of 7 patients. No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response. Therefore, acyclovir- and/or foscarnet-resistant HSV-1 infections after allogeneic stem cell transplantation have become a concern; current strategies need to be reassessed and new strategies must be evaluated in this setting. PMID:11049772

  2. The production of migration inhibitory factor and reproductive capacity in allogeneic pregnancies.

    PubMed Central

    Tofoski, J. G.; Gill, T. J.

    1977-01-01

    Migration inhibitory factor (MIF) is produced during allogeneic pregnancies but not during syngeneic pregnancies. Removal of the paraaortic or paraaortic and renal lymph nodes significantly decreased MIF production whereas splenectomy did not. Removal of these regional lymph nodes decreased the mean litter size and increased the variance in the weights of the offspring, with the greatest changes occurring when both the paraaortic and renal lymph nodes were removed; splenectomy did not alter either parameter. None of the surgical procedures affected the gestation period significantly, but removal of the paraaortic and renal lymph nodes greatly reduced the rate of conception and increased the incidence of stillbirths. These findings support the proposition that a vigorous immune response occurs during allogeneic pregnancies and that this response provides reproductive advantages to the offspring. PMID:327826

  3. Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016.

    PubMed

    Ullmann, Andrew J; Schmidt-Hieber, Martin; Bertz, Hartmut; Heinz, Werner J; Kiehl, Michael; Krüger, William; Mousset, Sabine; Neuburger, Stefan; Neumann, Silke; Penack, Olaf; Silling, Gerda; Vehreschild, Jörg Janne; Einsele, Hermann; Maschmeyer, Georg

    2016-09-01

    Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria. PMID:27339055

  4. BET bromodomain inhibition suppresses graft-versus-host disease after allogeneic bone marrow transplantation in mice

    PubMed Central

    Sun, Yaping; Wang, Ying; Toubai, Tomomi; Oravecz-Wilson, Katherine; Liu, Chen; Mathewson, Nathan; Wu, Julia; Rossi, Corinne; Cummings, Emily; Wu, Depei; Wang, Shaomeng

    2015-01-01

    Acute graft-versus-host disease (GVHD) is the major obstacle of allogeneic bone marrow transplantation (BMT). Bromodomain and extra-terminal (BET) protein inhibitors selectively block acetyl-binding pockets of the bromodomains and modulate histone acetylation. Here, we report that inhibition of BET bromodomain (BRD) proteins with I-BET151 alters cytokine expression in dendritic cells (DCs) and T cells, including surface costimulatory molecules, in vitro and in vivo cytokine secretion, and expansion. Mechanistic studies with I-BET151 and JQ1, another inhibitor, demonstrate that these effects could be from disruption of association between BRD4 and acetyl-310 RelA of nuclear factor kappa B. Short-term administration early during BMT reduced GVHD severity and improved mortality in two different allogeneic BMT models but retained sufficient graft-versus-tumor effect. Thus inhibiting BRD proteins may serve as a novel approach for preventing GVHD. PMID:25778533

  5. Transplantation of Tail Skin to Study Allogeneic CD4 T Cell Responses in Mice

    PubMed Central

    Rossi, Simona W.

    2014-01-01

    The study of T cell responses and their consequences during allo-antigen recognition requires a model that enables one to distinguish between donor and host T cells, to easily monitor the graft, and to adapt the system in order to answer different immunological questions. Medawar and colleagues established allogeneic tail-skin transplantation in mice in 1955. Since then, the skin transplantation model has been continuously modified and adapted to answer specific questions. The use of tail-skin renders this model easy to score for graft rejection, requires neither extensive preparation nor deep anesthesia, is applicable to animals of all genetic background, discourages ischemic necrosis, and permits chemical and biological intervention. In general, both CD4+ and CD8+ allogeneic T cells are responsible for the rejection of allografts since they recognize mismatched major histocompatibility antigens from different mouse strains. Several models have been described for activating allogeneic T cells in skin-transplanted mice. The identification of major histocompatibility complex (MHC) class I and II molecules in different mouse strains including C57BL/6 mice was an important step toward understanding and studying T cell-mediated alloresponses. In the tail-skin transplantation model described here, a three-point mutation (I-Abm12) in the antigen-presenting groove of the MHC-class II (I-Ab) molecule is sufficient to induce strong allogeneic CD4+ T cell activation in C57BL/6 mice. Skin grafts from I-Abm12 mice on C57BL/6 mice are rejected within 12-15 days, while syngeneic grafts are accepted for up to 100 days. The absence of T cells (CD3-/- and Rag2-/- mice) allows skin graft acceptance up to 100 days, which can be overcome by transferring 2 x 104 wild type or transgenic T cells. Adoptively transferred T cells proliferate and produce IFN-γ in I-Abm12-transplanted Rag2-/- mice. PMID:25147005

  6. Early Lung Computed Tomography Scan after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Cornetto, Marie Alice; Chevret, Sylvie; Abbes, Sarah; de Margerie-Mellon, Constance; Hussenet, Claire; Sicre de Fontbrune, Flore; Tazi, Abdellatif; Ribaud, Patricia; Bergeron, Anne

    2016-08-01

    A lung computed tomography (CT) scan is essential for diagnosing lung diseases in hematopoietic stem cell transplantation (HSCT) recipients. As a result, lung CT scans are increasingly prescribed in the early phase after allogeneic HSCT, with no assessment of the added value for global patient management. Among 250 patients who underwent allogeneic HSCT in our center over a 2-year period, we evaluated 68 patients who had at least 1 lung CT scan within the first 30 days post-transplantation. The median interval between allogeneic HSCT and lung CT scan was 8.5 days. Patients who underwent an early lung CT scan were more immunocompromised and had a more severe course. Fever was the main indication for the CT scan (78%). The lung CT scan was abnormal in 52 patients, including 17 patients who had an abnormal pre-HSCT CT scan. A therapeutic change was noted in 37 patients (54%) within 24 hours after the lung CT scan. The main changes included the introduction of corticosteroids (n = 23; 62%), especially in patients with a normal CT scan (89%). In univariate models, we found that a normal pretransplantation CT scan (P = .002), the absence of either dyspnea (P = .029) or hypoxemia (P = .015), and a serum C-reactive protein level <10 mg/L (P = .004) were associated with a normal post-HSCT lung CT scan. We found that the association of these variables could predict the normality of early post-HSCT lung CT scans. Pretransplantation lung CT scans are useful for the interpretation of subsequent lung CT scans following allogeneic HSCT, which are frequently abnormal. Early post-HSCT lung CT scans are helpful in patient management, but prescriptions could be more targeted. PMID:27189110

  7. A Novel Cancer Vaccine Strategy Based on HLA-A*0201 Matched Allogeneic Plasmacytoid Dendritic Cells

    PubMed Central

    Aspord, Caroline; Charles, Julie; Leccia, Marie-Therese; Laurin, David; Richard, Marie-Jeanne; Chaperot, Laurence; Plumas, Joel

    2010-01-01

    Background The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. Methods and Findings Stimulation of PBMC from HLA-A*0201+ donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer+ CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. Conclusions These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer. PMID:20454561

  8. Subcutaneous infection caused by Blastoschizomyces capitatus post allogeneic hematopoietic transplant and its successful treatment with voriconazole.

    PubMed

    Devadas, S K; Bhat, V; Khattry, N

    2015-08-01

    We describe a 33-year-old man with relapsed acute myelogenous leukemia who developed subcutaneous nodules >6 months after allogeneic hematopoietic stem cell transplant. These nodules were caused by Blastoschizomyces capitatus. The lesions progressed after treatment with a posaconazole suspension. The lesions resolved after switching to voriconazole, which was given for 21 weeks. B. capitatus is a rare infection affecting immunocompromised patients, which responds to azoles. PMID:26012493

  9. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors.

    PubMed

    Socié, G; Sélimi, F; Sedel, L; Frija, J; Devergie, A; Esperou Bourdeau, H; Ribaud, P; Gluckman, E

    1994-03-01

    In the present study we describe the incidence, clinical course, and management of avascular necrosis of bone following allogeneic bone marrow transplantation, and identify risk factors related to its development. All patients developing avascular necrosis of bone after allogeneic bone marrow transplantation between January 1974 and September 1992 were included in the analysis and were studied using the Hôpital Saint Louis Bone Marrow Transplant Database and hospital records. 27/727 allogeneic transplant recipients developed avascular necrosis leading to an 8.1% incidence at 5 years, by product limit estimate, ranging from 5% to 11.2%. Symptoms developed 119-1747 d (median 398 d) after transplantation. In these 27 patients a total of 52 joints were affected (mean 1.92 per patient, range 1-7). The hip joint was most often affected (69% of patients). All patients had joint pain that led to diagnosis by means of standard radiographs with or without the help of technetium-99 scans and/or magnetic resonance imaging. All but three patients received steroid therapy for acute graft-versus-host disease. Among 10 factors tested, three were shown to be significantly linked to an increased risk for developing avascular necrosis by multivariate analysis: male gender (relative risk (RR) 4.72, P = 0.002), age older than 16 (RR = 3.87, P = 0.004), and acute graft-versus-host disease requiring steroid therapy (RR = 6.30, P = 0.0002). 10 patients (37%) required joint replacement within 19 months (range 2-42) following diagnosis of avascular necrosis. In conclusion, avascular necrosis of bone is a frequent late complication of allogeneic bone marrow transplantation causing significant morbidity and requiring replacement surgery in one-third of affected patients. In this 18-year single-centre survey, older age, male gender and steroid therapy given for acute graft-versus-host disease were shown to independently increase the risk of avascular necrosis of bone. PMID:8043445

  10. Voriconazole-Induced Periostitis Mimicking Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation

    PubMed Central

    Oh, Annie; Rondelli, Damiano; Patel, Pritesh

    2016-01-01

    Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy. PMID:27403356

  11. Fungemia Caused by Zygoascus hellenicus in an Allogeneic Stem Cell Transplant Recipient

    PubMed Central

    Brandt, Mary E.; Kauffman, Carol A.; Pappas, Peter G.; Iqbal, Naureen; Arthington-Skaggs, Beth A.; Lee-Yang, Wendy; Smith, Maudy T.

    2004-01-01

    Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast. PMID:15243118

  12. Fungemia caused by Zygoascus hellenicus in an allogeneic stem cell transplant recipient.

    PubMed

    Brandt, Mary E; Kauffman, Carol A; Pappas, Peter G; Iqbal, Naureen; Arthington-Skaggs, Beth A; Lee-Yang, Wendy; Smith, Maudy T

    2004-07-01

    Zygoascus hellenicus (Candida hellenica) was isolated from a blood culture from a patient who had received an allogeneic stem cell transplant. The isolate displayed an antifungal susceptibility pattern of decreased susceptibility to fluconazole and itraconazole, high susceptibility to voriconazole, and low susceptibility to caspofungin. The organism was misidentified by a commercial yeast identification system. This is the first reported case of human infection with this rare ascomycetous yeast. PMID:15243118

  13. Allogeneic IgG combined with dendritic cell stimuli induces anti-tumor T cell immunity

    PubMed Central

    Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Burt, Bryan M; Prestwood, Tyler R.; Perlman, Nikola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Pusapati, Ganesh V.; Bhattacharya, Nupur; Engleman, Edgar G.

    2015-01-01

    While cancers grow in their hosts and evade host immunity through immunoediting and immunosuppression1–5, tumors are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumors are reliably rejected by host T cells, even when the tumor and host share the same major histocompatibility complex (MHC) alleles, the most potent determinants of transplant rejection6–10. How such tumor-eradicating immunity is initiated remains unknown, though elucidating this process could provide a roadmap for inducing similar responses against naturally arising tumors. We found that allogeneic tumor rejection is initiated by naturally occurring tumor-binding IgG antibodies, which enable dendritic cells (DC) to internalize tumor antigens and subsequently activate tumor-reactive T cells. We exploited this mechanism to successfully treat autologous and autochthonous tumors. Either systemic administration of DC loaded with allogeneic IgG (alloIgG)-coated tumor cells or intratumoral injection of alloIgG in combination with DC stimuli induced potent T cell mediated anti-tumor immune responses, resulting in tumor eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumors and metastases, as well as the injected primary tumors. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumor antigens after culture with alloIgG-loaded DC, recapitulating our findings in mice. These results reveal that tumor-binding alloIgG can induce powerful anti-tumor immunity that can be exploited for cancer immunotherapy. PMID:25924063

  14. Nodular lymphocyte-predominant Hodgkin lymphoma.

    PubMed

    Savage, Kerry J; Mottok, Anja; Fanale, Michelle

    2016-07-01

    Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma with distinct clinicopathologic features. It is typified by the presence of lymphocyte predominant (LP) cells, which are CD20(+) but CD15(-) and CD30(-) and are found scattered amongst small B lymphocytes arranged in a nodular pattern. Despite frequent and often late or multiple relapses, the prognosis of NLPHL is very favorable. There is an inherent risk of secondary aggressive non-Hodgkin lymphoma (NHL) and studies support that risk is highest in those with splenic involvement at presentation. Given disease rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma (CHL). This review provides an overview of the existing literature describing pathological subtypes, outcome and treatment approaches for NLPHL. PMID:27496311

  15. T cell immunity using transgenic B lymphocytes

    NASA Astrophysics Data System (ADS)

    Gerloni, Mara; Rizzi, Marta; Castiglioni, Paola; Zanetti, Maurizio

    2004-03-01

    Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (102). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.

  16. Macroautophagy in T Lymphocyte Development and Function

    PubMed Central

    He, Ming-Xiao; McLeod, Ian X.; Jia, Wei; He, You-Wen

    2011-01-01

    Macroautophagy (referred to as autophagy) is a fundamental intracellular process characterized by the sequestration of cytoplasmic compartments through double-membrane vesicles, termed autophagosomes. Recent studies have established important roles of autophagy in regulating T lymphocyte development and function. Resting T lymphocytes have basal levels of autophagy that is upregulated by T cell receptor stimulation. Several specific knockout or transgenic models have been developed during the past few years, and it has been revealed that autophagy plays an essential role in regulating thymocyte selection, peripheral T cell survival, and proliferation. The regulation of T cell development and function by autophagy is mediated through its role in regulating self-antigen presentation, intracellular organelle homeostasis, and energy production. Here we will review the current findings concerning how autophagy regulates T cell function, as well as compare different models in studying autophagy in T lymphocytes. PMID:22566906

  17. Temperature effects on lymphocyte transformation invitro.

    PubMed

    Hirsch, R L; Jeffries, B D; Gray, I

    1977-01-01

    Phytohemagglutinin (PHA)-induced transformation of normal rat peripheral lymphocytes has been studied at a wide range of culture temperatures (4 degrees C to 42 degrees C). Lymphocyte transformation was maximum at 37 degrees C while insignificant stimulation was observed between 4 degrees C and 30 degrees C. Temperatures above 37 degrees C produced sub=optimal transformation as measured by synthesis of DNA and protein, and appearance of lymphoblasts. Binding studies using 125I-PHA indicate that the low temperature inhibition of lymphocyte transformation could be a result of excess lectin (being available as a result of low temperature) bound to the cell surface, preventing the initiation of the molecular events associated with transformation. PMID:863471

  18. [T-LYMPHOCYTES AND TISSUE GROWTH FACTORS].

    PubMed

    Tishevskaya, N V; Gevorkyan, N M; Kozlova, N I

    2015-08-01

    Lympnoici regulation, in aciaition to ensuring tne protection of tne antigen, is aimecl at maintaining a qualitative, quantitative, structural and functional integrity of the body. T-lymphocytes and growth factors are involved in cell proliferation, differentiation, and tissue and organ regeneration. Lymphocyte's, sensitivity to homeostasis changes and their morphogenetic function are connected with a large number of receptors to bioactive substances and with their ability to syn- thesize and secrete hormones and tissue growth factors. At the same time tissue growth factors are involved in the development of thymocytes, in the differentiation of T helper and cytotoxic lymphocytes. Growth factors modulate the functions of Thl, Th2, Treg, Thl7, Th9. The important aspects of the interaction of T cells and EGF, TGF-P, FGF, VEGF, PlGF, HGF/SF in normal and pathological conditions are shown in this review. PMID:26591583

  19. Frequency of Cytotoxic T Lymphocyte Precursors to Herpes Simplex Virus Type 1 as Determined by Limiting Dilution Analysis

    PubMed Central

    Rouse, Barry T.; Larsen, Hal S.; Wagner, Hermann

    1983-01-01

    The conditions for establishing a limiting dilution assay to measure cytotoxic T lymphocyte precursors (CTL-P) against herpes simplex virus type 1 (HSV-1) were determined. Analysis by Poisson statistics demonstrated that the estimated frequency of HSV-1-reactive cells in the spleens of normal mice was less than 1/250,000. In contrast, mice immunized previously with infectious HSV-1 demonstrated a CTL-P frequency between 1/3,500 and 1/15,670. The generation of a maximum cytotoxic T lymphocyte response required that mice be primed in vivo with infectious virus. Immunization with inactivated virus either failed to elicit detectable CTL-P frequencies or gave frequencies markedly less than those induced with infectious virus. To obtain positive cultures, the responder cell population had to be exposed to stimulator splenocytes expressing viral antigens. Normal splenocytes without virus or normal splenocytes with T cell growth factor did not result in significant cytotoxicity. Split culture analysis comparing cytotoxicity against syngeneic and allogeneic virus-infected targets provided evidence for specificity, H-2 restriction, and the T cell nature of the CTL-P. It was determined that precursors were eliminated by treatment with anti-Thy 1, Lyt 2.1, or Lyt 1.1, indicating the CTL-P were Lyt 1+2+ cells. Cytotoxicity was reduced after treatment of the responders with anti-Lyt 2 plus complement, which gave further evidence of the T cell nature of the cytotoxic T lymphocytes. These experiments demonstrated the feasibility of using the limiting dilution approach as a highly sensitive and quantitative means to measure the cell-mediated immune response to HSV-1 antigens. PMID:6299949

  20. A cost comparison of allogeneic and preoperatively or intraoperatively donated autologous blood.

    PubMed

    Roberts, W A; Kirkley, S A; Newby, M

    1996-07-01

    We determined the cost of allogeneic packed red blood cells and autologous whole blood donated either preoperatively or in the operating room during hemodilution. Direct and indirect cost estimates were based on patients requiring simple transfusion and included procurement and preparation of the blood including testing performed, materials and time used, waste, and materials for administration. Data were derived from prospective blood bank time studies, material invoice records, and retrospective review of anesthesia times. Viral infection and transfusion reaction costs were accepted from previously published sources. Direct cost of purchasing and indirect costs of preparation resulted in an overall cost of $107.26 for the first unit of allogeneic packed red blood cells transfused. A second unit was slightly less costly ($100.89), as no type and screen was required and the same delivery set and filter can be used. The total cost of acquisition, processing, and transfusion of 1 U of preoperatively donated autologous blood was $97.83. The total cost of a 2-U transfusion of autologous whole blood donated in the operating room during acute normovolemic hemodilution was $83.10. These data suggest that autologous predonation of whole blood is somewhat less expensive than allogeneic packed red blood cells, and that hemodilution may be a cost effective alternative to autologous predonation in selected patients. PMID:8659723

  1. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    Hashimoto, Daigo; Chow, Andrew; Greter, Melanie; Saenger, Yvonne; Kwan, Wing-Hong; Leboeuf, Marylene; Ginhoux, Florent; Ochando, Jordi C.; Kunisaki, Yuya; van Rooijen, Nico; Liu, Chen; Teshima, Takanori; Heeger, Peter S.; Stanley, E. Richard; Frenette, Paul S.

    2011-01-01

    Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic. PMID:21536742

  2. Feasibility of combination allogeneic stem cell therapy for spinal cord injury: a case report

    PubMed Central

    2010-01-01

    Cellular therapy for spinal cord injury (SCI) is overviewed focusing on bone marrow mononuclear cells, olfactory ensheathing cells, and mesenchymal stem cells. A case is made for the possibility of combining cell types, as well as for allogeneic use. We report the case of 29 year old male who suffered a crush fracture of the L1 vertebral body, lacking lower sensorimotor function, being a score A on the ASIA scale. Stem cell therapy comprised of intrathecal administration of allogeneic umbilical cord blood ex-vivo expanded CD34 and umbilical cord matrix MSC was performed 5 months, 8 months, and 14 months after injury. Cell administration was well tolerated with no adverse effects observed. Neuropathic pain subsided from intermittent 10/10 to once a week 3/10 VAS. Recovery of muscle, bowel and sexual function was noted, along with a decrease in ASIA score to "D". This case supports further investigation into allogeneic-based stem cell therapies for SCI. PMID:21070647

  3. Engraftment syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation: incidence and effects on survival.

    PubMed

    Gorak, Edward; Geller, Nancy; Srinivasan, Ramaprasad; Espinoza-Delgado, Igor; Donohue, Teresa; Barrett, A John; Suffredini, Anthony; Childs, Richard

    2005-07-01

    Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor. Fifteen (10%) of 149 patients (median age, 53 years; range, 27-66 years) developed ES; the onset of symptoms occurred at a median of 10 days (range, 3-14 days), and they consisted of fever (100%), cough (53%), diffuse pulmonary infiltrates (100%), rash (13%), and room air hypoxia (87%). ES was more likely to develop in patients who received empiric amphotericin formulations after transplant conditioning (Fisher exact test; P=.007). In a multivariate analysis, older patient age, female sex, and treatment with amphotericin were predictors for the development of ES. Intravenous methylprednisolone led to the rapid resolution of ES; however, transplant-related mortality was significantly higher (cumulative incidence, 49% versus 16%; P=.0005), and median survival was significantly shorter (168 versus 418 days; P=.005) in patients with ES compared with non-ES patients. In conclusion, ES occurs commonly after cyclophosphamide/fludarabine-based nonmyeloablative transplantation and responds rapidly to corticosteroid treatment, but it is associated with a higher risk of nonrelapse mortality and with shorter overall survival. PMID:15983554

  4. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

    PubMed Central

    Ramadan, Safaa M.; Di Veroli, Ambra; Camboni, Agnese; Breccia, Massimo; Iori, Anna Paola; Aversa, Franco; Cupelli, Luca; Papayannidis, Cristina; Bacigalupo, Andrea; Arcese, William; Lo-Coco, Francesco

    2012-01-01

    The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed. PMID:22689684

  5. Reticulated platelets as a marker of platelet recovery after allogeneic stem cell transplantation.

    PubMed

    Michur, H; Maślanka, K; Szczepiński, A; Mariańska, B

    2008-12-01

    Reticulated platelets (RP) are the youngest forms of platelets in blood and reflect the rate of bone marrow platelet production. In the present study, we used flow cytometric analysis to determine the percentage of RPs in patients undergoing allogeneic stem cell transplantation. We investigated 10 patients after transplantation from HLA identical siblings: five with acute myeloid leukemia (AML), four with chronic myeloid leukemia (CML), and one patient with myelodysplastic syndrome (MDS). Of the patients examined, four patients underwent allogeneic bone marrow transplantation and six patients underwent peripheral blood stem cell transplantation. It was observed that the initially reduced percentage of RPs (2.9 +/- 1.7%; mean +/- SD) was significantly higher (P = 0.0109) in all patients (13.6 +/- 6.4%) in the following 10-26 days. The RP percentage peak preceded the recovery of peripheral platelet count up to 45.6 x 10(9)/l on average by 3 days. We found no difference in RP% between the AML and CML patients but we did observe that in CML patients the RP percentage increased on average 7 days earlier than in AML patients. The elevated RP percentage reflects increased bone marrow regeneration and can be considered an additional marker of thrombopoietic recovery in the patients undergoing allogeneic stem cell transplantation. PMID:18983304

  6. Outcome of Lower-Intensity Allogeneic Transplantation in non-Hodgkin Lymphoma After Autologous Transplant Failure

    PubMed Central

    Freytes, César O.; Zhang, Mei-Jie; Carreras, Jeanette; Burns, Linda J.; Gale, Robert Peter; Isola, Luis; Perales, Miguel-Angel; Seftel, Matthew; Vose, Julie M.; Miller, Alan M.; Gibson, John; Gross, Thomas G.; Rowlings, Philip A.; Inwards, David J.; Pavlovsky, Santiago; Martino, Rodrigo; Marks, David I.; Hale, Gregory A.; Smith, Sonali M.; Schouten, Harry C.; Slavin, Simon; Klumpp, Thomas R.; Lazarus, Hillard M.; van Besien, Koen; Hari, Parameswaran N.

    2012-01-01

    We studied the outcome of allogeneic transplantation after lower-intensity conditioning regimens (reduced-intensity [RIC] and non-myeloablative [NST]) in non-Hodgkin lymphoma (NHL) relapsing after autologous transplantation. Non-relapse mortality (NRM), lymphoma progression/relapse, progression-free survival (PFS) and overall survival (OS) were analyzed in 263 NHL patients. All had relapsed after a prior autologous transplant and then received allogeneic transplantation from related (n = 26) or unrelated donors (n= 237) after RIC (n = 128) or NST (n = 135), and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2006. Median follow-up of survivors was 68 months (range, 3–111). Three-year NRM was 44% (95% CI, 37%–50%). Lymphoma progression/relapse at three years was 35% (95% CI, 29%–41%). Three-year probabilities of PFS and OS were 21% (95% CI, 16%–27%) and 32% (95% CI, 27%–38%) respectively. Superior performance score, longer interval between transplants, total-body irradiation-based conditioning regimen and lymphoma remission at transplantation correlated with improved PFS. Allogeneic transplantation after lower-intensity conditioning is associated with significant NRM, but can result in long-term PFS. We describe a quantitative risk model based on pretransplant risk factors in order to identify those likely to benefit from this approach. PMID:22198543

  7. Frequent genomic alterations in epithelium measured by microsatellite instability following allogeneic hematopoietic cell transplantation in humans.

    PubMed

    Faber, Philipp; Fisch, Paul; Waterhouse, Miguel; Schmitt-Gräff, Annette; Bertz, Hartmut; Finke, Jürgen; Spyridonidis, Alexandros

    2006-04-15

    Although typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. We examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at 3 tetranucleotide and 3 mononucleotide microsatellite loci. Novel bands indicative of microsatellite instability (MSI) at tetranucleotide repeats were detected in laser-microdissected colonic crypts and in buccal smears of 75% and 42% of patients who received an allograft, respectively. In contrast, no MSI was found in similar tissues from control subjects and from patients after intensive chemotherapy or in buccal cells from patients after autologous HCT. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins. MSI in clinically intact oral mucosa was more frequently found at later time points after HCT. MSI was also found in 3 posttransplant squamous cell cancers examined. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT and may be implicated in the evolution of posttransplantation diseases, including secondary cancer. PMID:16368884

  8. Allogeneic hematopoietic cell transplantation for consolidation of VGPR or CR for newly diagnosed multiple myeloma.

    PubMed

    Nishihori, T; Ochoa-Bayona, J L; Kim, J; Pidala, J; Shain, K; Baz, R; Sullivan, D; Jim, H S; Anasetti, C; Alsina, M

    2013-09-01

    Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach in patients with multiple myeloma, but its use for consolidation of first remission has not yet been fully explored. Twenty-two myeloma patients with very good partial response (VGPR) or CR received allogeneic peripheral blood grafts as consolidation from HLA-matched donors between 2007 and 2012. Conditioning regimens were fludarabine (30 mg/m(2) i.v. if with bortezomib and 40 mg/m(2) i.v. when without bortezomib, × 4 days) plus melphalan (70 mg/m(2) intravenously × 2 days) with (n=13) or without (n=9) bortezomib (1.3 mg/m(2)). The cumulative incidence of grades II - IV acute GVHD at day 100 was 45% (95% CI: 24-65%) and moderate-to-severe chronic GVHD at 2 years was 46% (95% CI: 19-69%). With a median follow-up of 18 (range, 2-61) months, the 2-year PFS estimate is 74.8% (95% CI: 45-90%), which compares favorably with the 52% (95% CI: 35-66%) after autologous HCT for similar patients (a median follow-up of 30 (range, 9-55) months). We are conducting a phase 2 study to assess the efficacy of allogeneic HCT as post-remission therapy. PMID:23542223

  9. Appropriateness of allogeneic red blood cell transfusion: the international consensus conference on transfusion outcomes.

    PubMed

    Shander, Aryeh; Fink, Arlene; Javidroozi, Mazyar; Erhard, Jochen; Farmer, Shannon L; Corwin, Howard; Goodnough, Lawrence Tim; Hofmann, Axel; Isbister, James; Ozawa, Sherri; Spahn, Donat R

    2011-07-01

    An international multidisciplinary panel of 15 experts reviewed 494 published articles and used the RAND/UCLA Appropriateness Method to determine the appropriateness of allogeneic red blood cell (RBC) transfusion based on its expected impact on outcomes of stable nonbleeding patients in 450 typical inpatient medical, surgical, or trauma scenarios. Panelists rated allogeneic RBC transfusion as appropriate in 53 of the scenarios (11.8%), inappropriate in 267 (59.3%), and uncertain in 130 (28.9%). Red blood cell transfusion was most often rated appropriate (81%) in scenarios featuring patients with hemoglobin (Hb) level 7.9 g/dL or less, associated comorbidities, and age older than 65 years. Red blood cell transfusion was rated inappropriate in all scenarios featuring patients with Hb level 10 g/dL or more and in 71.3% of scenarios featuring patients with Hb level 8 to 9.9 g/dL. Conversely, no scenario with patient's Hb level of 8 g/dL or more was rated as appropriate. Nearly one third of all scenarios were rated uncertain, indicating the need for more research. The observation that allogeneic RBC transfusions were rated as either inappropriate or uncertain in most scenarios in this study supports a more judicious transfusion strategy. In addition, the large number of scenarios in which RBC transfusions were rated as uncertain can serve as a road map to identify areas in need of further investigation. PMID:21498040

  10. Secondary solid cancers after allogeneic hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning

    PubMed Central

    Brazauskas, Ruta; Rizzo, J. Douglas; Sobecks, Ronald M.; Wang, Zhiwei; Horowitz, Mary M.; Bolwell, Brian; Wingard, John R.; Socie, Gerard

    2011-01-01

    Risks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4× higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population. PMID:20926773

  11. Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation.

    PubMed

    Modi, Dipenkumar; Jang, Hyejeong; Kim, Seongho; Deol, Abhinav; Ayash, Lois; Bhutani, Divaya; Lum, Lawrence G; Ratanatharathorn, Voravit; Manasa, Richard; Mellert, Kendra; Uberti, Joseph P

    2016-09-01

    Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc. PMID:27238902

  12. Allogeneic adipose-derived stem cells regenerate bone in a critical-sized ulna segmental defect.

    PubMed

    Wen, Congji; Yan, Hai; Fu, Shibo; Qian, Yunliang; Wang, Danru; Wang, Chen

    2016-07-01

    Adipose-derived stem cells (ASCs) with multilineage potential can be induced into osteoblasts, adipocytes and chondrocytes. ASCs as seed cell are widely used in the field of tissue engineering, but most studies either use autologous cells as the source or an immunodeficient animal as the host. In our present study, we explored the feasibility of applying allogeneic ASCs and demineralized bone matrix (DBM) scaffolds for repairing tubular bone defects without using immunosuppressive therapy. Allogeneic ASCs were expanded and seeded on DBM scaffolds and induced to differentiate along the osteogenic lineage. Eight Sprague-Dawley (SD) rats were used in this study and bilateral critical-sized defects (8 mm) of the ulna were created and divided into two groups: with ASC-DBM constructs or DBM alone. The systemic immune response and the extent of bone healing were evaluated post-operatively. Twenty-four weeks after implantation, digital radiography (DR) testing showed that new bones had formed in the experimental group. By contrast, no bone tissue formation was observed in the control group. This study demonstrated that allogeneic ASCs could promote bone regeneration and repair tubular bone defects combined with DBM by histologically typical bone without systemic immune response. PMID:25819682

  13. Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

    SciTech Connect

    McGlave, P.B.; Miller, W.J.; Hurd, D.D.; Arthur, D.C.; Kim, T.

    1981-11-01

    We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern or demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease.

  14. Active suppression of host-vs-graft reaction in pregnant mice. VII. Spontaneous abortion of allogeneic CBA/J x DBA/2 fetuses in the uterus of CBA/J mice correlates with deficient non-T suppressor cell activity

    SciTech Connect

    Clark, D.A.; Chaput, A.; Tutton, D.

    1986-03-01

    The mammalian fetus has been viewed as an unusually successful type of allograft and unexplained spontaneous abortion as a possible example of maternal rejection. Previous studies have shown the presence of small lymphocytic suppressor cells in the murine decidua which block the generation and reactivation of anti-paternal cytotoxic T lymphocytes (CTL) and lymphokine-activated killer cells (LAK) by elaborating a factor that inhibits the response to interleukin 2 (IL 2). A deficiency of these suppressor cells was associated with implants of xenogeneic Mus caroli embryos in the Mus musculus uterus which are infiltrated by maternal lymphoid cells and aborted. A deficiency of such suppressor cells in the lymph nodes draining the uterus of CBA/J females in the process of aborting their semi-allogeneic CBA x DBA/2 F/sub 1/ progeny has also been shown. CBA/J females possess significantly lower levels of decidua-associated non-T suppressor cells on day 8.5 to 10.5 of allopregnancy than do mothers that will produce large litters of live babies. The F/sub 1/ embryos are infiltrated by maternal lymphocytes prior to abortion, and the infiltration and abortion rate appears to be augmented by pre-immunization with paternal DBA/2 spleen cells. The CBA/J x DBA/2J mating combination provides a model of spontaneous abortion in which immunologic factors play an important role and demonstrates that the association between deficiency of decidua-associated suppressor cells and xenopregnancy failure also holds true for the failure of allopregnancies resulting from natural within-species mating.

  15. Alemtuzumab in chronic lymphocytic leukemia

    PubMed Central

    Fraser, G.; Smith, C.A.; Imrie, K.; Meyer, R.

    2007-01-01

    Questions With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (cll)? What toxicities are associated with the use of alemtuzumab? Which patients are more likely—or less likely—to benefit from treatment with alemtuzumab? Perspectives Evidence was selected and reviewed by one member of the Hematology Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) and by methodologists. The practice guideline report was reviewed and approved by the Hema-tology dsg, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario. Outcomes Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates. Methodology A systematic review of the medline, embase, HealthStar, cinahl, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the pebc. Results The literature review found no published randomized controlled trials (rcts) that evaluated alem-tuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory cll. One rct evaluated alemtuzumab administered to consolidate a complete or partial response to first-line fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients

  16. Human malignant melanoma-derived progestagen-associated endometrial protein immunosuppresses T lymphocytes in vitro.

    PubMed

    Ren, Suping; Chai, Lina; Wang, Chunyan; Li, Changlan; Ren, Qiquan; Yang, Lihua; Wang, Fumei; Qiao, Zhixin; Li, Weijing; He, Min; Riker, Adam I; Han, Ying; Yu, Qun

    2015-01-01

    Progestagen-associated endometrial protein (PAEP) is a glycoprotein of the lipocalin family that acts as a negative regulator of T cell receptor-mediated activation. However, the function of tumor-derived PAEP on the human immune system in the tumor microenvironment is unknown. PAEP is highly expressed in intermediate and thick primary melanomas (Breslow's 2.5mm or greater) and metastatic melanomas, correlating with its expression in daughter cell lines established in vitro. The current study investigates the role of melanoma cell-secreted PAEP protein in regulating T cell function. Upon the enrichment of CD3+, CD4+ and CD8+ T cells from human peripheral blood mononuclear cells, each subset was then mixed with either melanoma-derived PAEP protein or PAEP-poor supernatant of gene-silenced tumor cells. IL-2 and IFN-γ secretion of CD4+ T cells significantly decreased with the addition of PAEP-rich supernatant. And the addition of PAEP-positive cell supernatant to activated lymphocytes significantly inhibited lymphocyte proliferation and cytotoxic T cell activity, while increasing lymphocyte apoptosis. Our result suggests that melanoma cell-secreted PAEP protein immunosuppresses the activation, proliferation and cytotoxicity of T lymphocytes, which might partially explain the mechanism of immune tolerance induced by melanoma cells within the tumor microenvironment. PMID:25785839

  17. Studies of Two Subpopulations of Human Lymphocytes Differing in Responsiveness to Concanavalin A

    PubMed Central

    Boldt, David; Skinner, Sister Ann Marie; Kornfeld, Stuart

    1972-01-01

    We have identified two populations of human lymphocytes differing in responsiveness to the plant mitogen concanavalin A (Con-A). When peripheral blood lymphocytes are passed through a nylon column a population of lymphocytes highly responsive to Con-A adheres to the fibers while a second population of cells relatively unresponsive to Con-A emerges from the column. The untreated peripheral blood lymphocytes are termed “unfiltered” cells while the lymphocytes which pass through the column are termed “filtered” cells. Under standard assay conditions the Con-A-stimulated DNA synthesis is 6.5-fold greater, and the percentage blast formation is four-to fivefold greater in the unfiltered than in the filtered population. Mixing unfiltered with filtered cells fails to induce responsiveness in the latter indicating that a “helper” cell is not involved. The failure of filtered cells to respond to Con-A is specific for that mitogen since both populations respond nearly equally to erythroagglutinating phytohemagglutinin (E-PHA) and the poke weed mitogen (PWM). Binding studies with Con-A-131I demonstrate that the unfiltered population possesses approximately three times as many Con-A receptor sites per cell as the filtered cells, although both cell populations bind the mitogen with the same affinity (apparent association constant [K] of 1.67 × 106m−1). The relationship between Con-A binding and lymphocyte activation was determined by measuring the effect on DNA synthesis of incubating the two lymphocyte populations with increasing amounts of Con-A. The concentration of Con-A required for half-maximal stimulation of DNA synthesis was 5-14 times greater for the filtered cells. However in the presence of very high Con-A concentrations the filtered cells achieved a maximal rate of DNA synthesis approaching that of the unfiltered population. These data implicate the decreased number of Con-A receptor sites on the filtered cells in their failure to respond to low

  18. AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

    ClinicalTrials.gov

    2016-03-16

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large

  19. What Are the Key Statistics for Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... for chronic lymphocytic leukemia? What are the key statistics for chronic lymphocytic leukemia? The American Cancer Society's ... in children. Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Last Medical Review: ...

  20. What Should You Ask Your Doctor about Chronic Lymphocytic Leukemia?

    MedlinePlus

    ... chronic lymphocytic leukemia? What should you ask your doctor about chronic lymphocytic leukemia? As you cope with ... need to have honest, open discussions with your doctor. You should feel comfortable asking any question, no ...

  1. What Should You Ask Your Doctor about Acute Lymphocytic Leukemia?

    MedlinePlus

    ... leukemia? What should you ask your doctor about acute lymphocytic leukemia? It is important to have frank, honest discussions ... answer many of your questions. What kind of acute lymphocytic leukemia (ALL) do I have? Do I have any ...

  2. What Are the Risk Factors for Acute Lymphocytic Leukemia?

    MedlinePlus

    ... lymphocytic leukemia? What are the risk factors for acute lymphocytic leukemia? A risk factor is something that affects your ... this is unknown. Having an identical twin with ALL Someone who has an identical twin who develops ...

  3. Response of lymphocytes to a mitogenic stimulus during spaceflight

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1989-01-01

    Several studies were performed that demonstrate that immunological activities of lymphocytes can be affected by spaceflight or by models that attempt to simulate some aspects of weightlessness. Included among these are the responses of lymphocytes to external stimuli such as mitogens and viruses. When cultures of lymphocytes were flown in space, the ability of the lymphocytes to respond to mitogens was inhibited. Similar results were obtained when lymphocytes from astronauts or animals just returned from space were placed into culture immediately upon return to earth, and when models of hypogravity were used. Lymphocytes placed in culture during spaceflights produced enhanced levels of interferon compared to control cultures. When cultures of lymphocytes were prepared for cosmonauts or rodents immediately upon return to earth, interferon production was inhibited. These results suggest that space flight can have profound effects on lymphocyte function, and that effects on isolated cells may be different from that on cells in the whole organism.

  4. Safety and Efficacy of Transplantation with Allogeneic Skin Tumors to Treat Chemically-Induced Skin Tumors in Mice.

    PubMed

    Zhang, Zhiwei; Sun, Hua; Zhang, Jianhua; Ge, Chunlei; Dong, Suwei; Li, Zhen; Li, Ruilei; Chen, Xiaodan; Li, Mei; Chen, Yun; Zou, Yingying; Qian, Zhongyi; Yang, Lei; Yang, Jinyan; Zhu, Zhitao; Liu, Zhimin; Song, Xin

    2016-01-01

    BACKGROUND Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice. MATERIAL AND METHODS FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety. The tumor-bearing ICR mice were transplanted with, or without, allogeneic skin tumors to test the efficacy. The body weights (BW), body condition scores (BCS), tumor volumes in situ, metastasis tumors, overall survival, and serum cytokines were measured longitudinally. RESULTS Transplantation with no more than 0.03 g allogeneic skin tumors from FVB/N mice to healthy ICR mice was safe. After transplantation with allogeneic skin tumors to treat tumor-bearing mice, it inhibited the growth of tumors slightly at early stage, accompanied by fewer metastatic tumors at 24 days after transplantation (21.05% vs. 47.37%), while there were no statistically significant differences in the values of BW, BCS, tumor volumes in situ, metastasis tumors, and overall survival between the transplanted and non-transplanted groups. The levels of serum interleukin (IL)-2 were significantly reduced in the controls (P<0.05), but not in the recipients, which may be associated with the tGVT response. CONCLUSIONS Our results suggest that transplantation with allogeneic skin tumors is a safe treatment in mice, which can induce short-term tGVT response mediated by IL-2. PMID:27587310

  5. High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment.

    PubMed

    Logan, Aaron C; Gao, Hong; Wang, Chunlin; Sahaf, Bita; Jones, Carol D; Marshall, Eleanor L; Buño, Ismael; Armstrong, Randall; Fire, Andrew Z; Weinberg, Kenneth I; Mindrinos, Michael; Zehnder, James L; Boyd, Scott D; Xiao, Wenzhong; Davis, Ronald W; Miklos, David B

    2011-12-27

    The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to aggregate cancer clone sequence variants arising from systematic and random artifacts occurring during IGH-HTS. We then compared the sensitivity of IGH-HTS, flow cytometry, and allele-specific oligonucleotide PCR for MRD quantification in 28 samples collected from 6 CLL patients following allogeneic HCT. Using amplimer libraries generated with consensus primers from patient blood samples, we demonstrate the sensitivity of IGH-HTS with 454 pyrosequencing to be 10(-5), with a high correlation between quantification by allele-specific oligonucleotide PCR and IGH-HTS (r = 0.85). From the same dataset used to quantify MRD, IGH-HTS also allowed us to profile IGH repertoire reconstitution after HCT-information not provided by the other MRD methods. IGH-HTS using consensus primers will broaden the availability of MRD quantification in CLL and other B cell malignancies, and this approach has potential for quantitative evaluation of immune diversification following transplant and nontransplant therapies. PMID:22160699

  6. High-throughput VDJ sequencing for quantification of minimal residual disease in chronic lymphocytic leukemia and immune reconstitution assessment

    PubMed Central

    Logan, Aaron C.; Gao, Hong; Wang, Chunlin; Sahaf, Bita; Jones, Carol D.; Marshall, Eleanor L.; Buño, Ismael; Armstrong, Randall; Fire, Andrew Z.; Weinberg, Kenneth I.; Mindrinos, Michael; Zehnder, James L.; Boyd, Scott D.; Xiao, Wenzhong; Davis, Ronald W.; Miklos, David B.

    2011-01-01

    The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to aggregate cancer clone sequence variants arising from systematic and random artifacts occurring during IGH-HTS. We then compared the sensitivity of IGH-HTS, flow cytometry, and allele-specific oligonucleotide PCR for MRD quantification in 28 samples collected from 6 CLL patients following allogeneic HCT. Using amplimer libraries generated with consensus primers from patient blood samples, we demonstrate the sensitivity of IGH-HTS with 454 pyrosequencing to be 10−5, with a high correlation between quantification by allele-specific oligonucleotide PCR and IGH-HTS (r = 0.85). From the same dataset used to quantify MRD, IGH-HTS also allowed us to profile IGH repertoire reconstitution after HCT—information not provided by the other MRD methods. IGH-HTS using consensus primers will broaden the availability of MRD quantification in CLL and other B cell malignancies, and this approach has potential for quantitative evaluation of immune diversification following transplant and nontransplant therapies. PMID:22160699

  7. Cancer Statistics: Acute Lymphocytic Leukemia (ALL)

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 6,590 % of All New Cancer Cases 0.4% Estimated Deaths in 2016 1,430 % of All Cancer ... of This Cancer : In 2013, there were an estimated 77,855 people living with acute lymphocytic leukemia ...

  8. In vitro responsiveness of lymphocytes to phytohemmagglutinin.

    PubMed

    Peterson, M L; Rommo, N; House, D; Harder, S

    1978-01-01

    Peripheral blood lymphocytes from 20 human subjects exposed to 784 microgram/m3 ozone for 4 hours, and from 11 subjects exposed to clean air for the same length of time were studied for in vitro responsiveness to phytohemagglutinin (PHA). Thymus-derived (T) lymphocyte response to PHA (normal response is proliferation of lymphocytes) was significantly suppressed (P less than .01) in samples obtained immediately after subjects' exposure to ozone. Recovery of response occurred 2 weeks postexposure. Responses were unchanged in subjects exposed to clean air. Existing studies suggest that ozone exposure may generate free radicals or other reactive molecules or both, that could be responsible for immediate changes in metabolic events leading to blockage or inhibition of deoxyribonucleic acid (DNA) synthesis in T lymphocytes as shown in this study. It is possible that some prerequisite to active cell metabolism such as ribonucleic acid (RNA) may be impaired by ozone exposure. The significance of the suppression of T-cell response noted in this study is that: (1) if continuous exposures to ozone are shown to induce an immunosuppressed state for a significant time period, an important factor in carcinogenesis might be elucidated; (2) immunosuppression may cause a progression of an already present tumor; (3) immunosuppression may enable endogenous latent infections such as tuberculosis to reactivate; and (4) immunosuppression may explain in part the relationship between chronic oxidant air pollution and influenza-like illnesses in population. PMID:646458

  9. Lymphocyte Functions in Space - Related Conditions

    NASA Technical Reports Server (NTRS)

    Risin, D.; Sundaresan, A.; Pellis, N. R.; Davson, David L. (Technical Monitor)

    1999-01-01

    Our previous studies showed that modeled (MMG) and true (STS-54 and STS-56) microgravity (MG) inhibit human lymphocyte locomotion. MMG also suppresses polyclonal and antigen-specific lymphocyte activation. Analysis of the relationship between activation deficits and the loss of locomotion in MG suggested a fundamental defect in signal transduction mechanism localized either at the PKC level or upstream at the cell membrane. FACS analysis of the expression of PKC isoforms in PBMC revealed that MMG selectively inhibits the PKC isoforms expression. The decrease was most prominent in PKC epsilon, less obvious in PKC delta and almost marginal and insignificant in PKC alpha. Western blot analysis confirmed these results (PKC epsilon protein expression was downregulated at 24, 72 and 96 hours in MG). We also found a decrease in PKC epsilon mRNA expression. MMG inhibited programmed cell death (PCD) in lymphocytes. Inhibition was observed in two types of experiments: 1) when PCD was induced by gamma-radiation of PBMC, and 2) when PCD in activated T cells was triggered by PHA-M or PMA + ionomycin restimulation. The established direct effects of MG on signal transduction mechanisms as well as on PCD in lymphocytes could contribute to the impairment of the immunity in space.

  10. Assays for B lymphocyte function.

    PubMed

    Bondada, Subbarao; Robertson, Darrell A

    2003-11-01

    This unit describes the antigenic stimulation of in vitro antibody production by B cells and the subsequent measurement of secreted antibodies. The first basic protocol is a generalized system for inducing in vitro antibody production and can accommodate various types of antigens under study. Secreted antibodies can then be measured with an enzyme-linked immunosorbent assay (ELISA) or other soluble-antibody detection systems. Alternatively, the number of antibody-producing cells can be quantified by plaque-forming cell (PFC) assays presented in this unit: the Cunningham-Szenberg and the Jerne-Nordin techniques. Both methods employ specially prepared slide chambers, described here, in which the antibody-producing B cells are mixed with complement and indicator sheep red blood cells (SRBC), or with trinitrophenol-modified SRBC (TNP-SRBC), with subsequent lysis and counting of plaques. Because IgM antibodies fix complement efficiently, whereas IgG and IgA antibodies do not, unmodified PFC assays measure only IgM antibodies. The assay can be modified, however, to measure all classes of antibodies or to enumerate total immunoglobulin-secreting B cells, as described in alternate protocols. Yet another method of measuring the number of antibody-producing B cells (in a class-specific fashion) is to use the ELISPOT technique described in UNIT 7.14. The resting B cells used in these procedures are prepared as described in the final support protocols for Percoll gradient centrifugation. PMID:18432909

  11. [Mixed marriages].

    PubMed

    Harmsen, C N

    1998-08-01

    The author examines the extent and characteristics of mixed marriages in the Netherlands. "Nine out of ten married persons born in Turkey or Morocco have a partner who was born in the same country. The majority of married Surinamese also have a partner originating from the same country. Those who spend (a part of) their youth in Indonesia (the former Dutch East Indies), on the other hand, are mostly married to someone born in the Netherlands." (EXCERPT) PMID:12294179

  12. Teratocarcinomas Arising from Allogeneic Induced Pluripotent Stem Cell-Derived Cardiac Tissue Constructs Provoked Host Immune Rejection in Mice

    PubMed Central

    Kawamura, Ai; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kashiyama, Noriyuki; Ito, Emiko; Watabe, Tadashi; Masuda, Shigeo; Toda, Koichi; Hatazawa, Jun; Morii, Eiichi; Sawa, Yoshiki

    2016-01-01

    Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models. PMID:26763872

  13. Blood lymphocyte subpopulations in breast cancer patients following radiotherapy.

    PubMed Central

    Petrini, B; Wasserman, J; Blomgren, H; Baral, E

    1977-01-01

    Both T and non-T lymphocytes decreased immediately following radiotherapy in breast cancer patients. The relative depletion of non-T lymphocytes, however, was more marked than that of T cells. 3 years later the number and the proportion of non-T lymphocytes was higher than immediately after radiotherapy, while T lymphocytes were still depressed. The proportion of cells with membrane-associated Ig was higher in patients 3 years following radiotherapy than in non-treated patients and healthy controls. There was no difference in the proportion of T and non-T lymphocytes between patients with and without metastases, respectively. PMID:330065

  14. Stimulation of human lymphocytes by Herpes simplex virus antigens.

    PubMed Central

    Starr, S E; Karatela, S A; Shore, S L; Duffey, A; Nahmias, A J

    1975-01-01

    Lymphocytes from individuals with laboratory evidence of prior infection with herpes simplex virus (HSV) type 1 or type 2 demonstrated transformation (av antigens. Higher stimulation indexes were obtained when lymphocytes were incubated with the homologous as compared with the heterologous antigen. Higher mean lymphocyte stimulation indexes were also demonstrated in seropositive as compared with seronegative individuals. Lymphocytes from children with HSV-1 stomatitis usually became responsive to HSV-1 antigen within 2 to 6 weeks after the onset of illness. Lymphocytes from infants with neonatal HSV-2 infection were stimulated by HSV-2 antigen. PMID:163788

  15. In vitro ozone exposure inhibits mitogen-induced lymphocyte proliferation and IL-2 production

    SciTech Connect

    Becker, S.; Jordan, R.L.; Orlando, G.S.; Koren, H.S.

    1989-01-01

    Human blood mononuclear cells were exposed to ozone in vitro and thereafter analyzed for competence in mitogen-induced proliferation as well as IL-1 and IL-2 production. Proliferative responses induced by phytohemagglutinin (PHA), concanavalin A (Con A), and pokeweed mitogen (PWM) were all depressed in lymphocytes exposed to an ozone concentration of 1 ppm for 4-6 h. The response to PWM was most sensitive to the ozone effect (38% suppression); responses to Con A and PHA were suppressed to a lesser extent, 23% and 18%, respectively, and were not significantly different from each other. PWM responses were affected at an ozone concentration as low as 0.1 ppm; however, no suppression of Con A-induced proliferation was seen below 0.18 ppm or of PHA-induced proliferation below 0.5 ppm. When lymphocytes and monocytes were exposed separately to ozone and then mixed back with control air-exposed monocytes or lymphocytes, both cell types appeared to be affected and the functional defects caused by the pollutant were additive. Monocyte IL-1 production induced by endotoxin was not affected by ozone exposure, while surface expression of HLA-DR on exposed monocytes was reduced by 40% 24 h after exposure. Moreover, lymphocytes exposed to ozone produced 46% less IL-2 while expressing similar surface density of IL-2 receptors. Taken together, these results show that exposure to ozone has distinct adverse effects on lymphocytes and monocytes, both of which are important in local immune defenses in the lung.

  16. Mixed results with mixed disulfides.

    PubMed

    Brigelius-Flohé, Regina

    2016-04-01

    A period of research with Helmut Sies in the 1980s is recalled. Our experiments aimed at an in-depth understanding of metabolic changes due to oxidative challenges under near-physiological conditions, i.e. perfused organs. A major focus were alterations of the glutathione and the NADPH/NADP(+) system by different kinds of oxidants, in particular formation of glutathione mixed disulfides with proteins. To analyze mixed disulfides, a test was adapted which is widely used until today. The observations in perfused rat livers let us believe that glutathione-6-phosphate dehydrogenase (G6PDH), i.a. might be activated by glutathionylation. Although we did not succeed to verify this hypothesis for the special case of G6PDH, the regulation of enzyme/protein activities by glutathionylation today is an accepted posttranslational mechanism in redox biology in general. Our early experimental approaches are discussed in the context of present knowledge. PMID:27095221

  17. Proteomic profiling of lymphocytes in autoimmunity, inflammation and cancer

    PubMed Central

    2014-01-01

    Lymphocytes play important roles in the balance between body defense and noxious agents involved in a number of diseases, e.g. autoimmune diseases, allergic inflammation and cancer. The proteomic analyses have been applied to identify and validate disease-associated and disease-specific biomarkers for therapeutic strategies of diseases. The proteomic profiles of lymphocytes may provide more information to understand their functions and roles in the development of diseases, although proteomic approaches in lymphocytes are still limited. The present review overviewed the proteomics-based studies on lymphocytes to headlight the proteomic profiles of lymphocytes in diseases, such as autoimmune diseases, allergic inflammation and cancer, with a special focus on lung diseases. We will explore the potential significance of diagnostic biomarkers and therapeutic targets from the current status in proteomic studies of lymphocytes and discuss the value of the currently available proteomic methodologies in the lymphocytes research. PMID:24397796

  18. Is lymphocytic (hashimoto) thyroiditis associated with suicide?

    PubMed

    Cina, Stephen J; Perper, Joshua A

    2009-09-01

    The histologic diagnosis of lymphocytic (Hashimoto) thyroiditis requires lymphocytic inflammation of the thyroid gland in combination with Hourthle cell metaplasia of follicular epithelial cells. Clinically, this autoimmune process has been associated with hypothyroidism and psychiatric conditions including depression. This retrospective study was designed to quantify the incidence and severity of lymphocytic thyroiditis in a series of nonconsecutive suicides compared with a cohort of motor vehicle accident victim controls. Eighty-one suicide victims (61 male, 20 female; age range 13-79 years, average 43) were compared with 88 age and gender matched controls (64 males, 24 females; age range 19-85 years, average 36). The degree of lymphocytic inflammation of the thyroid gland was graded on a scale of 0 to 3 (0 = no inflammation, 1 = mild inflammation, 2-3 moderate-to-marked inflammation with Hourthle cell metaplasia). Slides from each case were reviewed while blinded to the cause and manner of death in each case. Of these 169 total cases, 8 (4.7%) received a score of 3, whereas additional 7 (4.1%) received a grade of 2. Eighty-six percent of all of the cases showed no significant inflammation and recorded a score of 0. Of the 81 suicides, 3 had a score of 3, and 3 had a score of 2 (combined incidence of 7.4%). Within the control group, 5 of 88 cases scored 3 and another 4 scored 2 (combined incidence = 10.2%). Three males and 5 females scored 3 with an age range of 23 to 63 years, average 42. Incidental data tabulated showed that 19% of suicide victims were on psychoactive medications compared with 6% in the motor vehicle accident control group. No one on this study was on thyroid hormone replacement therapy. Depression is strongly linked to suicide and lymphocytic thyroiditis may be a cause of depression. Based on this study, however, the presence of lymphocytic thyroiditis cannot be used as a histologic adjunct to discriminate between suicide and accident in

  19. Bilateral Maxillary, Sphenoid Sinuses and Lumbosacral Spinal Cord Extramedullary Relapse of CML Following Allogeneic Stem Cell Transplant

    PubMed Central

    Hosseini, Soudabeh; Ansari, Shahla; Vosough, Parvaneh; Bahoush, Gholamreza; Hamidieh, Amir Ali; Chahardouli, Bahram; Shamsizadeh, Morteza; Mehrazma, Mitra; Dorgalaleh, Akbar

    2016-01-01

    Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. PMID:27252811

  20. Frequency of abnormal findings detected by comprehensive clinical evaluation at 1 year after allogeneic hematopoietic cell transplantation.

    PubMed

    Lee, Stephanie J; Seaborn, Travis; Mao, Frances J; Massey, Susan C; Luu, Ngoc Q; Schubert, Mary A; Chien, Jason W; Carpenter, Paul A; Moravec, Carina; Martin, Paul J; Flowers, Mary E D

    2009-04-01

    Consensus guidelines recommend various screening examinations for survivors after allogeneic hematopoietic cell transplantation (HCT), but how often these examinations detect abnormal findings is unknown. We reviewed the medical records of 118 patients who received comprehensive, standardized evaluations at 1 year after allogeneic HCT at Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Abnormal findings were common, including moderate to severe pulmonary dysfunction (16%), fasting hyperlipidemia (56%), osteopenia (52%), osteoporosis (6%), and active chronic graft-versus-host disease (cGVHD) (64%). Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases. Only 3% of patients had no abnormal findings. We conclude that comprehensive evaluation at 1 year after allogeneic HCT detects a high prevalence of medical problems. Longer follow-up is needed to determine whether early detection and intervention affect later morbidity and mortality. PMID:19285628

  1. Increasing the efficacy of antitumor glioma vaccines by photodynamic therapy and local injection of allogeneic glioma cells

    NASA Astrophysics Data System (ADS)

    Christie, Catherine E.; Peng, Qian; Madsen, Steen J.; Uzal, Francisco A.; Hirschberg, Henry

    2016-03-01

    Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage vaccines could be increased by: (1) PDT of the priming tumor cells, and (2) injection of allogeneic glioma cells directly into brain tumors. Experiments were conducted in an in vivo brain tumor model using Fisher rats and BT4C (allogeneic) and F98 (syngeneic) glioma cells. Preliminary results showed that vaccination alone had significantly less inhibitory effect on F98 tumor growth compared to the combination of vaccination and allogeneic cell (BT4C) injection.

  2. Bilateral Maxillary, Sphenoid Sinuses and Lumbosacral Spinal Cord Extramedullary Relapse of CML Following Allogeneic Stem Cell Transplant.

    PubMed

    Hosseini, Soudabeh; Ansari, Shahla; Vosough, Parvaneh; Bahoush, Gholamreza; Hamidieh, Amir Ali; Chahardouli, Bahram; Shamsizadeh, Morteza; Mehrazma, Mitra; Dorgalaleh, Akbar

    2016-04-01

    Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. PMID:27252811

  3. Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma

    PubMed Central

    Schmitz, Marian F.; Otten, Henny G.; Franssen, Laurens E.; van Dorp, Suzanne; Strooisma, Theo; Lokhorst, Henk M.; van de Donk, Niels W.C.J.

    2014-01-01

    In the course of multiple myeloma, patients may develop a M-protein band different from the original: secondary monoclonal gammopathy of undetermined significance. In this retrospective single center analysis, we describe the occurrence and clinical relevance of secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation (post-transplant monoclonal gammopathy of undetermined significance). A total of 138 patients who had undergone 139 allogeneic stem cell transplantations (39.6% in the upfront setting and 60.4% for relapsed multiple myeloma) were included in the study. Sixty-seven (48.2%) patients developed secondary monoclonal gammopathy of undetermined significance, after a median latency of 6.9 months. Secondary monoclonal gammopathy of undetermined significance occurred more often in patients who achieved at least very good partial response after allogeneic stem cell transplantation, compared to partial response or less (54.8% vs. 26.5%; P=0.005). The incidence was also higher in the upfront setting as compared to relapsed disease, or with a sibling donor compared to matched unrelated donor, but less often after T-cell depletion. Importantly, development of post-transplant monoclonal gammopathy of undetermined significance as a time-dependent variable independently predicted for superior progression-free and overall survival (median progression-free survival 37.5 vs. 6.3 months, P<0.001; median overall survival 115.3 vs. 31.0 months, P=0.004). Clinicians should be aware of the benign nature of this phenomenon, and secondary monoclonal gammopathy of undetermined significance should not be confused with relapse or progression of disease. (Trial registered with trialregister.nl; HOVON 108: NTR 2958.) PMID:25193963

  4. Production of donor-derived offspring by allogeneic transplantation of spermatogonia in the yellowtail (Seriola quinqueradiata).

    PubMed

    Morita, Tetsuro; Kumakura, Naoki; Morishima, Kagayaki; Mitsuboshi, Toru; Ishida, Masashi; Hara, Takashi; Kudo, Satomi; Miwa, Misako; Ihara, Shoko; Higuchi, Kentaro; Takeuchi, Yutaka; Yoshizaki, Goro

    2012-06-01

    Although the yellowtail (Seriola quinqueradiata) is the fish most commonly farmed in Japan, breeding of this species has not yet started. This is primarily due to the lack of sufficiently sophisticated methods for manipulating gametogenesis, which makes it difficult to collect gametes from specific dams and sires. If it were possible to produce large numbers of surrogate fish by transplanting germ cells isolated from donor individuals harboring desirable genetic traits, then the probability of acquiring gametes carrying the donor-derived haplotype would increase, and breeding programs involving this species might increase as a result. As a first step, we established a method for the allogeneic transplantation of yellowtail spermatogonia and the production of donor-derived offspring. Donor cells were collected from immature (10-month-old) yellowtail males with testes containing abundant type A spermatogonia, labeled with PKH26 fluorescent dye, and transferred into the peritoneal cavities of 8-day-old larvae. Fluorescence observation at 28 days post-transplantation revealed that PKH26-labeled cells were incorporated into recipients' gonads. To assess whether donor-derived spermatogonia could differentiate into functional gametes in the allogeneic recipient gonads, gametes collected from nine male and four female adult recipients were fertilized with wild-type eggs and milt. Analysis of microsatellite DNA markers confirmed that some of the first filial (F(1)) offspring were derived from donor fish, with the average contribution of donor-derived F(1) offspring being 66% and the maximum reaching 99%. These findings confirmed that our method was effective for transplanting yellowtail spermatogonia into allogeneic larvae to produce donor-derived offspring. PMID:22460666

  5. Distress Screening in Allogeneic Hematopoietic Stem Cell (HSCT) Caregivers and Patients

    PubMed Central

    Bevans, Margaret; Wehrlen, Leslie; Prachenko, Olena; Soeken, Karen; Zabora, James; Wallen, Gwenyth R.

    2011-01-01

    Family caregivers of allogeneic hematopoietic stem cell transplant (HSCT) patients are at risk for experiencing significant psychological distress yet screening caregivers has not been well studied. Objective This analysis explored the psychometric characteristics of the Distress Thermometer (DT) by examining its relationship, sensitivity and specificity relative to the Brief Symptom Inventory 18 (BSI-18) and the Multidimensional Fatigue Symptom Inventory (MFSI) in a sample of allogeneic HSCT caregivers and patients. Methods Longitudinal data were drawn from an ongoing intervention study for HSCT caregivers and patients. Data from one hundred and fifty-six English-speaking adults where patients (n=65) were receiving their first allogeneic HSCT with at least one adult caregiver (n=91) were eligible for this analysis. Study questionnaires were administered at baseline, initial discharge and 6 weeks following discharge. Results Construct validity was supported by significant relationships (p<0.001) between the DT and the BSI-18 GSI and the MFSI-Emotional subscales for caregivers and patients. The diagnostic utility of the DT for patients was good (AUC=.85±.05, p=.001), while for caregivers it was poor (AUC=.61±.08, p=.28). A DT cut point of 5 was supported for patients (sensitivity=1.0, specificity=.68), while for caregivers there was less confidence (sensitivity=.70, specificity=.52). Caregivers and patients reporting a higher number of problems had a greater level of distress (p<0.001). Conclusions These findings support the validity of the DT in screening for distress in HSCT caregivers and patients. Although the diagnostic utility of the DT for HSCT caregivers may be limited, understanding factors associated with distress can guide practice for this understudied population. PMID:21626610

  6. Outcome of lower-intensity allogeneic transplantation in non-Hodgkin lymphoma after autologous transplantation failure.

    PubMed

    Freytes, César O; Zhang, Mei-Jie; Carreras, Jeanette; Burns, Linda J; Gale, Robert Peter; Isola, Luis; Perales, Miguel-Angel; Seftel, Matthew; Vose, Julie M; Miller, Alan M; Gibson, John; Gross, Thomas G; Rowlings, Philip A; Inwards, David J; Pavlovsky, Santiago; Martino, Rodrigo; Marks, David I; Hale, Gregory A; Smith, Sonali M; Schouten, Harry C; Slavin, Simon; Klumpp, Thomas R; Lazarus, Hillard M; van Besien, Koen; Hari, Parameswaran N

    2012-08-01

    We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach. PMID:22198543

  7. Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia

    PubMed Central

    Litzow, Mark R.; Tarima, Sergey; Pérez, Waleska S.; Bolwell, Brian J.; Cairo, Mitchell S.; Camitta, Bruce M.; Cutler, Corey S.; de Lima, Marcos; DiPersio, John F.; Gale, Robert Peter; Keating, Armand; Lazarus, Hillard M.; Luger, Selina; Marks, David I.; Maziarz, Richard T.; McCarthy, Philip L.; Pasquini, Marcelo C.; Phillips, Gordon L.; Rizzo, J. Douglas; Sierra, Jorge; Tallman, Martin S.

    2010-01-01

    Therapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation. PMID:20032503

  8. Long-Term Survival and Late Deaths After Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Wingard, John R.; Majhail, Navneet S.; Brazauskas, Ruta; Wang, Zhiwei; Sobocinski, Kathleen A.; Jacobsohn, David; Sorror, Mohamed L.; Horowitz, Mary M.; Bolwell, Brian; Rizzo, J. Douglas; Socié, Gérard

    2011-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. Patients and Methods Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. Results Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. Conclusion The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed. PMID:21464398

  9. A Characterization of the Oral Microbiome in Allogeneic Stem Cell Transplant Patients

    PubMed Central

    Ames, Nancy J.; Sulima, Pawel; Ngo, Thoi; Barb, Jennifer; Munson, Peter J.; Paster, Bruce J.; Hart, Thomas C.

    2012-01-01

    Background The mouth is a complex biological structure inhabited by diverse bacterial communities. The purpose of this study is to describe the effects of allogeneic stem cell transplantation on the oral microbiota and to examine differences among those patients who acquired respiratory complications after transplantation. Methodology/Principal Findings All patients were consented at the National Institutes of Health, Clinical Center. Bacterial DNA was analyzed from patients' oral specimens using the Human Oral Microbe Identification Microarray. The specimens were collected from four oral sites in 45 allogeneic transplantation patients. Specimens were collected at baseline prior to transplantation, after transplantation at the nadir of the neutrophil count and after myeloid engraftment. If respiratory signs and symptoms developed, additional specimens were obtained. Patients were followed for 100 days post transplantation. Eleven patients' specimens were subjected to further statistical analysis. Many common bacterial genera, such as Streptococcus, Veillonella, Gemella, Granulicatella and Camplyobacter were identified as being present before and after transplantation. Five of 11 patients developed respiratory complications following transplantation and there was preliminary evidence that the oral microbiome changed in their oral specimens. Cluster analysis and principal component analysis revealed this change in the oral microbiota. Conclusions/Significance After allogeneic transplantation, the oral bacterial community's response to a new immune system was not apparent and many of the most common core oral taxa remained unaffected. However, the oral microbiome was affected in patients who developed respiratory signs and symptoms after transplantation. The association related to the change in the oral microbiota and respiratory complications after transplantation will be validated by future studies using high throughput molecular methods. PMID:23144704

  10. Storage of Allogeneic Vascular Grafts: Experience From a High-Volume Liver Transplant Institute

    PubMed Central

    Aydin, Cemalettin; Ince, Volkan; Otan, Emrah; Akbulut, Sami; Koc, Cemalettin; Kayaalp, Cuneyt; Yilmaz, Sezai

    2013-01-01

    Allogeneic vascular grafts are often required for vascular reconstruction during living donor liver transplantation. Such grafts are obtained prior to use, making storage conditions a critical issue for maintaining the integrity of the tissue to ensure a successful transplantation. This study describes an optimized storage protocol currently in use at a high-volume liver transplant center. Twenty-nine allogeneic vascular graft tissues obtained during cardiovascular surgery or from cadaveric donors were stored respectively in sterile 50 mL of Ringer lactate solution, without any preservation solutions or antimicrobials, at −22°C for a maximum of 3 months. Prior to use in vascular reconstruction, grafts were thawed in 0.9% NaCl solution at 37°C, and 1 × 0.5-cm2 tissue samples were collected for microbial culturing and viral serology. ABO compatibility was not performed for any patients receiving vascular grafts. During this prospective study, all 29 allogeneic vascular grafts were used for back-table vascular reconstruction in living donor liver transplantation procedures. A total of 16 grafts were from the saphenous vein, 10 were from the iliac vein, and 3 were from the iliac artery. Bacterial growth was not detected in any tissue samples taken from the stored grafts. No vascular graft-related complications occurred during the 5 months of follow-up. The successful vascular reconstructions achieved with all 29 study grafts demonstrate that the simple, inexpensive storage method described herein is feasible and safe. Randomized, controlled studies should be carried out to further optimize and standardize the technique. PMID:23701155

  11. Storage of allogeneic vascular grafts: experience from a high-volume liver transplant institute.

    PubMed

    Aydin, Cemalettin; Ince, Volkan; Otan, Emrah; Akbulut, Sami; Koc, Cemalettin; Kayaalp, Cuneyt; Yilmaz, Sezai

    2013-01-01

    Allogeneic vascular grafts are often required for vascular reconstruction during living donor liver transplantation. Such grafts are obtained prior to use, making storage conditions a critical issue for maintaining the integrity of the tissue to ensure a successful transplantation. This study describes an optimized storage protocol currently in use at a high-volume liver transplant center. Twenty-nine allogeneic vascular graft tissues obtained during cardiovascular surgery or from cadaveric donors were stored respectively in sterile 50 mL of Ringer lactate solution, without any preservation solutions or antimicrobials, at -22°C for a maximum of 3 months. Prior to use in vascular reconstruction, grafts were thawed in 0.9% NaCl solution at 37°C, and 1 × 0.5-cm(2) tissue samples were collected for microbial culturing and viral serology. ABO compatibility was not performed for any patients receiving vascular grafts. During this prospective study, all 29 allogeneic vascular grafts were used for back-table vascular reconstruction in living donor liver transplantation procedures. A total of 16 grafts were from the saphenous vein, 10 were from the iliac vein, and 3 were from the iliac artery. Bacterial growth was not detected in any tissue samples taken from the stored grafts. No vascular graft-related complications occurred during the 5 months of follow-up. The successful vascular reconstructions achieved with all 29 study grafts demonstrate that the simple, inexpensive storage method described herein is feasible and safe. Randomized, controlled studies should be carried out to further optimize and standardize the technique. PMID:23701155

  12. Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation.

    PubMed

    Sackett, S D; Brown, M E; Tremmel, D M; Ellis, T; Burlingham, W J; Odorico, J S

    2016-04-01

    Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives. PMID:26970668

  13. Four successful pregnancies in a patient with mucopolysaccharidosis type I treated by allogeneic bone marrow transplantation.

    PubMed

    Remérand, G; Merlin, E; Froissart, R; Brugnon, F; Kanold, J; Janny, L; Deméocq, F

    2009-12-01

    To date, little is known about the fertility of women suffering from mucopolysaccharidosis type I (MPS I). We report on a female patient with MPS I treated by allogeneic bone marrow transplantation (BMT) at the age of 4 years (after a conditioning regimen containing busulfan 16 mg/kg and cyclophosphamide 100 mg/kg) who had four successful pregnancies without any reproductive assistance. Clinical and biological examinations of the children were normal. On the basis of this case, we discuss the fertility counselling of female MPS I patients at the time of BMT. PMID:19280364

  14. Correction of enzyme deficiency in mice by allogeneic bone marrow transplantation with total lymphoid irradiation

    SciTech Connect

    Slavin, S.; Yatziv, S.

    1980-12-05

    Enzyme deficiency was corrected in mice after allogeneic bone marrow transplantation with occurrence of graft versus host disease. Beta-Glucuronidase-deficient C3H/HeJ mice were treated with total lymphoid irradiation. Normal bone marrow cells (30 x 10(6)) from BALB/o to C3H/HeJ chimeras (> 90 percent circulating donor-type cells) without graft versus host disease. Beta-Glucuronidase activity increases to normal levels in all chimeras as measured in the liver and in the plasma. Activity was maintained throughout an observation period of 7 months.

  15. Controversies in autologous and allogeneic hematopoietic cell transplantation in peripheral T/NK-cell lymphomas.

    PubMed

    Shustov, Andrei

    2013-03-01

    Peripheral T-cell and NK-cell lymphomas (PT/NKCL) are a heterogeneous group of lymphoid neoplasms with poor outcomes. There is no consensus on the best front line therapy or management of relapsed/refractory disease. The use of autologous and allogeneic hematopoietic cell transplantation (HCT) has been studied in both settings to improve outcomes. Multiple retrospective and several prospective trials were reported. While at first sight the outcomes in the relapsed/refractory setting appear similar in B-cell and T-cell lymphomas when treated with high dose therapy (HDT) and autologous HCT, it is becoming obvious that only specific subtypes of PTCL benefit from this approach (i.e. anaplastic large cell lymphoma [ALCL] and angioimmunoblastic lymphoma [AITL] in second CR). In less favorable histologies, HDT seems to provide limited benefit, with the majority of patients experiencing post-transplant relapse. The use of autologous HCT to consolidate first remission has been evaluated in several prospective trials. Again, the best results were observed in ALCL, but the superiority of this approach over chemotherapy alone needs confirmation in randomized trials. In less favorable histologies, high-dose consolidation resulted in low survival rates comparable to those obtained with chemotherapy alone, and without randomized trials it is hard to recommend this strategy to all patients with newly diagnosed PT/NKCL. Allogeneic HCT might provide potent and potentially curative graft-vs-lymphoma effect and overcome chemotherapy resistance. Only a few studies have been reported to date on allogeneic HCT in PT/NKCL. Based on available data, eligible patients benefit significantly from this approach, with 50% or more patients achieving long-term disease control or cure, although at the expense of significant treatment related mortality (TRM). Reduced-intensity conditioning regimens appear to have lower TRM and might extend this approach to older patients. With the recent approval of

  16. Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mishra, Asmita; Anasetti, Claudio

    2016-08-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population. PMID:27521324

  17. Plasmacytoid dendritic cells in allogeneic hematopoietic cell transplantation: benefit or burden?

    PubMed Central

    Auletta, JJ; Devine, SM; Waller, EK

    2016-01-01

    Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and have important roles in hematopoietic engraftment, GvHD and graft-versus-leukemia responses following allogeneic hematopoietic cell transplantation (HCT). In addition, pDCs mediate antiviral immunity, particularly as they are the body’s primary cellular source of type I interferon. Given their pleiotropic roles, pDCs have emerged as cells that critically impact transplant outcomes, including overall survival. In this article, we will review the pre-clinical and clinical literature, supporting the crucial roles that pDCs assume as key immune effector cells during HCT. PMID:26642333

  18. Bone marrow ablation followed by allogeneic marrow grafting during first complete remission of acute nonlymphocytic leukemia

    SciTech Connect

    Forman, S.J.; Spruce, W.E.; Farbstein, M.J.

    1983-03-01

    Of 33 patients who had undergone allogeneic bone marrow transplantation during first complete remission of acute nonlymphocytic leukemia, 21 patients have now been followed in continued complete remission for 6-64 mo (median greater than 18 mo) without maintenance chemotherapy. The median age of the surviving patients is 27 yr. Transplant-related complications occurring throughout the first year after marrow grafting were fatal in 7 patients, and leukemic recurrence led to the death of 5 patients. The actuarial long-term disease-free survival is 60% and the actuarial remission rate is 79%.

  19. Induction of allogeneic unresponsiveness by supralethal irradiation and bone marrow reconstitution. [Dogs

    SciTech Connect

    Rapaport, F.T.; Bachvaroff, R.J.; Akiyama, N.; Sato, T.

    1980-09-01

    Supralethally irradiated dogs were reconstituted wth their own stored bone marrow and were challenged at various time intervals with a kidney allograft. The data suggest that transplanted bone marrow cells may participate directly in the events leading to allogenic unresponsiveness. The time interval between marrow cell replacement and kidney allotransplantation required for optimal results suggest that at least one cycle of cell turnover by the replaced stem cells is needed in order to produce unresponsiveness. Host irradiation and reconstitution with stored autologous marrow may be useful in the treatment of certain forms of cancer.

  20. Strategies to Reduce Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

    PubMed Central

    Mawad, Raya; Lionberger, Jack M.; Pagel, John M.

    2013-01-01

    The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant. PMID:23456518

  1. Cell Death Mechanisms Induced by Cytotoxic Lymphocytes

    PubMed Central

    Chávez-Galán, L; Arenas-Del Angel, M C; Zenteno, E; Chávez, R; Lascurain, R

    2009-01-01

    One of the functions of the immune system is to recognize and destroy abnormal or infected cells to maintain homeostasis. This is accomplished by cytotoxic lymphocytes. Cytotoxicity is a highly organized multifactor process. Here, we reviewed the apoptosis pathways induced by the two main cytotoxic lymphocyte subsets, natural killer (NK) cells and CD8+ T cells. In base to recent experimental evidence, we reviewed NK receptors involved in recognition of target-cell, as well as lytic molecules such as perforin, granzymes-A and -B, and granulysin. In addition, we reviewed the Fas-FasL intercellular linkage mediated pathway, and briefly the cross-linking of tumor necrosis factor (TNF) and TNF receptor pathway. We discussed three models of possible molecular interaction between lytic molecules from effector cytotoxic cells and target-cell membrane to induction of apoptosis. PMID:19254476

  2. Methionine dependency of cultured human lymphocytes.

    PubMed

    Hall, C A; Begley, J A; Chu, R C

    1986-06-01

    Human peripheral blood lymphocytes stimulated with phytohemagglutinin and a lymphocyte model consisting of the RPMI 6410 cell, a human virus-transformed B cell, required added methionine (Met) for growth of the cultures. This failure to meet all needs for Met via endogenous synthesis, which is characteristic of oncogenic transformation, occurred even in the presence of adequate homocysteine, methylfolate (5-CH3-H4PteGlu) and cobalamin (Cbl)-dependent methionine synthetase activity. Folinic acid (5-CHO-H4PteGlu), which provides available folate independently of Cbl, improved growth only slightly in the absence of Met. Free Cbl at 222 nM, an amount great enough to alter other intracellular events, failed to increase growth in the absence of Met, but 0.22 nM Cbl bound to transcobalamin II did, however, enhance growth. PMID:3703873

  3. Lymphocyte transformation in presumed ocular histoplasmosis

    SciTech Connect

    Ganley, J.P.; Nemo, G.J.; Comstock, G.W.; Brody, J.A.

    1981-08-01

    Lymphocytes from individuals with inactive macular disciform lesions of presumed ocular histoplasmosis challenged with three histoplasmin antigens incorporated tritiated thymidine at a significantly higher rate than histoplasmin-stimulated lymphocytes of matched control and peripheral scar groups. This finding is consistent with the etiologic association of the disciform ocular syndrome and previous systemic infection with Histoplasma capsulatum. The disciform group had a higher mean response than the other two groups to pokeweed mitogen but not to phytohemagglutinin and had higher mean counts per minute to the specific antigens Toxoplasma gondii, Blastomyces dermatitidis, Cryptococcus neoformans, Mycobacterium tuberculosis, M battery, and M gaus, but not to Candida albicans. These data would suggest that individuals with the disciform lesion of presumed ocular histoplasmosis have a hyperreactive cellular immune response; this response may play an important role in the development of the disciform.

  4. Lymphocytes subsets reference values in childhood.

    PubMed

    Tosato, F; Bucciol, G; Pantano, G; Putti, M C; Sanzari, M C; Basso, G; Plebani, M

    2015-01-01

    Immunophenotyping of blood lymphocyte subsets and activation markers is a basic tool in the diagnostic process of primary immunodeficiency diseases, its use becoming more and more widespread as the knowledge about these illnesses increases. However, the availability of reliable reference values, which need to be age-matched for the pediatric population, is a pre-requisite for the reliable interpretation of immunophenotyping data. Aim of this study is to analyze the lymphocyte subsets and activation markers distribution in children aged 0-18 years referring to the University Hospital of Padova and to create age-matched reference values expressed by percentiles, thus providing a valuable guideline for the interpretation of the immunophenotype. PMID:25132325

  5. Effect of weightlessness on lymphocyte proliferation

    NASA Technical Reports Server (NTRS)

    Cogoli, A.

    1981-01-01

    An experiment to study the effect of weightlessness on lymphocyte proliferation to detect possible alteration of the cells responsible for the immune response during long-duration space flights is described. Human lymphocytes in culture medium will be delivered shortly before launch in an incubator which will be kept at 37C. Mitogen will be added to the culture. A control without mitogen will be run in parallel. After 70 hours of incubation, radioactive thymidine will be added. After two hours, cellular activity will be stopped by fixation and incubator power switched off. Later, the amount of incorporated thymidine will be determined and the cell morphology and the distribution of cell organelles will be investigated.

  6. Allogeneic mRNA-based electrotransfection of autologous dendritic cells and specific antitumor effects against osteosarcoma in rats.

    PubMed

    Yu, Zhe; Qian, Jixian; Wu, Jiachang; Gao, Jie; Zhang, Minghua

    2012-12-01

    Vaccination with dendritic cells (DCs) transfected with tumor-derived mRNA antigen has emerged as a promising strategy for generating protective immunity in mammals. However, the integration of allogeneic osteosarcoma mRNA and autologous DCs has not been fully examined. This study was designed to investigate the antitumor effects of tumor vaccine produced by autologous DCs transfected of allogeneic osteosarcoma mRNA through electroporation in tumor-bearing rats model. In the present study, extraction of Wistar rat tumor mRNA was performed as a two-step procedure. First, total RNA was extracted by use of Trizol; then, mRNA purification was performed by use of polyT-coated magnetic beads. Then, we transfected the allogeneic-derived tumor mRNA to Sprague-Dawley (SD) rat bone marrow-derived DCs through electroporation. The tumor vaccine was applied to tumor-bearing rats model, and the specific antitumor effects of the tumor vaccine were observed. The immunization using autologous DCs electrotransfected with allogeneic osteosarcoma total RNA induced specific CTL responses, which were statistically significant (P < 0.05), and the cytotoxic activity was confirmed in cold target inhibition assays and using mAbs blocking MHC class I molecules. In in vivo experiments, 70 % of the rats immunized with allogeneic osteosarcoma RNA transfected to DCs were typically able to reject tumor challenge and remained tumor-free. Vaccinated survivors developed long immunological memory and were able to reject a subsequent rechallenge with the same tumor cells but not a syngeneic unrelated tumor line. In the present study, we demonstrated that allogeneic tumor mRNA isolated from rat osteosarcoma cell line could be applied to produce tumor vaccine inducing specific antitumor effects, especially in DC-based immunotherapy strategy. This study also provides the foundations for an effective and broadly applicable treatment to a wide range of cancer indications for which tumor-associated antigens

  7. Novel agents for chronic lymphocytic leukemia

    PubMed Central

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL. PMID:23680477

  8. Predictive Value of Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio in Patients with Coronary Slow Flow

    PubMed Central

    Çetin, Mustafa; Kiziltunc, Emrullah; Elalmış, Özgül Uçar; Çetin, Zehra Güven; Demirçelik, Muhammed Bora; Çiçekçioğlu, Hülya; Kurtul, Alparslan; Özkan, Selçuk; Avan, Candan Mansuroğlu; Örnek, Ender; Ulusoy, Feridun Vasfi

    2016-01-01

    Background Increased microvascular resistance due to chronic inflammation is assumed to be one of the mechanisms associated with coronary slow flow (CSF). Previous studies have shown that the platelet-to-lymphocyte ratio (PLR) and the neutrophil-lymphocyte ratio (NLR) are markers of inflammation for various diseases. In this study we aimed to evaluate the relationship between CSF and PLR-NLR. Methods Seventy-eight patients with CSF and 50 patients with normal coronary flow were enrolled into this study. The study subjects underwent medical examination and testing, after which their platelet-to-lymphocyte ratios and NLR values were calculated. An independent observer measured the coronary flow rate by Thrombolysis in Myocardial Infarction Frame Count (TFC) method. The platelet-to-lymphocyte ratio and NLR values were compared between the groups and correlation analysis was performed to explore the relationship between mean TFC with PLR and NLR. Results Platelet-to-lymphocyte ratio and NLR values were significantly higher in patients with CSF (p < 0.001). There was a positive significant correlation between TFC with NLR and PLR (Spearman’s Rho: 0.59, p < 0.001 and Spearman’s Rho: 0.30, p = 0.001, respectively). Multivariate logistic regression analysis revealed that NLR is the one independent predictor for CSF. Conclusions This study demonstrated an association between CSF and PLR-NLR. Although the exact mechanism could not be explained, our findings support the possible role of inflammation in CSF physiopathology. PMID:27274171

  9. Same sibling marrow following cord allogeneic transplantation as therapy for second relapse acute promyelocytic leukemia in a pediatric patient.

    PubMed

    De Oliveira, Satiro N; Kao, Roy L; Pham, Andrew; Smith, LaMarr Taylor; Kempert, Pamela; Moore, Theodore B

    2016-03-01

    Optimal therapy for relapsed APL in pediatric patients is controversial. Allogeneic HSCT is an alternative, with event-free survival of 70-75%. We report a pediatric patient with APL who relapsed 28 months after CBT from her sibling and then was treated with BMT from the same donor. Bone marrow was selected for higher cell dose, donor availability, and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months after BMT. This case suggests the potential role of GVL activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients. PMID:26849401

  10. Primary immunodeficiencies of the B lymphocyte.

    PubMed

    Moise, Ana; Nedelcu, Filofteia Daniela; Toader, Maria Adela; Sora, Steluta Mihaela; Tica, Anca; Ferastraoaru, Denisa Elena; Constantinescu, Ileana

    2010-01-01

    The immune response consists of two main components: humoral immunity represented by B lymphocytes and cellular immunity maintained by the T lymphocytes. Immunoglobulins, produced by B-lymphocytes, are the main mediators of humoral immunity, and deficiencies at this level affect the body's response to infection. Plasmocytes produce nine antibody izotypes: immunoglobulins G (IgG1, IgG2, IgG3, IgG4), immunoglobulins M (IgM), immunoglobulins A (IgA1, IgA2), immunoglobulins D (IGD) and immunoglobulins E (IgE). Primary hypogammaglobulinemias are characterized by the occurrence of recurrent infections and, paradoxically, by the occurrence of autoimmune diseases. Characteristic for these diseases is that symptoms occur at 7-9 months after birth, when transplacental antibody titers transmitted from the mother decrease, and the infant's body is unable to synthesize them to normal levels. Primary hypogammaglobulinemias are transmitted genetically, but mutations at the molecular level are still not fully understood. The most common are: Bruton agammaglobulinemia, transient newborn hypogammaglobulinemia, selective immunoglobulin deficiency and variable common immunodeficiency. Treatment consists of monthly antibiotics and immunoglobulins, depending on antibody titers (except for IgA deficiency). PMID:20302197

  11. Lymphocyte reactivity in patients with gonococcal urethritis.

    PubMed Central

    Rosenthal, L; Sandström, E

    1978-01-01

    Lymphocyte reactivity to virulent gonococcal antigen T2 and the non-pathogenic Neisseria pharyngis (NPN) has been studied by using the 14C-thymidine uptake in cell cultures from 42 patients with gonococcal urethritis and from 18 controls. The DNA synthesis in cell cultures with T2 antigen was higher in 21 female patients than in the 18 controls. No differences in DNA synthesis were observed in antigen-stimulated cell cultures from patients with single or multiple infections, from patients with urogenital complication, or from controls. Gonococcal antibodies in the serum were detected by the gonococcal complement-fixation test (GCFT). A study of the possible correlation between the outcome of the serological test and the cellular response to gonococcal antigen showed that 14C-thymidine uptake in lymphocyte cultures from male patients with negative GCFT, stimulated with T2 antigen, was much lower than the thymidine uptake in stimulated cell cultures from all the other male and female patients (P less than 0.001). The DNA synthesis was higher in cell cultures from seronegative women than from seronegative men (P less than 0.01). A significant difference (P less than 0.01) was also noted in the lymphocyte reactivity to gonococcal antigen between controls and all patients, except in those men who gave negative results to the serological tests. There were no differences between these two groups with respect to the thymidine uptake in NPN-stimulated cell cultures. PMID:678955

  12. ACTIVATION OF T LYMPHOCYTES IN ATHEROSCLEROTIC PLAQUES

    PubMed Central

    Grivel, Jean-Charles; Ivanova, Oxana; Pinegina, Natalia; Blank, Paul S.; Shpektor, Alexander; Margolis, Leonid B.; Vasilieva, Elena

    2011-01-01

    Objective To decipher the immunological mechanisms of plaque maturation and rupture, it is necessary to analyze the phenotypes and distribution of individual lymphocytes which migrate to the plaques as well as their activation at different stages of plaque formation. Methods and Results We developed a protocol to isolate plaque-residing immune cells and analyze their status using polychromatic flow cytometry. We found that the composition and phenotype of T lymphocytes in the plaques differs from that in blood. CD4 and, in particular, CD8+ T cells in plaques are highly activated; the fraction of CD8 T cells co-expressing CD25 and HLA-DR in plaques was 10 times larger than in blood. Conclusions The first flow-cytoanalysis of individual T cells in atherosclerotic plaques indicates that plaques represent a separate immunological compartment from blood with lymphocytes characterized by a high level of T cells activation, which is compatible with the presence of antigen(s) that trigger infiltration activation of these cells. The ability to isolate and characterize these cells may lead to the identification of such antigens. PMID:21960562

  13. Microgravity and Cellular Consequences in Lymphocyte Function

    NASA Technical Reports Server (NTRS)

    Pellis, Neal R.; Sundaresan, Alamelu

    2004-01-01

    Mammalian cells adapt to the environment of low gravity and express a series of responses, some possibly from direct effects on cells and others based on environmental conditions created by microgravity. Human lymphocytes in microgravity culture are functionally diminished in activation and locomotion. Both processes are integral to optimal immune response to fight pathogens. The NASA Rotating-wall vessel (RWV) is a well-accepted analog for microgravity culture on the ground. Gene array experiments and immunoblotting identified upstream events in human lymphocytes adapting to microgravity analog culture. Microgravity induces selective changes, many of which are cell membrane related. Results showed that upstream of PKC in the T cell activation cascade, PLC-gamma and LAT are significantly diminished. ZAP 70 which controls LAT activation is also down regulated in modeled microgravity. Thus events governing cell shape might warrant attention in microgravity conditions. The goal of this study is to delineate response suites that are consequential, direct or indirect effects of the microgravity environment and which of these are essential to lymphocytes

  14. Shigella impairs T lymphocyte dynamics in vivo

    PubMed Central

    Salgado-Pabón, Wilmara; Celli, Susanna; Arena, Ellen T.; Nothelfer, Katharina; Roux, Pascal; Sellge, Gernot; Frigimelica, Elisabetta; Bousso, Philippe; Sansonetti, Philippe J.; Phalipon, Armelle

    2013-01-01

    The Gram-negative enteroinvasive bacterium Shigella flexneri is responsible for the endemic form of bacillary dysentery, an acute rectocolitis in humans. S. flexneri uses a type III secretion system to inject effector proteins into host cells, thus diverting cellular functions to its own benefit. Protective immunity to reinfection requires several rounds of infection to be elicited and is short-lasting, suggesting that S. flexneri interferes with the priming of specific immunity. Considering the key role played by T-lymphocyte trafficking in priming of adaptive immunity, we investigated the impact of S. flexneri on T-cell dynamics in vivo. By using two-photon microscopy to visualize bacterium–T-cell cross-talks in the lymph nodes, where the adaptive immunity is initiated, we provide evidence that S. flexneri, via its type III secretion system, impairs the migration pattern of CD4+ T cells independently of cognate recognition of bacterial antigens. We show that bacterial invasion of CD4+ T lymphocytes occurs in vivo, and results in cell migration arrest. In the absence of invasion, CD4+ T-cell migration parameters are also dramatically altered. Signals resulting from S. flexneri interactions with subcapsular sinus macrophages and dendritic cells, and recruitment of polymorphonuclear cells are likely to contribute to this phenomenon. These findings indicate that S. flexneri targets T lymphocytes in vivo and highlight the role of type III effector secretion in modulating host adaptive immune responses. PMID:23417297

  15. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    PubMed

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma. PMID:27324214

  16. Blood leukocyte and spleen lymphocyte immune response of spleen lymphocytes and whole blood leukocytes of hamsters

    SciTech Connect

    Peters, B.A.; Sothmann, M.; Wehrenberg, W.B. )

    1989-01-01

    This study was designed to evaluate the effects of chronic physical activity on the immune response of spleen lymphocytes and whole blood leukocytes of hamsters. Animals were kept sedentary or allowed to exercise spontaneously on running wheels for eight weeks. Physically active animals averaged 12 kilometers per day. The immune response of spleen lymphocytes whole blood leukocytes was evaluated by {sup 3}H-thymidine incorporation in response to Concanavalin A or lipopolysaccharide. There was no treatment effect between physically active and sedentary hamster in response of spleen lymphocytes. The immune response of whole blood leukocytes to these mitogens was significantly greater in physically active vs. sedentary hamsters. These results demonstrate that chronic physical activity has the capacity to modulate immunoresponses.

  17. Mixed chimerism to induce tolerance for solid organ transplantation

    SciTech Connect

    Wren, S.M.; Nalesnik, M.; Hronakes, M.L.; Oh, E.; Ildstad, S.T. )

    1991-04-01

    Chimerism, or the coexistence of tissue elements from more than one genetically different strain or species in an organism, is the only experimental state that results in the induction of donor-specific transplantation tolerance. Transplantation of a mixture of T-cell-depleted syngeneic (host-type) plus T-cell-depleted allogeneic (donor) bone marrow into a normal adult recipient mouse (A + B----A) results in mixed allogeneic chimerism. Recipient mice exhibit donor-specific transplantation tolerance, yet have full immunocompetence to recognize and respond to third-party transplantation antigens. After complete hematolymphopoietic repopulation at 28 days, animals accept a donor-specific skin graft but reject major histocompatibility complex (MHC) locus-disparate third-party grafts. We now report that permanent graft acceptance can also be achieved when the graft is placed at the time of bone marrow transplantation. Histologically, grafts were viable and had only minimal inflammatory changes. This model may have potential future clinical application for the induction of donor-specific transplantation tolerance.

  18. The 'euthyroid sick syndrome': incidence, risk factors and prognostic value soon after allogeneic bone marrow transplantation.

    PubMed

    Vexiau, P; Perez-Castiglioni, P; Socié, G; Devergie, A; Toubert, M E; Aractingi, S; Gluckman, E

    1993-12-01

    We studied the incidence of thyroid function abnormalities observed soon after allogeneic bone marrow transplantations (BMT) and their predictive value on the overall prognosis. Free serum thyroxine, free serum triiodothyronine, total serum reverse triiodothyronine and serum thyrotropin levels were systematically measured in 78 patients before and 3 months after BMT. 41 (52%) had normal hormone levels and 37 (48%) had abnormal ones, among whom four (5%) had peripheral compensated hypothyroidism and 33 (43%) were described as having 'euthyroid sick syndrome' (low thyroxine state, or low T3 syndrome). Two factors strongly influenced the appearance of thyroid abnormalities: steroid dose at the time of thyroid function testing, and age (< or = 16 years/ > 16 years). Among the younger patients, 21 had no thyroid abnormalities, while five did. Among the older patients, 20 had no thyroid abnormalities, while 32 did (P < 0.001). The occurrence of thyroid abnormalities seemed to influence survival strongly, since the 30-month projected survival time was 83% for patients without abnormalities whereas it was 49% for patients with an abnormal profile (P < 0.001). In conclusion, evidence obtained among our population reveals that euthyroid sick syndrome indicates a poor prognosis and that it is very important to monitor thyroid hormone levels (particularly free hormones) soon after allogeneic BMT and regularly thereafter. PMID:7918043

  19. [Influence of obstetric factors on the quality of cord blood units collected for allogeneic transplantation].

    PubMed

    Atanassova, V; Atanassova, M; Nikolov, A; Zlatkov, V; Mihaylova, A; Naumova, E

    2012-01-01

    Umbilical cord blood (CB) as a source of haematopoietic stem cells for allogeneic transplantation has many advantages over bone marrow and peripheral blood, however, a main limitation to its use in clinical setting is cell numbers. This study aimed to assess the impact of mother/neonatal factors on the quality of CB units, collected for allogeneic transplantation. We analyzed 33 CB units collected in University Hospital of Obstetrics and Gynaecology "Maichin dom" and donated to the National public bank for stem cells, University Hospital "Alexandrovska", Sofia. A significant increase (p < 0.001) of total nucleated cell (TNC) values was found after CB processing. A trend of higher values of CD34+ cells was observed in CB units obtained from vaginal deliveries compared to Cesarian section births, and from female newborns compared to their male counterparts. CD34+ cell number positively correlated with CD34+ percentage and TNC count. Our preliminary data demonstrate the need of a large retrospective evaluation of different obstetric factors in order to establish criteria for appropriate selection in our country of umbilical cord blood donors for public banking. PMID:23234008

  20. New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia.

    PubMed

    Tadokoro, Mika; Kanai, Rie; Taketani, Takeshi; Uchio, Yuji; Yamaguchi, Seiji; Ohgushi, Hajime

    2009-06-01

    Mesenchymal stem cells (MSCs) can show osteogenic differentiation capability when implanted in vivo, as well as cultured in vitro; therefore we attempted to use allogeneic MSCs for an 8-month-old patient with hypophosphatasia. MSCs were obtained by culture expansion of fresh marrow from the patient's father. Some of the MSCs were further cultured under osteogenic conditions on a culture dish or porous hydroxyapatite ceramics, resulting in cultured osteoblasts and osteogenic constructs, respectively. The MSCs and osteoblasts were injected into the patient, and the constructs were implanted locally. After traditional bone marrow transplantation, the MSCs, osteoblasts, and osteogenic constructs were used for treatment and to improve the patient's respiratory condition and skeletal abnormality. The condition worsened again, and an MSC booster shot was administered. At the same time, the construct was retrieved. The respiratory condition improved, and the retrieved construct showed de novo bone derived from both donor and patient cells. We demonstrated the importance of allogeneic MSC transplantation for hypophosphatasia and the constructs as an alternative to bone fragments that provided further osteogenic capability in the patient. PMID:19446101

  1. Survival in a recent cohort of mechanically ventilated pediatric allogeneic hematopoietic stem cell transplantation recipients.

    PubMed

    van Gestel, Josephus P J; Bollen, Casper W; Bierings, Marc B; Boelens, Jaap Jan; Wulffraat, Nico M; van Vught, Adrianus J

    2008-12-01

    There is ongoing discussion whether survival improved for children requiring mechanical ventilation after hematopoietic stem cell transplantation (HSCT). We reviewed the outcomes of 150 children who received an allogeneic HSCT between January 1999 and April 2007, in a pediatric university hospital in The Netherlands. Thirty-five of the 150 patients received mechanical ventilation on 38 occasions. None of the recorded risk factors was significantly associated with the requirement of mechanical ventilation. Sixteen admissions resulted in death in the intensive care unit (ICU), giving a case fatality rate of 42% (95% confidence interval 26%-58%). ICU mortality was associated with multiorgan failure on the second day of admission and with the use of high frequency oscillatory ventilation. Patients had higher pediatric risk of mortality scores than in previous studies, reflecting higher acuity of illness on admission to the ICU. Six-month survival in patients discharged from the ICU was 82%. Compared to previous studies, we found an improvement in ICU survival and survival 6 months after ICU discharge in a recent cohort of ventilated children after allogeneic HSCT, even though our patients were more severely ill. Our results are promising, but they need to be confirmed in larger, preferably multicenter, studies. PMID:19041061

  2. Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

    PubMed Central

    Basak, Grzegorz W.; Soverini, Simona; Martinelli, Giovanni; Mauro, Michael J.; Müller, Martin C.; Hochhaus, Andreas; Chuah, Charles; Dufva, Inge H.; Rege-Cambrin, Giovanna; Saglio, Giuseppe; Michallet, Mauricette; Labussière, Hélène; Morisset, Stéphane; Hayette, Sandrine; Etienne, Gabriel; Olavarria, Eduardo; Zhou, Wei; Peter, Senaka; Apperley, Jane F.; Cortes, Jorge

    2011-01-01

    T315I+ Philadelphia chromosome–positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited. We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABLT315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome–positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P = .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P = .0011) and unrelated stem cell donor (hazard ratio 2.98, P = .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABLT315I mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors. PMID:21926354

  3. Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia.

    PubMed

    Wood, William A; Lee, Stephanie J; Brazauskas, Ruta; Wang, Zhiwei; Aljurf, Mahmoud D; Ballen, Karen K; Buchbinder, David K; Dehn, Jason; Freytes, Cesar O; Lazarus, Hillard M; Lemaistre, Charles F; Mehta, Paulette; Szwajcer, David; Joffe, Steven; Majhail, Navneet S

    2014-06-01

    Adolescents and young adults (AYAs, ages 15 to 40 years) with cancer have not experienced survival improvements to the same extent as younger and older patients. We compared changes in survival after myeloablative allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL) among children (n = 981), AYAs (n = 1218), and older adults (n = 469) who underwent transplantation over 3 time periods: 1990 to 1995, 1996 to 2001, and 2002 to 2007. Five-year survival varied inversely with age group. Survival improved over time in AYAs and paralleled that seen in children; however, overall survival did not change over time for older adults. Survival improvements were primarily related to lower rates of early treatment-related mortality in the most recent era. For all cohorts, relapse rates did not change over time. A subset of 222 AYAs between the ages of 15 and 25 at 46 pediatric or 49 adult centers were also analyzed to describe differences by center type. In this subgroup, there were differences in transplantation practices among pediatric and adult centers, although HCT outcomes did not differ by center type. Survival for AYAs undergoing myeloablative allogeneic HCT for ALL improved at a similar rate as survival for children. PMID:24607554

  4. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678. PMID:25587040

  5. Cytotoxic activity of allogeneic natural killer cells on U251 glioma cells in vitro.

    PubMed

    Guo, Meng; Wu, Tingting; Wan, Lixin

    2016-07-01

    The present study aimed to observe the cytotoxic activity of allogeneic natural killer (NK) cells on U251 glioma cells and to investigate their mechanism of action to establish an effective treatment strategy for neuroglioma. Cell survival curves, colony formation assays and karyotype analysis were performed to investigate the characteristics of U251 glioma cells. The present study demonstrated that natural killer group 2, member D (NKG2D)‑major histocompatibility complex class I‑related chain A/B (MICA/B) interactions contributed to the cytotoxic effect of NK cells on K562 and U251 cells. In antibody‑blocking assays to inhibit NKG2D ligands, the cytotoxic activity was not completely attenuated, which suggested that other signaling pathways contribute to the cytotoxic activity of NK cells on tumor cells in addition to the NKG2D‑mediated activity. The present study identified that the expression levels of NKG2D ligands on the surface of target cells influenced the strength of the NK cell immune response. Furthermore, allogeneic NK cells were observed to kill glioma cells in vitro, and this anticancer activity is associated with the rate of NKG2D expression on the surface of glioma cells. PMID:27175912

  6. Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

    PubMed Central

    Lin, Guiting; Lue, Tom F.

    2012-01-01

    Mesenchymal stem cells (MSCs) are well known for their immunomodulatory capabilities. In particular, their immunosuppressive property is believed to permit their allogeneic or even xenogeneic transplantation into immunocompetent recipients without the use of immunosuppressants. Adipose-derived stem cell (ADSC), owing to its ease of isolation from an abundant tissue source, is a promising MSC for the treatment of a wide range of diseases. ADSC has been shown to lack major histocompatibility complex-II expression, and its immunosuppressive effects mediated by prostaglandin E2. Both preclinical and clinical studies have shown that allogeneic transplantation of ADSCs was able to control graft-versus-host disease. In regard to xenotransplantation a total of 27 preclinical studies have been published, with 20 of them performed with the investigators' intent. All 27 studies used ADSCs isolated from humans, possibly due to the wide availability of lipoaspirates. On the other hand, the recipients were mouse in 13 studies, rat in 11, rabbit in 2, and dog in 1. The targeted diseases varied greatly but all showed significant improvements after ADSC xenotransplantation. For clinical application in human medicine, ADSC xenotransplantation offers no obvious advantage over autotransplantation. But in veterinary medicine, xenotransplantation with porcine ADSC is a practical alternative to the costly and inconvenient autotransplantation. PMID:22621212

  7. Susceptibility of neonatal T cells and adult thymocytes to peripheral tolerance to allogeneic stimuli

    PubMed Central

    do Canto, Fábio B; Lima, Celso; Teixeira, Ivan A; Bellio, Maria; Nóbrega, Alberto; Fucs, Rita

    2008-01-01

    We studied the tolerization of neonatal thymocytes (NT), neonatal splenocytes (NS) and adult thymocytes (AT), transferred to syngeneic nude (nu/nu) hosts previously injected with semi-allogeneic splenocytes, without any supportive immunosuppressive treatment. This protocol allows the study of peripheral tolerance in the absence of the thymus. BALB/c neonatal T cells and ATs were able to expand in syngeneic BALB/c nu/nu mice and functionally reconstituted an allogeneic response, rejecting (BALB/c × B6.Ba) F1 splenocytes transferred 3–4 weeks after injection of BALB/c cells. However, if (BALB/c × B6.Ba) F1 cells were injected into BALB/c nude hosts 30 days before transfer of NT, NS or AT cells, the F1 population was preserved and specific tolerance to B6 allografts was established. Furthermore, transfer to lymphopenic F1 nu/nu showed that tolerance could be established only for neonatal populations, showing that unique properties of neonatal T cells allow their tolerization in both lymphopenic and non-lymphopenic conditions, in the absence of suppressive immunotherapy. These results bring empirical support to the possibility of T-cell engraftment in immunodeficient patients showing partial identity with donor major histocompatibility complex (MHC) genes; the manipulation of immunological maturity of donor T cells may be the key for successful reconstitution of immunocompetence without induction of graft-versus-host disease. PMID:18462348

  8. A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy

    PubMed Central

    Valton, Julien; Guyot, Valérie; Marechal, Alan; Filhol, Jean-Marie; Juillerat, Alexandre; Duclert, Aymeric; Duchateau, Philippe; Poirot, Laurent

    2015-01-01

    The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients. When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor αβ-deficient CAR T cells. We demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCRαβ at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies. PMID:26061646

  9. Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure.

    PubMed

    Ayas, Mouhab; Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette; Abdel-Azim, Hisham; Alter, Blanche P; Anderlini, Paolo; Battiwalla, Minoo; Bierings, Marc; Buchbinder, David K; Bonfim, Carmem; Camitta, Bruce M; Fasth, Anders L; Gale, Robert Peter; Lee, Michelle A; Lund, Troy C; Myers, Kasiani C; Olsson, Richard F; Page, Kristin M; Prestidge, Tim D; Radhi, Mohamed; Shah, Ami J; Schultz, Kirk R; Wirk, Baldeep; Wagner, John E; Deeg, H Joachim

    2015-10-01

    A second allogeneic hematopoietic cell transplantation (HCT) is the sole salvage option for individuals who develop graft failure after their first HCT. Data on outcomes after second HCT in patients with Fanconi anemia (FA) are scarce. Here we report outcomes after second allogeneic HCT for FA (n = 81). The indication for second HCT was graft failure after the first HCT. Transplantations were performed between 1990 and 2012. The timing of the second HCT predicted subsequent graft failure and survival. Graft failure was high when the second HCT was performed less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between the first HCT and second HCT was less than 3 months, compared with 23% when the interval was longer (P < .001). Consequently, the 1-year survival rate was substantially lower when the interval between the first and second HCTs was less than 3 months compared with longer (23% vs 58%; P = .001). The corresponding 5-year probability of survival was 16% and 45%, respectively (P = .006). Taken together, these data suggest that fewer than one-half of patients with FA undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to reduce the rate of graft failure after first HCT. PMID:26116087

  10. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient. PMID:25674158

  11. Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis

    PubMed Central

    Kumar, Shaji; Zhang, Mei-Jie; Li, Peigang; Dispenzieri, Angela; Milone, Gustavo A.; Lonial, Sagar; Krishnan, Amrita; Maiolino, Angelo; Wirk, Baldeep; Weiss, Brendan; Freytes, César O.; Vogl, Dan T.; Vesole, David H.; Lazarus, Hillard M.; Meehan, Kenneth R.; Hamadani, Mehdi; Lill, Michael; Callander, Natalie S.; Majhail, Navneet S.; Wiernik, Peter H.; Nath, Rajneesh; Kamble, Rammurti T.; Vij, Ravi; Kyle, Robert A.; Gale, Robert Peter

    2011-01-01

    Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001). PMID:21690560

  12. Predictors of invasive fungal infection in pediatric allogeneic hematopoietic SCT recipients.

    PubMed

    Hol, J A; Wolfs, T F W; Bierings, M B; Lindemans, C A; Versluys, A B J; Wildt de, A; Gerhardt, C E; Boelens, J J

    2014-01-01

    This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis. PMID:24121212

  13. Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents.

    PubMed

    Li, Xiaxin; Brazauskas, Ruta; Wang, Zhiwei; Al-Seraihy, Amal; Baker, K Scott; Cahn, Jean-Yves; Frangoul, Haydar A; Gajewski, James L; Hale, Gregory A; Hsu, Jack W; Kamble, Rammurti T; Lazarus, Hillard M; Marks, David I; Maziarz, Richard T; Savani, Bipin N; Shah, Ami J; Shah, Nirali; Sorror, Mohamed L; Wood, William A; Majhail, Navneet S

    2014-04-01

    We conducted a nested case-control study within a cohort of 6244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents after allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States, and had survived ≥ 6 months from transplantation. Overall, 160 patients with AVN and 478 control subjects matched by year of transplant, length of follow-up and transplant center were identified. Patients and control subjects were confirmed via central review of radiology, pathology, and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender, and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared with patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with nonmalignant diseases and those who had received reduced-intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression after hematopoietic cell transplantation for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication. PMID:24388803

  14. Sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation: Incidence, risk factors and outcomes.

    PubMed

    Yakushijin, K; Atsuta, Y; Doki, N; Yokota, A; Kanamori, H; Miyamoto, T; Ohwada, C; Miyamura, K; Nawa, Y; Kurokawa, M; Mizuno, I; Mori, T; Onizuka, M; Taguchi, J; Ichinohe, T; Yabe, H; Morishima, Y; Kato, K; Suzuki, R; Fukuda, T

    2016-03-01

    This retrospective study was conducted in Japan to determine the incidence, risk factors and outcomes of sinusoidal obstruction syndrome (SOS) after allogeneic hematopoietic stem cell transplantation (HSCT). Among 4290 patients undergoing allogeneic HSCT between 1999 and 2010, 462 were diagnosed with SOS according to the Seattle criteria (cumulative incidence, 10.8%). The cumulative incidence of SOS diagnosed by the modified Seattle criteria was 9.3%. Of 462 patients, 107 met the Baltimore criteria and 168 had severe SOS with renal and/or respiratory failure. The median onset for SOS was 12 days after HSCT (range, -2-30). Overall survival at day 100 was 32% for SOS and 15% for severe SOS. Multivariate analyses showed that significant independent risk factors for SOS were the number of HSCTs, age, performance status, hepatitis C virus-seropositivity, advanced disease status and myeloablative regimen. SOS was highly associated with overall mortality (hazard ratio, 2.09; P<0.001). Our retrospective survey showed that the cumulative incidence of SOS in Japan was 10.8%, similar to that previously reported in Western countries, and that the overall survival of patients who developed SOS was low. Furthermore, several risk factors were identified. Preventive and therapeutic strategies for high-risk SOS patients must be established to improve overall survival. PMID:26595082

  15. Antigen mRNA-transfected, allogeneic fibroblasts loaded with NKT-cell ligand confer antitumor immunity.

    PubMed

    Fujii, Shin-ichiro; Goto, Akira; Shimizu, Kanako

    2009-04-30

    The maturation of dendritic cells (DCs) in situ by danger signals plays a central role in linking innate and adaptive immunity. We previously demonstrated that the activation of invariant natural killer T (iNKT) cells by administration of alpha-galactosylceramide (alpha-GalCer)-loaded tumor cells can act as a cellular adjuvant through the DC maturation. In the current study, we used allogeneic fibroblasts loaded with alpha-GalCer and transfected with antigen-encoding mRNA, thus combining the adjuvant effects of iNKT-cell activation with delivery of antigen to DCs in vivo. We found that these cells produce antigen protein and activate NK and iNKT cells. When injected into major histocompatibility complex (MHC)-mismatched mice, they elicited antigen-specific T-cell responses and provided tumor protection, suggesting that these immune responses depend on host DCs. In addition, antigen-expressing fibroblasts loaded with alpha-GalCer lead to a more potent T-cell response than those expressing NK cell ligands. Thus, glycolipid-loaded, mRNA-transfected allogeneic fibroblasts act as cellular vectors to provide iNKT-cell activation, leading to DC maturation and T-cell immunity. By harnessing the innate immune system and generating an adaptive immune response to a variety of antigens, this unique tool could prove clinically beneficial in the development of immunotherapies against malignant and infectious diseases. PMID:19164596

  16. Kaposi's sarcoma following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia.

    PubMed

    de Medeiros, B C; Rezuke, W N; Ricci, A; Tsongalis, G; Shen, P U; Bona, R D; Feingold, J M; Edwards, R L; Tutschka, P J; Bilgrami, S

    2000-01-01

    Unlike solid organ transplantation, Kaposi's sarcoma (KS) occurs rarely following hematopoietic stem cell transplantation (HSCT). In fact, only 5 cases of KS have been reported after allogeneic or autologous HSCT. The usual treatment combines a substantial decrease in, or elimination of, immunosuppressive therapy along with local measures such as surgical excision, cryotherapy or radiation therapy. A 46-year-old woman with chronic myelogenous leukemia who had received an allogeneic HSCT previously from an HLA-identical sibling, presented on day +814 with human herpes virus-8-associated KS involving her left lower extremity. She had been on continuous immunosuppressive therapy since her transplant because of chronic graft-versus-host disease. The intensity of immunosuppressive therapy was decreased once a diagnosis of KS had been established. However, the nodular lesions continued to progress in size and number. Therefore, a course of irradiation was administered to sites of bulk disease on her legs. Furthermore, thalidomide was initiated along with a topical retinoid, alitretinoin 0.1% gel applied twice daily to the nonirradiated lesions. This approach yielded a partial response in both irradiated and nonirradiated lesions over the course of the following 7 months. Both thalidomide and alitretinoin 0.1% gel appear to be beneficial in HSCT-associated KS and exhibit tolerable side effects. PMID:11154986

  17. Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation.

    PubMed

    Ikpeazu, C; Davidson, M K; Halteman, D; Browning, P J; Brandt, S J

    2000-01-01

    Endothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients. PMID:10905767

  18. Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

    PubMed

    Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

    2005-03-01

    Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure. PMID:15522953

  19. Pushing the envelope—nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation

    PubMed Central

    Pingali, SR; Champlin, RE

    2016-01-01

    Allogeneic hematopoietic cell transplantation (HCT) was originally developed to allow delivery of myeloablative doses of chemotherapy and radiotherapy. With better understanding of disease pathophysiology, the graft vs malignancy (GVM) effect of allogeneic hematopoietic transplantation and toxicities associated with myeloablative conditioning (MAC) regimens, the focus shifted to developing less toxic conditioning regimens to reduce treatment-related morbidity without compromising survival. Although HCT with MAC is preferred to reduced intensity conditioning (RIC) for most patients ≤ 60 years with AML/myelodysplastic syndrome and ALL, RIC and nonmyeloablative (NMA) regimens allow HCT for many otherwise ineligible patients. Reduced intensity preparative regimens have produced high rates of PFS for diagnoses, which are highly sensitive to GVM. Relapse of the malignancy is the major cause of treatment failure with RIC/NMA HCT. Incorporation of novel agents like bortezomib or lenalidomide, addition of cellular immunotherapy and use of targeted radiation therapies could further improve outcome. In this review, we discuss commonly used RIC/NMA regimens and promising novel regimens. PMID:25985053

  20. Bone Marrow Harvesting of Allogeneic Donors in an Outpatient Setting: A Single-Center Experience.

    PubMed

    Lisenko, Katharina; Stadtherr, Peter; Bruckner, Thomas; Pavel, Petra; Heilig, Christoph E; Schmitt, Anita; Puthenparambil, Joe; Brandt, Juliane; Ho, Anthony D; Dreger, Peter; Witzens-Harig, Mathias; Wuchter, Patrick

    2016-03-01

    The aim of this retrospective study was to assess the safety and efficacy of bone marrow (BM) harvesting of allogeneic donors in an outpatient setting. Data of 226 related and unrelated donors who underwent BM harvest under general anesthesia at our institution from 2002 to 2014 were analyzed. Sixteen patients were a priori planned for admission for social reasons and 210 patients underwent BM harvesting with the intention to perform this procedure on an outpatient basis. To identify factors that predispose for hospital admission, we retrospectively analyzed donor characteristics and collection parameters. Outpatient treatment was performed in 178 of 210 donors (85%), whereas 32 donors (15%) required admission for clinical reasons (mainly clinically relevant anemia and circulatory problems). These individuals were not significantly different in sex distribution, age, donor's body weight, and the proportion of related donors from those who were not admitted. However, we found a significantly higher collection volume per kilogram donor's body weight in inpatients compared with volume for outpatients (16 versus 13 mL/kg body weight, P < .001). Severe adverse events or deaths occurred neither in the inpatient nor in the outpatient setting. Our study demonstrated that BM harvest in an outpatient setting is safe and feasible for the majority of allogeneic donors. A high volume of BM represented a major risk factor for inpatient admission. PMID:26551634