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Sample records for allogeneic spleen cells

  1. Booster irradiation to the spleen following total body irradiation. A new immunosuppressive approach for allogeneic bone marrow transplantation

    SciTech Connect

    Lapidot, T.; Singer, T.S.; Salomon, O.; Terenzi, A.; Schwartz, E.; Reisner, Y.

    1988-10-15

    Graft rejection presents a major obstacle for transplantation of T cell-depleted bone marrow in HLA-mismatched patients. In a primate model, after conditioning exactly as for leukemia patients, it was shown that over 99% of the residual host clonable T cells are concentrated in the spleen on day 5 after completion of cytoreduction. We have now corroborated these findings in a mouse model. After 9-Gy total body irradiation (TBI), the total number of Thy-1.2+ cells in the spleen reaches a peak between days 3 and 4 after TBI. The T cell population is composed of both L3T4 (helper) and Lyt-2 (suppressor) T cells, the former being the major subpopulation. Specific booster irradiation to the spleen (5 Gy twice) on days 2 and 4 after TBI greatly enhances production of donor-type chimera after transplantation of T cell-depleted allogeneic bone marrow. Similar enhancement can be achieved by splenectomy on day 3 or 4 after TBI but not if splenectomy is performed 1 day before TBI or 1 day after TBI, strengthening the hypothesis that, after lethal TBI in mice, the remaining host T cells migrate from the periphery to the spleen. These results suggest that a delayed booster irradiation to the spleen may be beneficial as an additional immunosuppressive agent in the conditioning of leukemia patients, in order to reduce the incidence of bone marrow allograft rejection.

  2. Human spleen and red blood cells

    NASA Astrophysics Data System (ADS)

    Pivkin, Igor; Peng, Zhangli; Karniadakis, George; Buffet, Pierre; Dao, Ming

    2016-11-01

    Spleen plays multiple roles in the human body. Among them is removal of old and altered red blood cells (RBCs), which is done by filtering cells through the endothelial slits, small micron-sized openings. There is currently no experimental technique available that allows us to observe RBC passage through the slits. It was previously noticed that people without a spleen have less deformable red blood cells, indicating that the spleen may play a role in defining the size and shape of red blood cells. We used detailed RBC model implemented within the Dissipative Particle Dynamics (DPD) simulation framework to study the filter function of the spleen. Our results demonstrate that spleen indeed plays major role in defining the size and shape of the healthy human red blood cells.

  3. Stromal Cell Subsets Directing Neonatal Spleen Regeneration

    PubMed Central

    Tan, Jonathan K. H.; Watanabe, Takeshi

    2017-01-01

    Development of lymphoid tissue is determined by interactions between stromal lymphoid tissue organiser (LTo) and hematopoietic lymphoid tissue inducer (LTi) cells. A failure for LTo to receive appropriate activating signals during embryogenesis through lymphotoxin engagement leads to a complete cessation of lymph node (LN) and Peyer’s patch development, identifying LTo as a key stromal population for lymphoid tissue organogenesis. However, little is known about the equivalent stromal cells that induce spleen development. Here, by dissociating neonatal murine spleen stromal tissue for re-aggregation and transplant into adult mouse recipients, we have identified a MAdCAM-1+CD31+CD201+ spleen stromal organizer cell-type critical for new tissue formation. This finding provides an insight into the regulation of post-natal spleen tissue organogenesis, and could be exploited in the development of spleen regenerative therapies. PMID:28067323

  4. 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

  5. Angiogenesis after transplantation of auto- and allogenic cells.

    PubMed

    Fatkhudinov, T Kh; Bol'shakova, G B; Komissarova, S V; Arutyunyan, I V; Rzhaninova, A A; Goldstein, D V

    2010-10-01

    Neoangiogenesis after transplantation of auto- and allogenic mononuclears and multipotent stromal cells from the bone marrow was studied on the model of inflammatory angiogenesis. Transplanted auto- and allogenic cells stimulate the formation of new blood vessels in the granulation tissue, this manifesting in an increase in the quantity and volume density of blood vessels. The most pronounced angiogenesis was observed after transplantation of allogenic mononuclears and multipotent stromal cells. It was associated with intense inflammatory infiltration, with less numerous and mature collagen fibers in the granulation tissue. Injection of allogenic cells led to stimulation and chronization of inflammation, infiltration with inflammatory and poorly differentiated cells, and more pronounced and lasting angiogenesis. However, neither auto-, nor allogenic transplanted labeled cells were detected in the walls of new blood vessels. Hence, it seems that bone marrow mononuclears and multipotent stromal cells stimulated angiogenesis mainly at the expense of production of angiogenic factors, and after transplantation of allogenic cells also by stimulating the inflammation.

  6. [Aspergillus galactomannan detection in allogenic hematopoietic cell transplantation].

    PubMed

    Rovira Tarrats, Montserrat; Puig de la Bellacasa, Jorge

    2003-09-01

    Invasive aspergillosis has become the leading cause of death after allogeneic hematopoietic stem cell transplantation. This is partially due to the lack of a prompt diagnosis. Recently the detection of Aspergillus galactomannan antigen by means an ELISA technique in serum has been described. The objective of this study was to validate its usefulness in the allogeneic hematopoietic stem cell transplantation setting.

  7. Redefining Myeloid Cell Subsets in Murine Spleen.

    PubMed

    Hey, Ying-Ying; Tan, Jonathan K H; O'Neill, Helen C

    2015-01-01

    Spleen is known to contain multiple dendritic and myeloid cell subsets, distinguishable on the basis of phenotype, function and anatomical location. As a result of recent intensive flow cytometric analyses, splenic dendritic cell (DC) subsets are now better characterized than other myeloid subsets. In order to identify and fully characterize a novel splenic subset termed "L-DC" in relation to other myeloid cells, it was necessary to investigate myeloid subsets in more detail. In terms of cell surface phenotype, L-DC were initially characterized as a CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) subset in murine spleen. Their expression of CD43, lack of MHCII, and a low level of CD11c was shown to best differentiate L-DC by phenotype from conventional DC subsets. A complete analysis of all subsets in spleen led to the classification of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(lo)Ly6G(-) cells as monocytes expressing CX3CR1, CD43 and CD115. Siglec-F expression was used to identify a specific eosinophil population, distinguishable from both Ly6C(lo) and Ly6C(hi) monocytes, and other DC subsets. L-DC were characterized as a clear subset of CD11b(hi)CD11c(lo)MHCII(-)Ly6C(-)Ly6G(-) cells, which are CD43(+), Siglec-F(-) and CD115(-). Changes in the prevalence of L-DC compared to other subsets in spleens of mutant mice confirmed the phenotypic distinction between L-DC, cDC and monocyte subsets. L-DC development in vivo was shown to occur independently of the BATF3 transcription factor that regulates cDC development, and also independently of the FLT3L and GM-CSF growth factors which drive cDC and monocyte development, so distinguishing L-DC from these commonly defined cell types.

  8. Chemokine Receptor Signatures in Allogeneic Stem Cell Transplantation

    DTIC Science & Technology

    2015-08-01

    CCR5 in particular) closely correlated with vitamin D levels (Ganetsky et al. Vitamin D Deficiency Predicts Acute Cutaneous Graft- Versus-Host...Frey NV, Vonderheide RH, Porter DL, Reshef R: Vitamin D Deficiency Predicts Acute Cutaneous Graft-Versus-Host Disease in Reduced-Intensity Allogeneic...effect of vitamin D levels on T-cell function by conducting functional assays and gene expression profiling of day-30 T-cells from allogeneic HSCT

  9. Chemokine Receptor Signatures in Allogeneic Stem Cell Transplantation

    DTIC Science & Technology

    2014-08-01

    after allogeneic HSCT without compromising the graft-versus- leukemia (GVL) effect. Using deep sequencing of the T-cell receptor beta chain (TCRB...application was funded - “The role of surface NKG2D expression by NK cells in the graft-versus- leukemia response”. In addition I recently participated as

  10. 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

  11. Clinical Allogeneic and Autologous Islet Cell Transplantation: Update

    PubMed Central

    2011-01-01

    Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities. PMID:21785738

  12. 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.

  13. Littoral-cell angioma of the spleen: a case report.

    PubMed

    Cosme, Angel; Tejada, Angel; Bujanda, Luis; Vaquero, Manuel; Elorza, José Luis; Ojeda, Evelia; Goikoetxea, Unai

    2007-12-28

    Littoral-cell angioma (LCA) is a primary splenic vascular tumor that arises from the normal littoral cells lining the sinus channels of the splenic red pulp. We report a case of LCA of the spleen, which has been infrequently communicated in the literature. A 76-year-old man with a 2-wk history of weight loss, abdominal pain and changes in bowel habits was admitted to our hospital. Imaging studies (CT and MRI) showed multiple lesions in the spleen. Splenectomy was performed. Lining cells were positive for CD31/CD68 markers. Our case was associated with a serrated colonic adenoma. LCA is a benign vascular tumor of the spleen that needs to be included in the differential diagnosis of multiple splenic nodules.

  14. Eltrombopag for Treatment of Thrombocytopenia after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Tanaka, Takashi; Inamoto, Yoshihiro; Yamashita, Takuya; Fuji, Shigeo; Okinaka, Keiji; Kurosawa, Saiko; Kim, Sung-Won; Tanosaki, Ryuji; Fukuda, Takahiro

    2016-05-01

    Persistent thrombocytopenia is a common complication after allogeneic hematopoietic cell transplantation (HCT). Eltrombopag is an oral thrombopoietin receptor agonist whose efficacy against persistent thrombocytopenia after allogeneic HCT has not been well characterized. This retrospective study evaluated the safety and efficacy of eltrombopag in 12 consecutive patients with persistent thrombocytopenia after allogeneic HCT. Eltrombopag was started at 12.5 mg once daily and the dose was increased by 12.5 mg daily every week until platelet counts exceeded 50,000/μL. Five patients had prolonged isolated thrombocytopenia (PIT) and 7 patients had secondary failure of platelet recovery (SFPR). The cumulative incidence rate of successful platelet recovery to ≥50,000/μL without transfusion support was 60% in PIT patients and 71% in SFPR patients. No patients discontinued the drug because of adverse events or intolerability. Notably, the rate of platelet recovery was higher (100% versus 58%; P = .0017) and recovery was faster (median, 33 days versus 137 days; P = .0078) in patients with normal numbers of bone marrow megakaryocytes before starting eltrombopag than in those with decreased numbers of megakaryocytes. Eltrombopag is a promising treatment for both PIT and SFPR after allogeneic HCT. The number of megakaryocytes in bone marrow before eltrombopag treatment may predict the response to eltrombopag.

  15. Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model.

    PubMed

    Ito, M; Shizuru, J A

    1999-01-01

    It is known that an important curative benefit of allogeneic bone marrow transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft-vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells contained within the graft because T-cell depletion of bone marrow results in increased rates of disease relapse post-transplantation. We previously demonstrated successful engraftment of highly purified hematopoietic stem cells (HSCs) transplanted across major histocompatibility complex (MHC) barriers in mice. In the present study, we have developed a preclinical model of allogeneic HSC transplantation into lymphoma-inoculated mice, allowing us to directly test whether purified HSCs have measurable GVT activity. We then performed cotransfer studies of HSCs with purified immune cells to identify which population(s) confers tumor protection and the mechanism by which such cells suppress tumor growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD). Although there appears to be no functional difference between BM- and splenic-derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective, whereas transplantation of equivalent doses of CD3+ cells purified from spleen resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect recipient mice from tumors was studied using immune defective mice as donors. We found that an intact pathway of perforin-dependent cytolysis, as well as an intact Fas-ligand pathway, is required in order to exert maximal anti-tumor activity.

  16. Prospective study of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced renal cell cancer.

    PubMed

    Lin, Mao; Xu, Kecheng; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, LiZhi

    2017-03-05

    In this study, the clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for advanced renal cell cancer was evaluated. From July to December 2016, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n=30); and (2) the cryoablation combined with allogenic NK cells group (n=30). The clinical efficacy, quality of life, immune function, and other related indicators were evaluated. Combining allogeneic NK cells with cryoablation had a synergistic effect, not only enhancing the immune function and improving the quality of life of the patients, but also significantly exhibiting good clinical efficacy of the patients. This study is the first clinical trial that has evaluated the safety and efficacy of allogenic NK cells combined with cryosurgery for the treatment of renal cell cancer.

  17. Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

    PubMed Central

    2016-01-01

    Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs) injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM) or adipose tissue derived MSCs (ad-MSCs) were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89%) were positive for anti-bovine serum albumin (BSA) antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection. PMID:27648075

  18. 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.

  19. 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.

  20. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

    PubMed Central

    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

    2015-01-01

    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

  1. 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

  2. Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

    ClinicalTrials.gov

    2016-04-26

    Thalassemia; Sickle Cell Disease; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic-granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Schwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Fanconi Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia

  3. Bone Marrow Derived Hematopoietic Stem and Progenitor Cells Infiltrate Allogeneic and Syngeneic Transplants

    PubMed Central

    Fan, Z.; Enjoji, K.; Tigges, J. C.; Toxavidis, V.; Tchipashivili, V.; Gong, W.; Strom, T. B.; Koulmanda, M.

    2015-01-01

    Lineage (CD3e, CD11b, GR1, B220 and Ly-76) negative hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) infiltrate islet allografts within 24 h posttransplantation. In fact, lineagenegative Sca-1+cKit+ (“LSK”) cells, a classic signature for HSCs, were also detected among these graft infiltrating cells. Lineage negative graft infiltrating cells are functionally multi-potential as determined by a standard competitive bone marrow transplant (BMT) assay. By 3 months post-BMT, both CD45.1 congenic, lineage negative HSCs/HPCs and classic “LSK” HSCs purified from islet allograft infiltrating cells, differentiate and repopulate multiple mature blood cell phenotypes in peripheral blood, lymph nodes, spleen, bone marrow and thymus of CD45.2 hosts. Interestingly, “LSK” HSCs also rapidly infiltrate syngeneic islet transplants as well as allogeneic cardiac transplants and sham surgery sites. It seems likely that an inflammatory response, not an adaptive immune response to allo-antigen, is responsible for the rapid infiltration of islet and cardiac transplants by biologically active HSCs/HPCs. The pattern of hematopoietic differentiation obtained from graft infiltrating HSCs/HPCs, cells that are recovered from inflammatory sites, as noted in the competitive BMT assay, is not precisely the same as that of intra-medullary HSCs. This does not refute the obvious multi-lineage potential of graft infiltrating HSCs/HPCs. PMID:25387427

  4. Use of allogeneic NK cells for cancer immunotherapy

    PubMed Central

    Geller, Melissa A; Miller, Jeffrey S

    2012-01-01

    Controversy exists as to the role that the immune system plays in cancer therapy. While the immune system has been proposed to scavenge the body to prevent microscopic transformation from forming cancer, it has been difficult to mount its potential of shrinking established tumors. NK cells are components of the innate immune system. They can recognize targets without prior sensitization, making them ideal candidates to manipulate for therapeutic use against cancer. Initially, autologous NK cells were directed against tumors but it was realized that NK cells that recognize self cells are inhibited. More encouraging advances have been made with allogeneic NK cell therapy in clinical trials to overcome this limitation. In this article, we present developments in NK cell adoptive immunotherapy for hematologic and solid tumor malignancies. PMID:22091681

  5. Donor lymphocyte infusion after allogeneic stem cell transplantation.

    PubMed

    Castagna, Luca; Sarina, Barbara; Bramanti, Stefania; Perseghin, Paolo; Mariotti, Jacopo; Morabito, Lucio

    2016-06-01

    Allogeneic stem cell transplantation (allo-SCT) is considered the cornerstone in the treatment of several malignant and not malignant hematological diseases. However, relapse of hematological disease after allo-SCT is considered the most challenging point in the field. The risk can be reduced through optimal patients, donor and disease selection before allo-SCT, but harnessing donor immune system is an appealing way to treat or avoid disease relapse. Donor lymphocyte infusion (DLI) is a simple and effective therapy after allo-SCT. In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use.

  6. Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica.

    PubMed

    Greco, Raffaella; Bondanza, Attilio; Vago, Luca; Moiola, Lucia; Rossi, Paolo; Furlan, Roberto; Martino, Gianvito; Radaelli, Marta; Martinelli, Vittorio; Carbone, Maria Rosaria; Lupo Stanghellini, Maria Teresa; Assanelli, Andrea; Bernardi, Massimo; Corti, Consuelo; Peccatori, Jacopo; Bonini, Chiara; Vezzulli, Paolo; Falini, Andrea; Ciceri, Fabio; Comi, Giancarlo

    2014-03-01

    Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option.

  7. Management of infections complicating allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hiemenz, John W

    2009-07-01

    The use of allogeneic hematopoietic stem cell transplantation for the treatment of hematologic malignancies, as well as some benign hematologic disorders, has continued to grow over the last 10 years. The availability of this procedure to an increasing number of patients has been facilitated by the use of newer techniques, including reduced intensity conditioning (RIC) regimens, peripheral blood stem cells (PBSCs) and cord blood as donor sources, graft manipulation such as selective T-cell depletion, and other in vitro and in vivo attempts to reduce the risk and severity of graft-versus-host disease (GVHD) after transplantation without losing the potential benefits of a graft-versus-tumor effect for patients with hematologic malignancies. The underlying theme of many of these newer techniques has been to minimize the severity and duration of transplant-related immune suppression, thus reducing the risk of morbidity and mortality from infectious complications. This article reviews immune suppression and recovery that occur after allogeneic stem cell transplantation, with changes in the epidemiology, and some of the recent advances that have been made in management of infectious complications.

  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.

  9. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    PubMed

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  10. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Sánchez-Martínez, Diego; Lanuza, Pilar M.; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A.; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments. PMID:27833611

  11. Activity of host-derived T cells which differentiate in nude mice grafted with co-isogenic or allogeneic thymuses.

    PubMed

    Kindred, B; Loor, F

    1974-05-01

    If nude mice are grafted with a neonatal thymus, host type precursor cells develop within the graft thymus and after about 6 wk the T-cell population of the thymus, spleen, and lymph nodes is of host type. However, immunological responsiveness produced in nude mice in this manner is incomplete: (a) the ability to react to T-cell mitogens in vitro is greater than in untreated nudes but lower than in normal mice; (b) the response to T-cell dependent antigens is less than normal; and (c) the rejection of skin grafts is slower than in normal animals. Whether host precursor cells which differentiate in an allogeneic thymus are able to reject skin grafts from thymus donor strain appears to depend on the strain combination used.

  12. Effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    SciTech Connect

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-02-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. /sup 51/Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras.

  13. Dynamics of Red Cells in Spleen: How Does Vesiculation Happen?

    NASA Astrophysics Data System (ADS)

    Zhu, Qiang; Salehyar, Sara; Cabrales, Pedro; Asaro, Robert

    2016-11-01

    Vesiculation of red blood cells as a result of local separation between lipid bilayer and cytoskeleton is known to happen in vivo, most likely inside spleen where they sustain large mechanical loads during the passage through venus slits. There is, however, little knowledge about the detailed scenario and condition. We address this question via a fluid-cell interaction model by coupling a multiscale model of the cell membrane (including molecular details) with a fluid dynamics model based on boundary-integral equations. A numerical flow channel is created where the cell is driven through a narrow slit by pressure (imitating the transit through venus slits in spleen). The concentration is the occurrence of large dissociation (negative) pressure between the skeleton/membrane connection that promotes separation, a precursor of vesicle formation. Critical levels for the negative pressure are estimated using published data. By following the maximum range of pressure, we conclude that for vesiculation to happen there must be biochemical influences (e.g. binding of degraded haemoglobin) that significantly reduce effective attachment density. This is consistent with reported trends in vesiculation that are believed to occur in cases of various hereditary anemias and during blood storage. Our findings also suggest the criticality of understanding the biochemical phenomena involved with cytoskeleton/membrane attachment.

  14. Modeling of Red Blood Cells and Related Spleen Function

    NASA Astrophysics Data System (ADS)

    Peng, Zhangli; Pivkin, Igor; Dao, Ming

    2011-11-01

    A key function of the spleen is to clear red blood cells (RBCs) with abnormal mechanical properties from the circulation. These abnormal mechanical properties may be due to RBC aging or RBC diseases, e.g., malaria and sickle cell anemia. Specifically, 10% of RBCs passing through the spleen are forced to squeeze into the narrow slits between the endothelial cells, and stiffer cells which get stuck are killed and digested by macrophages. To investigate this important physiological process, we employ three different approaches to study RBCs passage through these small slits, including analytical theory, Dissipative Particle Dynamics (DPD) simulation and Multiscale Finite Element Method (MS-FEM). By applying the analytical theory, we estimate the critical limiting geometries RBCs can pass. By using the DPD method, we study the full fluid-structure interaction problem, and compute RBC deformation under different pressure gradients. By employing the MS-FEM approach, we model the lipid bilayer and the cytoskeleton as two distinct layers, and focus on the cytoskeleton deformation and the bilayer-skeleton interaction force at the molecular level. Finally the results of these three approaches are compared to each other and correlated to the experimental observations.

  15. 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

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

    PubMed

    Landgren, Ola; 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

    2009-05-14

    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.

  17. Transport of diseased red blood cells in the spleen

    NASA Astrophysics Data System (ADS)

    Peng, Zhangli; Pivkin, Igor; Dao, Ming

    2012-11-01

    A major function of the spleen is to remove old and diseased red blood cells (RBCs) with abnormal mechanical properties. We investigated this mechanical filtering mechanism by combining experiments and computational modeling, especially for red blood cells in malaria and sickle cell disease (SCD). First, utilizing a transgenic line for 3D confocal live imaging, in vitro capillary assays and 3D finite element modeling, we extracted the mechanical properties of both the RBC membrane and malaria parasites for different asexual malaria stages. Secondly, using a non-invasive laser interferometric technique, we optically measured the dynamic membrane fluctuations of SCD RBCs. By simulating the membrane fluctuation experiment using the dissipative particle dynamics (DPD) model, we retrieved mechanical properties of SCD RBCs with different shapes. Finally, based on the mechanical properties obtained from these experiments, we simulated the full fluid-structure interaction problem of diseased RBCs passing through endothelial slits in the spleen under different fluid pressure gradients using the DPD model. The effects of the mechanical properties of the lipid bilayer, the cytoskeleton and the parasite on the critical pressure of splenic passage of RBCs were investigated separately. This work is supported by NIH and Singapore-MIT Alliance for Science and Technology (SMART).

  18. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-01-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  19. Reprint of: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-02-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  20. Chlamydia pneumoniae respiratory infection after allogeneic stem cell transplantation.

    PubMed

    Geisler, William M; Corey, Lawrence

    2002-03-27

    Chlamydia pneumoniae is a common cause of upper and lower respiratory tract infections in immunocompetent patients; however, its role as a respiratory pathogen in immunocompromised hosts has been infrequently recognized. We describe C. pneumoniae lower respiratory tract infection in a 19-year-old male after allogeneic stem cell transplantation. The patient developed fever on day +14, and a subsequent computed tomography scan of the chest revealed a right lateral pleural-based opacity, which was then resected during thoracoscopy. Diagnosis was made by culture and staining of the resected tissue with C. pneumoniae-specific monoclonal antibodies, and azithromycin was administered. To the best of our knowledge, this is the first report of C. pneumoniae respiratory infection after stem cell or marrow transplantation. C. pneumoniae often coexists with other etiologic agents of pneumonia in immunocompromised patients. Considering the infrequency of infections from this organism in this clinical setting, one must still rule out other more likely respiratory pathogens.

  1. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

    2016-01-01

    The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

  2. Allogeneic stem cell transplantation for the treatment of refractory scleromyxedema.

    PubMed

    Shayegi, Nona; Alakel, Nael; Middeke, Jan Moritz; Schetelig, J; Mantovani-Löffler, Luisa; Bornhäuser, Martin

    2015-02-01

    Scleromyxedema is a rare disorder of connective tissue with unknown etiology. Its manifestation includes a generalized mucin deposition, which is frequently associated with paraproteinemia. The course of scleromyxedema is progressive and often lethal. As a result of its poorly understood pathogenesis, there is no causative treatment option. The efficacy of cytoreductive agents and autologous stem cell transplantation has been reported, but so far allografting as a treatment option has not yet been documented. Herein, we report on a patient with severe neurologic involvement and refractory course attaining durable remission after receiving an allogeneic hematopoietic cell transplant from an human leukocyte antigen-matched sibling. This case not only illustrates a potential new treatment option for selected patients, but also provides insights into the pathogenesis of this rare disease.

  3. 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

  4. Paclitaxel inhibits the hyper-activation of spleen cells by lipopolysaccharide and induces cell death

    PubMed Central

    Kim, Hyun-Ji

    2016-01-01

    Paclitaxel was isolated from the bark of the Pacific yew, Taxus brevifolia, and used as an anticancer agent. Paclitaxel prevents cancer cell division by inhibiting spindle fiber function, inducing cell death. A recent study demonstrated that paclitaxel binds to myeloid differentiation protein-2 of Toll-like receptor 4 and prevents the signal transduction of lipopolysaccharide (LPS). Paclitaxel converts immune cells hypo-responsive to LPS. In this study, we investigated whether paclitaxel can inhibit the phenotype and function of immune cells. To accomplish this, we used spleen cells, a major type of immune cell, LPS, a representative inflammatory agent and a mitogen for B lymphocytes. LPS profoundly increased the activation and cytokine production of spleen cells. However, paclitaxel significantly inhibited LPS-induced hyper-activation of spleen cells. Furthermore, we found that paclitaxel induced cell death of LPS-treated spleen cells. These results suggest that paclitaxel can inhibit the hyper-immune response of LPS in spleen cells via a variety of mechanisms. These findings suggest that paclitaxel can be used as a modulating agent for diseases induced by hyper-activation of B lymphocytes. Taken together, these results demonstrate that paclitaxel inhibits the function of spleen cells activated by LPS, and further induces cell death. PMID:27030196

  5. 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.

  6. 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.

  7. SUCCESSFUL FERTILITY RESTORATION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

    PubMed Central

    Gharwan, Helen; Neary, Nicola M.; Link, Mary; Hsieh, Matthew M.; Fitzhugh, Courtney D.; Sherins, Richard J.; Tisdale, John F.

    2015-01-01

    Objective Myeloablative conditioning regimens given prior to hematopoietic stem cell transplantation (HSCT) frequently cause permanent sterility in men. In patients with sickle cell disease (SCD) we use a nonmyeloablative regimen with sirolimus, alemtuzumab, and low-dose total-body irradiation (300 centigrays) with gonadal shielding preceding allogeneic HSCT. We report here the restoration of azoospermia in a patient with SCD after allogeneic HSCT. We discuss the impact of our patient’s underlying chronic medical conditions and the therapies he had received (frequent blood transfusions, iron chelating drugs, ribavirin, hydroxyurea, opioids), as well as the impact of the nonmyeloablative conditioning regimen on male gonadal function, and we review the literature on this topic. Methods We determined the patient’s reproductive hormonal values and his semen parameters before, during, and after HSCT and infertility treatment. In addition, we routinely measured his serum laboratory parameters pertinent to SCD and infertility, such as iron and ferritin levels. A karyotype analysis was performed to assess the potential presence of Klinefelter syndrome. Finally, imaging studies of the patient’s brain and testes were done to rule out further underlying pathology. Results A 42-year-old man with SCD, transfusional iron overload, and hepatitis C underwent a nonmyeloablative allogeneic HSCT. One year later he desired to father a child but was found to be azoospermic in the context of hypogonadotropic hypogonadism. Restoration of fertility was attempted with human chorionic gonadotropin (2,000 IU) plus human menopausal gonadotropin (75 IU follicle-stimulating hormone) injected subcutaneously 3 times weekly. Within 6 months of treatment, the patient’s serum calculated free testosterone value normalized, and his sperm count and sperm motility improved. After 10 months, he successfully initiated a pregnancy through intercourse. The pregnancy was uncomplicated, and a healthy

  8. Osteogenic activity of bone marrow-derived mesenchymal stem cells (BMSCs) seeded on irradiated allogenic bone.

    PubMed

    Tohma, Yasuaki; Dohi, Yoshiko; Ohgushi, Hajime; Tadokoro, Mika; Akahane, Manabu; Tanaka, Yasuhito

    2012-02-01

    Allogenic bone grafting, a technique used in orthopaedic surgery, has several problems, including low osteogenic activity. To overcome the problem, this study aimed to determine whether in vivo osteogenesis could be enhanced using allogenic irradiated bone grafts after seeding with autologous bone marrow-derived mesenchymal stem cells (BMSCs). The allogenic bone cylinders were extracted from ACI rats and sterilized by irradiation. Donor BMSCs were obtained from fresh Fischer 344 (F344) rat bone marrow by cell culture. The allogenic bone with or without BMSCs were transplanted subcutaneously into syngeneic F344 rats. At 4 weeks after transplantation, high alkaline phosphatase (ALP) activity, bone-specific osteocalcin mRNA expression and newly formed bone were detected in the allogenic bone with BMSCs. The origin of the newly formed bone was derived from cultured donor BMSCs. However, none of these identifiers of osteogenesis were detected in either the fresh or the irradiated allogenic bone without BMSCs. These results indicate the availability of autologous BMSCs to heighten the osteogenic response of allogenic bone. Our present tissue-engineering method might contribute to a wide variety of allogenic bone grafting techniques in clinical settings.

  9. Immune tolerance of mice allogenic tooth transplantation induced by immature dendritic cells

    PubMed Central

    Li, Wenying; Deng, Feng; Wang, Yu; Ma, Ce; Wang, Yurong

    2015-01-01

    As a common procedure in dentistry for replacing a missing tooth, allogenic tooth transplantation has encountered many difficulties in the clinical application because of immunological rejection. It is hypothesized that immature dendritic cell injection might be a potential alternative method to avoid or alleviate immunological rejection in allogenic tooth transplantation. To test this hypothesis, a mouse model of allogenic and autogeneic tooth transplantation was to established test the immunosuppressive effect of immature dendritic cells (imDCs) derived from donor bone marrows on transplant rejection in allogenic tooth transplantation. 2 × 106 imDCs generated with 50 U/ml GM-CSF were injected to each recipient mouse by two ways: tail vein injection 7 days before transplantation or regional dermal injection at day 0 and day 3 after transplantation. Groups of autogeneic tooth transplantation and allogenic tooth transplantation without any treatment were set as control groups. The effects were evaluated with histopathology and immunohistochemistry. We found there was no obvious rejection in autogeneic tooth transplantation group; tail intravenous injection group showed obviously alleviated rejection while local injection group and none-treatment allogenic tooth transplantation group both showed severe rejection. Our results suggested that the rejection of allogenic tooth transplantation could be alleviated by tail vein injection of donor bone marrow-derived imDCs though it could not be completely eliminated. The clinical application of imDCs in allogenic tooth transplantation still needs further deep research. PMID:26131099

  10. Mouse host unlicensed NK cells promote donor allogeneic bone marrow engraftment.

    PubMed

    Alvarez, Maite; Sun, Kai; Murphy, William J

    2016-03-03

    Natural killer (NK) cells exist as subsets based on expression of inhibitory receptors that recognize major histocompatibility complex I (MHCI) molecules. NK cell subsets bearing MHCI binding receptors for self-MHCI have been termed as "licensed" and exhibit a higher ability to respond to stimuli. In the context of bone marrow transplantation (BMT), host licensed-NK (L-NK) cells have also been demonstrated to be responsible for the acute rejection of allogeneic and MHCI-deficient BM cells (BMCs) in mice after lethal irradiation. However, the role of recipient unlicensed-NK (U-NK) cells has not been well established with regard to allogeneic BMC resistance. After NK cell stimulation, the prior depletion of host L-NK cells resulted in a marked increase of donor engraftment compared with the untreated group. Surprisingly, this increased donor engraftment was reduced after total host NK cell depletion, indicating that U-NK cells can actually promote donor allogeneic BMC engraftment. Furthermore, direct coculture of U-NK cells with allogeneic but not syngeneic BMCs resulted in increased colony-forming unit cell growth in vitro, which was at least partially mediated by granulocyte macrophage colony-stimulating factor (GM-CSF) production. These data demonstrate that host NK cell subsets exert markedly different roles in allogeneic BMC engraftment where host L- and U-NK cells reject or promote donor allogeneic BMC engraftment, respectively.

  11. Allogeneic Mesenchymal Stem Cell Transplantation in Dogs With Keratoconjunctivitis Sicca

    PubMed Central

    Bittencourt, Maura K. W.; Barros, Michele A.; Martins, João Flávio P.; Vasconcellos, Jose Paulo C.; Morais, Bruna P.; Pompeia, Celine; Bittencourt, Matheus Domingues; Evangelho, Karine dos Santos; Kerkis, Irina; Wenceslau, Cristiane V.

    2016-01-01

    Keratoconjunctivitis sicca (KCS) is a dysfunction in tear production associated with clinical signs, which include conjunctival hyperemia, ocular discharge, discomfort, pain, and, eventually, corneal vascularization and pigmentation. Immunosuppressive drugs are routinely administrated for long periods to treat KCS but with side effects and limited results. Evaluation of the clinical benefits of intralacrimal transplantation of allogeneic mesenchymal stem cells (MSCs) in dogs with mild–moderate and severe KCS was done. A total of 24 eyes with KCS from 15 dogs of different breeds were enrolled in the present study. A single transplantation of MSCs (1 × 106) directly into lacrimal glands (dorsal and third eyelid) was performed. The Schirmer tear tests (STTs) and ocular surface improvements were used to assess short- and long-term effects of these cells. The STTs were carried out on day 0 (before MSCs transplantation) and on days 7, 14, 21, and 28, as well as 6 and 12 months after MSC transplantation. Our data demonstrate that allogeneic MSC transplantation in KCS dogs is safe since no adverse effects were observed immediately after transplantation and in short- and long-term follow-ups. A statistically significant increase in the STT and ocular surface improvements was found in all eyes studied. In all the eyes with mild–moderate KCS, STT values reverted to those of healthy eyes, while in eyes with severe KCS, although complete reversion was not found, there was improvement in tear production and in other clinical signs. Our study shows that a single dose of a low number of MSCs can be used to treat KCS in dogs. In contrast to immunosuppressive drug use, MSC transplantation has an effect over a long period (up to 12 months), even after a single administration, and does not require daily drug administration. PMID:28003932

  12. Immune signatures of protective spleen memory CD8 T cells

    PubMed Central

    Brinza, Lilia; Djebali, Sophia; Tomkowiak, Martine; Mafille, Julien; Loiseau, Céline; Jouve, Pierre-Emmanuel; de Bernard, Simon; Buffat, Laurent; Lina, Bruno; Ottmann, Michèle; Rosa-Calatrava, Manuel; Schicklin, Stéphane; Bonnefoy, Nathalie; Lauvau, Grégoire; Grau, Morgan; Wencker, Mélanie; Arpin, Christophe; Walzer, Thierry; Leverrier, Yann; Marvel, Jacqueline

    2016-01-01

    Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy. PMID:27883012

  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. Toll-like receptor polymorphisms in allogeneic hematopoietic cell transplantation.

    PubMed

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

    2015-02-01

    To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms 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 ≤ .001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease-free survival (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.16 to 1.85]; P = .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 to 1.83], P = .010; female donor: HR, 2.78 [95% CI, 1.43 to 5.41], P = .003), disease-free survival (male donor: HR, 1.45 [95% CI, 1.12 to 1.87], P = .005; female donor: HR, 2.34 [95% CI, 1.18 to 4.65], P = .015), and treatment-related mortality (male donor: HR, 1.49 [95% CI, 1.09 to 2.04], P = .012; female donor: HR, 3.12 [95% CI, 1.44 to 6.74], P = .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.

  15. 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

  16. Increased incidence of murine graft-versus-host disease after allogeneic bone marrow transplantation by previous infusion of syngeneic bone marrow cells

    SciTech Connect

    Waer, M.; Ang, K.K.; van der Schueren, E.; Vandeputte, M.

    1984-10-01

    Different groups of BALB/c mice received supralethal total-body irradiation (TBI; 8.5 Gy, day 0). When 30 x 10(6) allogeneic (C57B1) bone marrow (BM) cells were infused with or without 10 x 10(6) syngeneic (BALB/c) bM cells on day 1, many animals (60%) died from graft-versus-host disease (GVHD). Typing of peripheral blood leukocytes for donor antigens showed that, respectively, 22/22 and 17/21 of the mice in both groups became chimeric. When syngeneic bone marrow was given on day 1 and allogeneic bone marrow on day 2 after TBI, a similar number of animals (21/23) became chimeric, but GVHD occurred more frequently in this group (25/26 mice, P less than 0.01). When the syngeneic bone marrow cells were replaced by spleen cells, or when the transplantation of allogeneic bone marrow was delayed till days 3 or 6 after TBI, almost all mice rejected the allogeneic BM graft and became long-term survivors. BALB/c mice receiving 30 x 10(6) C57B1 BM cells after 17 daily fractions of 0.2 Gy of total lymphoid irradiation (TLI), showed a high incidence of chimerism (15/17) and in none of the latter animals was GVHD observed. Despite the high incidence of GVHD in the mice receiving allogeneic BM after TBI and syngeneic BM transplantation, as compared with mice prepared with TLI which do not develop GVHD, suppressor cells were as easily induced after TBI and syngeneic BM transplantation as after TLI.

  17. Use of spleen organ cultures to monitor hemopoietic progenitor cell regeneration following irradiation and marrow transplantation

    SciTech Connect

    von Melchner, H.; Metcalf, D.; Mandel, T.E.

    1980-11-01

    After lethal irradiation of C57BL mice followed by the injection of 10/sup 7/ marrow cells, total cellularity and progenitor cell levels exceeded pretreatment levels within 12 days in the spleen, but regeneration remained incomplete in the marrow. The exceptional regenerative capacity of progenitor populations in the spleen was observed in organ cultures of spleen slices prepared 24 h after irradiation and transplantation, excluding continuous repopulation from the marrow as a significant factor in splenic regeneration.

  18. Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

    PubMed Central

    Bensinger, William I.

    2007-01-01

    Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. PMID:18070719

  19. T cell regeneration after allogenic bone marrow transplantation

    PubMed Central

    Favrot, Marie; Janossy, G.; Tidman, N.; Blacklock, Hilary; Lopez, Elisa; Bofill, Margarita; Lampert, I.; Morgenstein, G.; Powles, R.; Prentice, H. G.; Hoffbrand, A. V.

    1983-01-01

    Various T cell subsets were characterized by double immunofluorescent staining using monoclonal antibodies (MoAb) in blood, bone marrow (BM) and tissues of 29 patients after allogeneic BM transplantation (BMT). In an attempt to prevent graft versus host disease (GvHD), 15 patients received cyclosporin A (Cy A). In the remaining 14 patients the BM was pre-incubated with a MoAb, OKT3. The regeneration of T4+ subset was delayed and the level of T8+ cells was abnormally high even 1 year after engraftment. This did not have any predictive value for the appearance of complications such as GvHD or severe viral infections. The number of T8+ cells was lower in the group of patients who received Cy A than in the OKT3 group (0·7±0·2 vs 1·5±0·3×109/1 at day 90). In contrast to normal individuals, the T4/T8 ratio in both blood and regenerating BM of BMT patients was <1. A sizeable subset of circulating T cells expressed the phenotype T8+,T10+,HNK-1+,DR+. Circulating cells of this phenotype were transiently very high (up to 50%) in patients with active GvHD or suffering from severe viral infection. This subpopulation of lymphocytes was not found in the epidermal infiltrate that accompanied GvHD where the predominant phenotype was T8+,T1-,T10-,HNK-1-,DR-. We conclude therefore that after BMT the number and phenotype of circulating T cells reflects the T cell distribution seen in the regenerating BM. PMID:6352107

  20. Alternative donor allogeneic hematopoietic cell transplantation for hemoglobinopathies.

    PubMed

    Alfraih, Feras; Aljurf, Mahmoud; Fitzhugh, Courtney D; Kassim, Adetola A

    2016-04-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative therapy for patients with hemoglobinopathies, mainly severe sickle cell disease (SCD) and thalassemia (TM). However, the applicability of HSCT has been limited mainly by donor availability, with a less than 25%-30% of eligible patients having human leukocyte antigen (HLA)-matched sibling donors. Previous outcomes using alternate donor options have been markedly inferior due to increased regimen-related toxicity, transplant-related mortality, graft failure, and graft-versus-host disease (GVHD). Advances in transplant technology, including high-resolution HLA typing, improved GVHD prophylactic approaches with tolerance induction, and better supportive care over the last decade, are addressing these historical challenges, resulting in increasing donor options. Herein, we review alternate donor HSCT approaches for severe SCD and TM using unrelated donors, umbilical cord blood units, or related haploidentical donors. Though this is an emerging field, early results are promising and in selected patients, this may be the preferred option to mitigate against the age-related morbidity and early mortality associated with these disorders.

  1. [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.

  2. 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

  3. Immunoevasive Pericytes From Human Pluripotent Stem Cells Preferentially Modulate Induction of Allogeneic Regulatory T Cells

    PubMed Central

    Domev, Hagit; Milkov, Irina; Dar, Ayelet

    2014-01-01

    Isolated microvessel-residing pericytes and pericytes from human pluripotent stem cells (hPSCs) exhibit mesenchymal stem cell-like characteristics and therapeutic properties. Despite growing interest in pericyte-based stem cell therapy, their immunogenicity and immunomodulatory effects on nonactivated T cells are still poorly defined, in particular those of vasculogenic hPSC pericytes. We found that tissue-embedded and unstimulated cultured hPSC- or tissue-derived pericytes constitutively expressed major histocompatibility complex (MHC) class I and the inhibitory programmed cell death-ligand 1/2 (PD-L1/2) molecules but not MHC class II or CD80/CD86 costimulatory molecules. Pretreatment with inflammatory mediators failed to induce an antigen-presenting cell-like phenotype in stimulated pericytes. CD146+ pericytes from hPSCs did not induce activation and proliferation of allogeneic resting T cells independent of interferon (IFN)-γ prestimulation, similarly to pericytes from human brain or placenta. Instead, pericytes mediated a significant increase in the frequency of allogeneic CD25highFoxP3+ regulatory T cells when cocultured with nonactivated peripheral blood T cells. Furthermore, when peripheral blood CD25high regulatory T cells (Tregs) were depleted from isolated CD3+ T cells, pericytes preferentially induced de novo formation of CD4+CD25highFoxP3+CD127−, suppressive regulatory T cells. Constitutive expression of PD-L1/2 and secretion of transforming growth factor-β by hPSC pericytes directly regulated generation of pericyte-induced Tregs. Pericytes cotransplanted into immunodeficient mice with allogeneic CD25− T cells maintained a nonimmunogenic phenotype and mediated the development of functional regulatory T cells. Together, these findings reveal a novel feature of pericyte-mediated immunomodulation distinguished from immunosuppression, shared by native tissue pericytes and hPSC pericytes, and support the notion that pericytes can be applied for

  4. An ultrastructural study, effects of Proteus vulgaris OX19 on the rabbit spleen cells.

    PubMed

    Gul, Nursel; Ozkorkmaz, Ebru Gokalp; Kelesoglu, Ilknur; Ozluk, Aydin

    2013-01-01

    Effects of Proteus vulgaris OX19 on the spleen cells of rabbits were investigated. Control group (n=5) and Proteus treated group (n=5) of New Zealand male rabbits were used in this study. Bacteria were injected to the rabbits in five days periods with increasing dosages for one month. Thin sections were examined by transmission electron microscope (Jeol 100CXII). Ultrastructural changes were defined in spleen tissue cells due to the antigenic stimulation of bacteria. Spleen cells observed in control group were in normal structure and cells were in close contact with each other. However, spleen cells of Proteus treated group displayed structural changes with regard to the control group in electron microscopic examinations. Chemotaxis of macrophages, forming of pseudopodia and presence of phagocytic vacuoles were observed. Lymphocytes, the major cells of spleen revealed mitotic activity. In addition, chromatin condensation in nucleus and dilatations in perinuclear space were significant. Interactions of lymphocytes and macrophages were noteworthy.

  5. Hypomethylating agents after allogeneic blood stem cell transplantation

    PubMed Central

    Rautenberg, Christina; Haas, Rainer; Kobbe, Guido

    2016-01-01

    Allogeneic blood stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), but relapse remains the major cause of treatment failure. So far, therapeutic options for patients with AML or MDS who relapse after allo-SCT generally consisted of palliative care, low-dose or intensive chemotherapy as well as cellular therapies such as donor lymphocyte infusions (DLI) and second transplantation in selected cases. Nevertheless, the prognosis of patients with myeloid malignancies relapsing after allo-SCT remains dismal therefore asking for novel treatment strategies. Considering their well-balanced profile of good efficacy and moderate toxicity in the non-transplant setting, the hypomethylating agents (HMA) azacitidine (Aza) and decitabine (DAC) have also been tested either alone or in combination with DLI in the post-transplant period. This review summarizes the current knowledge about the use of these two HMA as pre-emptive, salvage or consolidation therapy mostly retrieved from retrospective studies but also from a few prospective trials. Within this review, we also comment on some practical issues such as optimal dose and schedule, the choice of HMA candidates and the role of additional cellular interventions. Finally, we also give an overview on the assumed mode of actions, ongoing research, clinical studies and potential combination partners aiming to improve this treatment approach. PMID:28066786

  6. Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation.

    PubMed

    Felder-Puig, R; Peters, C; Matthes-Martin, S; Lamche, M; Felsberger, C; Gadner, H; Topf, R

    1999-07-01

    The purpose of this study was to assess the psychosocial adjustment of patients who had been treated with allogeneic stem cell transplantation (SCT) in our clinic. Selection criteria for patients were to be aged 14-30 years at the time of the follow-up, to be at least 2 years post-SCT and to have a very good knowledge of German. Among 31 eligible patients, 26 participated (84% response rate). The patients were between 15 and 27 years old and were on average 7 years (range 2-13) post-SCT. Research instruments consisted of a demographic questionnaire and various subscales of established psychological measures for which data from a sample of bone cancer survivors and population norms were available. About 35% of patients showed high levels of anxiety, 62% appeared to be extremely sensitive and vulnerable, and 35% showed strong, unfulfilled needs in their love lives. In the other domains tested (self-esteem, family and peer relationships, school/vocational performance, etc), no noticeable differences were found between the subjects and comparable populations. There was no significant association between psychosocial outcome and demographic features or clinical data. Our results suggest that patients who underwent SCT in their childhood or adolescence are at risk of developing long-term emotional or social problems. Due to the retrospective design of our study and the small sample size, no predictive factors for psychosocial distress could be identified.

  7. 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.

  8. Inhibition of allogeneic T-cell response by Kupffer cells expressing indoleamine 2,3-dioxygenase

    PubMed Central

    Yan, Mao-Lin; Wang, Yao-Dong; Tian, Yi-Feng; Lai, Zhi-De; Yan, Lv-Nan

    2010-01-01

    AIM: To explore the possibility and mechanism of inhibiting allogeneic T-cell responses by Kupffer cells (KC) pretreated with interferon-γ (IFN-γ) in vitro. METHODS: The expressions of indoleamine 2,3-dioxygenase (IDO) mRNA and FasL mRNA in KC pretreated with IFN-γ were studied with real-time polymerase chain reaction (PCR). The catabolism of tryptophan by IDO from KC was analyzed by high performance liquid chromatography. Allogeneic T-cell response was used to confirm the inhibition of KC in vitro. The proliferation of lymphocytes was detected using [3H] thymidine incorporation. Cell cycle and lymphocyte apoptosis were evaluated by flow cytometric assay. RESULTS: Real-time PCR revealed IDO mRNA and FasL mRNA expressions in KC pretreated with IFN-γ, and IDO catabolic effect was confirmed by a decrease in tryptophan and increase in kynurenine concentration. KC expressing IDO and FasL in BABL/c mice acquired the ability to suppress the proliferation of T-cells from C57BL/6, which could be blocked by addition of 1-methyl-tryptophan and anti-FasL antibody. KC expressing IDO could induce allogeneic T-cell apoptosis. CONCLUSION: In addition to Fas/FasL pathway, IDO may be another mechanism for KC to induce immune tolerance. PMID:20128035

  9. Computed tomography of the spleen and liver in sickle cell disease

    SciTech Connect

    Magid, D.; Fishman, E.K.; Siegelman, S.S.

    1984-08-01

    The spleen was assessed in 10 patients with sickle cell disease studied with computed tomography (CT) for abdominal pain and/or unexplained fever. Patients with homozygous sickle cell anemia were found to have small, densely calcified spleens with occasional low-density infarcts. Five of six had hepatomegaly, and there was one case each of hepatic abscess, infarcts, and hemochromatosis. All patients with heterozygous sickle cell disease were found to have splenomegaly, with a variety of findings including acute hemorrhage, acute and chronic infarcts, rupture, and possible sequestration. It was concluded that CT is useful for evaluating the status of the spleen and liver in symptomatic patients with sickle cell disease.

  10. 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

  11. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis.

    PubMed

    Heidenreich, D; Kreil, S; Nolte, F; Reinwald, M; Hofmann, W-K; Klein, S A

    2016-01-01

    Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram-negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis.

  12. Phosphoprotein phosphatase of bovine spleen cell nuclei: physicochemical properties

    SciTech Connect

    Rezyapkin, V.I.; Leonova, L.E.; Komkova, A.I.

    1986-01-10

    The physicochemical properties of phosphoprotein phosphatase (EC 1.3.1.16) from bovine spleen cell nuclei were studied. The enzyme possesses broad substrate specificity and catalyzes the dephosphorylation of phosphocasein, ATP, ADP, and p-nitrophenyl phosphate (pNPP). K/sub m/ for ATP, ADP, and pNPP are equal to 0.44, 0.43, and 1.25 mM, respectively. M/sub r/ of the enzyme, according to the data of gel filtraction of Sephadex G-75 and electrophoresis in polyacrylamide gel of various concentrations is approx. 33,000. In electrophoresis in the presence of SDS, two protein bands with M/sub r/ 12,000 and 18,000 are detected. In the enzyme molecule, acid amino acid residues predominate; two free SH groups and two disulfide bridges are detected. Phosphoprotein phosphatase is a glycoprotein, containing approx. 22% carbonhydrates. The protein possesses a supplementary absorption maximum at 560 nm. Ammonium molybdate is a competitive inhibitor with K/sub i/ 0.37 ..mu..M, while sodium fluoride is a noncompetitive inhibitor with K/sub i/ 1.3 mM. Incubation in the presence of 2 mM phenylmethylsulfonyl fluoride for 25 h leads to a loss of approx. 46% of the enzymatic activity. Ammonium molybdate, sodium fluoride, and PMSF are reversible inhibitors. Modifications of the SH groups, NH/sub 2/ groups, and histidine leads to a decrease in the enzymatic activity. Incubation of phosphoprotein phosphatase with (..gamma..-/sup 32/P)ATP leads to the incorporation of 0.33 mole /sup 33/P per mole of the enzyme. The mechanism of hydrolysis of the phosphodiester bond, catalyzed by the enzyme, is discussed.

  13. Dengue virus-induced thymus-derived suppressor cells in the spleen of mice.

    PubMed Central

    Tandon, P; Chaturvedi, U C; Mathur, A

    1979-01-01

    Adoptive transfer of spleen cells obtained from mice given three weekly i.p. doses of dengue type 2 virus (DV) suppressed DV antigen-specific antibody secretion as detected by the Jerne plaque technique. This suppression was produced by non-glass-adherent cells but not by glass-adherent cells. Immune spleen cells depleted of macrophages by carbonyl iron treatment had higher suppressor activity. Immune spleen cell homogenate could transfer the activity equally well. The immune spleen cells were separated into T and B lymphocytes by a nylon wool column. B lymphocytes had no suppressor activity; almost all the suppressor activity was present in T lymphocytes. Thus, macrophages and B lymphocytes had no suppressor activity; it was mediated by T lymphocytes through soluble factors. PMID:160396

  14. Critical Role of Sensitized Serum in Rejection of Allogeneic Bone Marrow Cells

    PubMed Central

    Xu, Lu-Hong; Fang, Jian-Pei; Weng, Wen-Jun; Xu, Hong-Gui

    2014-01-01

    Objective: Humoral immunity has been clearly implicated in solid organ transplantation, but little is known about the relationship between humoral immunity and hematopoietic stem cell transplantation. This study was designed to investigate that relationship. Materials and Methods: Sensitized serum was obtained from a sensitized murine model established by allogeneic splenocyte transfusion. Sensitized serum was incubated with allogeneic bone marrow cells (BMCs) in vitro and the cytotoxicity was evaluated by the complement-dependent cytotoxicity method. Mice were transplanted with allogeneic BMCs incubated with sensitized serum after lethal irradiation. The engraftment was assayed by hematopoietic recovery and chimera analysis. Moreover, mice received passive transfer of sensitized serum 1 day prior to transplantation. Mortality was scored daily after bone marrow transplantation. Results: The in vitro experiments showed that sensitized serum was capable of impairing allogeneic BMCs through the complement-dependent cytotoxicity pathway. The animal studies showed that BMCs incubated with sensitized serum failed to rescue mice from lethal irradiation. The engraftment assay showed that the allogeneic BMCs incubated with sensitized serum were rejected with time in the recipients. Furthermore, the mice died of marrow graft rejection by transfer of sensitized serum prior to transplantation. Conclusion: Taken together, our results indicated that sensitized serum played a critical role in graft rejection during hematopoietic stem cell transplantation. PMID:25330519

  15. Spleen histology in children with sickle cell disease and hereditary spherocytosis: hints on the disease pathophysiology.

    PubMed

    Pizzi, Marco; Fuligni, Fabio; Santoro, Luisa; Sabattini, Elena; Ichino, Martina; De Vito, Rita; Zucchetta, Pietro; Colombatti, Raffaella; Sainati, Laura; Gamba, Piergiorgio; Alaggio, Rita

    2017-02-01

    Hereditary spherocytosis (HS) and sickle cell disease (SCD) are associated with splenomegaly and spleen dysfunction in pediatric patients. Scant data exist on possible correlations between spleen morphology and function in HS and SCD. This study aimed to assess the histologic and morphometric features of HS and SCD spleens, to get possible correlations with disease pathophysiology. In a large series of spleens from SCD, HS, and control patients, the following parameters were considered: (i) macroscopic features, (ii) lymphoid follicle (LF) density, (iii) presence of perifollicular marginal zones, (iv) presence of Gamna-Gandy bodies, (v) density of CD8-positive sinusoids, (vi) density of CD34-positive microvessels, (vii) presence/distribution of fibrosis and smooth muscle actin (SMA)-positive myoid cells, and (viii) density of CD68-positive macrophages. SCD and HS spleens had similar macroscopic features. SCD spleens had lower LF density and fewer marginal zones than did HS spleens and controls. SCD also showed lower CD8-positive sinusoid density, increased CD34-positive microvessel density and SMA-positive myoid cells, and higher prevalence of fibrosis and Gamna-Gandy bodies. HS had lower LF and CD8-positive sinusoid density than did controls. No significant differences were noted in red pulp macrophages. By multivariate analysis, most HS spleens clustered with controls, whereas SCD grouped separately. A multiparametric score could predict the degree of spleen changes irrespective of the underlying disease. In conclusion, SCD spleens display greater histologic effacement than HS, and SCD-related changes suggest impaired function due to vascular damage. These observations may contribute to guide the clinical management of patients.

  16. Efficient natural defense mechanisms against Listeria monocytogenes in T and B cell-deficient allogeneic bone marrow radiation chimeras. Preactivated macrophages are the main effector cells in an early phase after bone marrow transfer

    SciTech Connect

    Roesler, J.; Groettrup, E.B.; Baccarini, M.; Lohmann-Mattes, M.L. )

    1989-09-01

    Radiation chimeras in the early phase after bone marrow transplantation are a good model to study the efficiency of the body's nonspecific defense system represented by macrophages (M phi), polymorphonuclear cells (PMN), and NK cells. These cell types are present in large numbers in spleen and liver at that time, whereas the specific immune system represented by T and B cells is functionally deficient. We previously reported enhanced activities in vitro of M phi (and PMN) from recipient animals in an early phase after allogeneic bone marrow transfer. We here demonstrate that these activities result in enhanced spontaneous resistance against Listeria monocytogenes in vivo: CFU of L. monocytogenes in spleen and liver 48 h after infection were about 1 or 2 to 4 log steps less than in untreated control mice of donor or host haplotype. This enhanced resistance decreased over the 4-mo period after marrow transfer. Preactivated M phi were identified as the most important effector cells. Isolated from spleen and peritoneal cavity, they performed enhanced killing of phagocytosed Listeria. Such preactivated M phi occurred in recipient animals after transfer of allogeneic but not of syngeneic bone marrow. The precise mechanism of M phi activation in the allogeneic radiation chimera in the complete absence of any detectable T cell function is not clear at present. However, these preactivated M phi display an important protective effect against L. monocytogenes: chimeras could eliminate Listeria without acquisition of positive delayed-type sensitivity when infected with 10(3) bacteria. An inoculum of 5 . 10(3) L. monocytogenes resulted either in prolonged survival compared with normal mice of the recipient haplotype or in definitive survival accompanied by a positive delayed-type sensitivity.

  17. Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Khalaf, Ahmed M; Hashim, Mahmoud A; Alsharabati, Mohammed; Fallon, Kenneth; Cure, Joel K; Pappas, Peter; Mineishi, Shin; Saad, Ayman

    2017-03-10

    BACKGROUND Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. CASE REPORT We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. CONCLUSIONS Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.

  18. Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Khalaf, Ahmed M.; Hashim, Mahmoud A.; Alsharabati, Mohammed; Fallon, Kenneth; Cure, Joel K.; Pappas, Peter; Mineishi, Shin; Saad, Ayman

    2017-01-01

    Patient: Male, 44 Final Diagnosis: Cerebral toxoplasmosis after HSCT Symptoms: Hemiparesis • muscle weakness Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. Case Report: We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. Conclusions: Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions. PMID:28280256

  19. Component(s) of Sendai virus that can induce interferon in mouse spleen cells.

    PubMed Central

    Ito, Y; Hosaka, Y

    1983-01-01

    To identify the active component of Sendai virus that induces interferon in mouse spleen cells, infectious and noninfectious viruses, envelope particles derived from them, and isolated hemagglutinin-neuraminidase (HN) glycoproteins were examined for interferon induction. The interaction between membranous structures containing Sendai virus HN glycoprotein and the receptors on the cell surface was shown to be sufficient for interferon induction in mouse spleen cells, suggesting that the actual inducer of interferon in mouse spleen cells is the HN glycoprotein of Sendai virus. When mouse spleen cells were stimulated in vitro with Sendai virus grown in eggs or LLC-MK2 cells or with membranous structures containing glycoproteins obtained from these viruses, interferon could be detected in the culture fluid. Furthermore, isolated HN glycoprotein per se could induce interferon in the cells. A linear correlation was found between the titer of interferon induced and the hemagglutinating activity of the membranous structure containing the HN glycoprotein. It was concluded from these findings that HN glycoprotein was the active component of Sendai virus responsible for interferon induction in mouse spleen cells and that viral RNA and F glycoprotein were not required. The results also showed that the interaction between HN glycoprotein and receptors on the cell surface triggered production of type I interferon (IFN-alpha and IFN-beta). Although when Sendai virus was incubated at 56 degrees C for 5 min it lost its hemolytic and hemagglutinating activities, it induced a considerable amount of interferon in the culture fluid of mouse spleen cells. The interferon-inducing ability of heat-inactivated virus could be absorbed with mouse spleen cells but not with sheep erythrocytes or mouse erythrocytes, indicating that the inactivated virus retained ability to bind to mouse lymphoid cells. PMID:6301988

  20. Eosinophils from hematopoietic stem cell recipients suppress allogeneic T cell proliferation.

    PubMed

    Andersson, Jennie; Cromvik, Julia; Ingelsten, Madeleine; Lingblom, Christine; Andersson, Kerstin; Johansson, Jan-Erik; Wennerås, Christine

    2014-12-01

    Eosinophilia has been associated with less severe graft-versus-host disease (GVHD), but the underlying mechanism is unknown. We hypothesized that eosinophils diminish allogeneic T cell activation in patients with chronic GVHD. The capacity of eosinophils derived from healthy subjects and hematopoietic stem cell (HSC) transplant recipients, with or without chronic GVHD, to reduce allogeneic T cell proliferation was evaluated using a mixed leukocyte reaction. Eosinophil-mediated inhibition of proliferation was observed for the eosinophils of both healthy subjects and patients who underwent HSC transplantation. Eosinophils from patients with and without chronic GVHD were equally suppressive. Healthy eosinophils required cell-to-cell contact for their suppressive capacity, which was directed against CD4(+) T cells and CD8(+) T cells. Neither eosinophilic cationic protein, eosinophil-derived neurotoxin, indoleamine 2,3-dioxygenase, or increased numbers of regulatory T cells could account for the suppressive effect of healthy eosinophils. Real-time quantitative PCR analysis revealed significantly increased mRNA levels of the immunoregulatory protein galectin-10 in the eosinophils of both chronic GVHD patients and patients without GVHD, as compared with those from healthy subjects. The upregulation of galectin-10 expression in eosinophils from patients suggests a stimulatory effect of HSC transplantation in itself on eosinophilic galectin-10 expression, regardless of chronic GVHD status. To conclude, eosinophils from HSC transplant recipients and healthy subjects have a T cell suppressive capacity.

  1. Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy.

    PubMed

    Gyurkocza, B; Lazarus, H M; Giralt, S

    2017-02-27

    Patients with acute myeloid leukemia (AML) who fail to achieve complete remission (CR) have a dismal prognosis. Although data suggest that durable remissions can be achieved in approximately 30% of patients with refractory or relapsed AML after allogeneic hematopoietic cell transplantation (HCT), only a small fraction of those patients are offered this therapeutic option. Importantly, patients with primary refractory AML have distinctly better outcomes following allogeneic HCT than those with refractory relapse. Access to suitable donors could be one of the main barriers in these situations. However, with recent developments in the field of allogeneic HCT, such as alternative donor sources, high-resolution HLA-typing, reduced intensity conditioning regimens and improvements in supportive care, this approach has the potential to offer long-term survival for patients with refractory and relapsed AML and should be considered as early after diagnosis as possible. Incorporating novel agents into the conditioning regimen or as post-transplant maintenance therapy could further improve outcomes and render older or medically infirm patients with refractory or relapsed AML eligible for allogeneic HCT. In this review, we summarize existing data on allogeneic HCT in patients with refractory or relapsed AML and explore novel approaches with the potential to improve outcomes in this patient population.Bone Marrow Transplantation advance online publication, 27 February 2017; doi:10.1038/bmt.2017.8.

  2. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Whangbo, J; Ritz, J; Bhatt, A

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota. PMID:27526283

  3. The effect of peripheral lymphoid cells on the incidence of lethal graft versus host disease following allogeneic mouse bone marrow transplantation

    SciTech Connect

    Almaraz, R.; Ballinger, W.; Sachs, D.H.; Rosenberg, S.A.

    1983-02-01

    Experiments were performed to study the role of circulating lymphoid cells in the incidence of lethal graft versus host disease (GVHD) in radiation-induced fully allogeneic mouse chimeras. The incidence of GVHD was reduced significantly in BALB/c leads to C57BL/6 radiation chimeras if bone marrow donors were exsanguinated immediately prior to marrow harvest. Chimeras resulting from the injection of bone marrow from bled donors exhibited only donor cells in spleen, bone marrow and peripheral blood and normal levels of Thy 1+ and Ia+ cells were found in each of these lymphoid compartments. The addition of as few as 3 X 10(4) peripheral mononuclear cells to the marrow from exsanguinated donors uniformly led to lethal GVHD. /sup 51/Cr-labeled cell traffic studies revealed that prior exsanguination of marrow donors led to about a 70% reduction in the number of circulating mononuclear cells contaminating the bone marrow at the time of marrow harvest. This decrease in contaminating peripheral cells was calculated to be in the appropriate range to account for the decreased GVHD seen when marrow from exsanguinated donors was used. It thus appears that peripheral cells contaminating marrow can be an important factor in causing lethal GVHD in allogeneic radiation chimeras. These results raise the possibility that the fulminant GVHD seen in human marrow transplantation is in part due to the major contamination of bone marrow with peripheral blood that results from the techniques currently used for human bone marrow harvest.

  4. Allogeneic Mesenchymal Precursor Cell Therapy to Limit Remodeling After Myocardial Infarction: The Effect of Cell Dosage

    PubMed Central

    Hamamoto, Hirotsugu; Gorman, Joseph H.; Ryan, Liam P.; Hinmon, Robin; Martens, Timothy P.; Schuster, Michael D.; Plappert, Theodore; Kiupel, Matti; St. John-Sutton, Martin G.; Itescu, Silviu; Gorman, Robert C.

    2011-01-01

    Background This experiment assessed the dose-dependent effect of a unique allogeneic STRO-3–positive mesenchymal precursor cell (MPC) on postinfarction left ventricular (LV) remodeling. The MPCs were administered in a manner that would simulate an off-the-self, early postinfarction, preventative approach to cardiac cell therapy in a sheep transmural myocardial infarct (MI) model. Methods Allogeneic MPCs were isolated from male crossbred sheep. Forty-six female sheep underwent coronary ligation to produce a transmural LV anteroapical infarction. One hour after infarction, the borderzone myocardium received an injection of 25, 75, 225, or 450 × 106 MPCs, or cell medium. Echocardiography was performed at 4 and 8 weeks after MI to quantify LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF), and infarct expansion. CD31 and smooth muscle actin (SMA) immunohistochemical staining was performed on infarct and borderzone specimens to quantify vascular density. Results Compared with controls, low-dose (25 and 75 × 106 cells) MPC treatment significantly attenuated infarct expansion and increases in LVEDV and LVESV. EF was improved at all cell doses. CD31 and SMA immunohistochemical staining demonstrated increased vascular density in the borderzone only at the lower cell doses. There was no evidence of myocardial regeneration within the infarct. Conclusion Allogeneic STRO-3 positive MPCs attenuate the remodeling response to transmural MI in a clinically relevant large-animal model. This effect is associated with vasculogenesis and arteriogenesis within the borderzone and infarct and is most pronounced at lower cell doses. PMID:19231391

  5. Tailored strategy for AML patients receiving allogeneic peripheral blood stem cell transplantation.

    PubMed

    Sohn, Sang Kyun; Kim, Jong Gwang; Kim, Dong Hwan

    2006-10-01

    Considering the heterogeneity of acute myelogenous leukemia (AML), along with the pros and cons of allogeneic peripheral blood stem cell transplantation (PBSCT), a tailored strategy is needed to minimize the transplant-related mortality and maximize the transplant outcomes in AML patients exhibiting certain factors that have an impact on the post-transplant quality of life and outcomes. The factors that need to be considered when tailoring a strategy in an allogeneic PBSCT setting include the recipient's performance status and co-morbid disease include AML risk stratification, disease status, expected severity of graft-versus-host disease, and the necessity of a graft-versus-leukemia effect. Accordingly, this review article describes a possible tailoring strategy for AML patients receiving allogeneic PBSCT based on certain factors influencing the transplant outcome.

  6. Diffuse Hepatic and Spleen Uptake of Tc-99m MDP on Bone Scintigraphy Resembling Liver-Spleen Scintigraphy in a Patient of Plasma Cell Tumor.

    PubMed

    Ravanbod, Mohammad Reza; Nemati, Reza; Javadi, Hamid; Nabipour, Iraj; Assadi, Majid

    2014-01-01

    The present case demonstrates a diffuse intense hepatic and, to a lesser degree, spleen, Tc-99m MDP uptake on a routine bone scintigraphy resembling liver-spleen imaging. A 49-year-old female with a history of anaplastic plasma cell tumor and suffering from bone pain was referred for bone scintigraphy to evaluate possible bone metastases. The bone scintigraphy showed diffuse hepatic and spleen uptake of Tc-99m MDP resembling liver-spleen imaging. Furthermore, bone uptake of Tc-99m MDP was significantly diminished and there were no abnormal foci throughout the skeleton. The bone scintigraphy of the present case of an anaplastic plasma cell tumor suggests the possible presence of amyloidosis.

  7. Allogeneic hematopoietic stem cell transplantation in children with sickle cell disease.

    PubMed

    Locatelli, Franco; Pagliara, Daria

    2012-08-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment for sickle cell disease (SCD), being successful in around 85-90% of patients. Mortality and long-term morbidity (including infertility, gonadal failure, and chronic graft-vs.-host disease) associated with conventional approaches curtail the number of patients who undergo allo-HSCT. Recently, it has been demonstrated that cord blood is as effective as and possibly safer than bone marrow in pediatric patients with SCD. Likewise, transplant strategies based on the use of reduced-intensity regimens and the induction of mixed chimerism have been explored to decrease allo-HSCT short- and long-term complications.

  8. Nocardia pseudobrasiliensis as an Emerging Cause of Opportunistic Infection after Allogeneic Hematopoietic Stem Cell Transplantation▿

    PubMed Central

    Lebeaux, David; Lanternier, Fanny; Degand, Nicolas; Catherinot, Emilie; Podglajen, Isabelle; Rubio, Marie-Thérèse; Suarez, Felipe; Lecuit, Marc; Mainardi, Jean-Luc; Lortholary, Olivier

    2010-01-01

    We report the case of a 55-year-old man who exhibited a nodular pneumonia 4 months after an allogeneic hematopoietic stem cell transplantation. Culture of the bronchoalveolar lavage fluid revealed Nocardia pseudobrasiliensis. This recently described carbapenem-resistant species should be included in the differential diagnosis of fungal infection in this setting. PMID:19940053

  9. 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

  10. Induction of transplantation tolerance in rats by spleen allografts. I. Evidence that rats tolerant of spleen allografts contain two phenotypically distinct T suppressor cells

    SciTech Connect

    Duncan, W.R.; Stepkowski, S.M.; Bitter-Suermann, H.

    1986-05-01

    We have examined suppressor cell activity in transplantation tolerant (TT) rats bearing vascularized spleen allografts in several different donor-recipient combinations. More than 60% of WAG (RT-1u) and 65% of AGUS (RT-1l) spleen allografts were permanently accepted when transplanted to AGUS and PVG (RT-1c) rats, respectively. All (WAG X AGUS)F1 to AGUS and (AGUS X PVG)F1 to PVG spleen allografts survived indefinitely. Unseparated LNC, TDL, and whole T cell or W3/25+, OX8- T cell populations obtained from AGUS rats bearing (WAG X AGUS)F1 spleens exhibited reduced mixed lymphocyte reaction (MLR) responses to the spleen donor, and to some extent to BN(RT1n) third-party stimulators, but responded normally to PVG.A(RT1a) stimulators. Coculture experiments demonstrated that lymph node cells (LNC) and thoracic duct lymphocytes (TDL) of TT rats contain RT1 specific suppressor cells. Furthermore, T cells isolated from all donor-recipient combinations contained two phenotypically distinct suppressor cell populations: a radiosensitive W3/25+, OX8- (Th/i) and a relatively radioresistant W3/25-, OX8+ (Ts/c). These Ts may be responsible for the maintenance of TT.

  11. 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

  12. Up-to-date tools for risk assessment before allogeneic hematopoietic cell transplantation.

    PubMed

    Elsawy, M; Sorror, M L

    2016-10-01

    Cure of malignant and non-malignant hematological diseases is potentially possible after allogeneic hematopoietic stem cell transplantation (HCT). Accurate evaluation of the risk-benefit ratio for an individual patient could improve the decision-making process about transplant, which ultimately would increase the likelihood of success. Several transplant-related models were designed in an effort to optimize decision-making about suitable candidates for allogeneic HCT. In 1998, The European Society for Blood and Marrow Transplantation (EBMT) developed a five-component pretransplantation risk scoring system for patients with CML. The EBMT score was later tested in patients with various hematological disorders, and it was shown to stratify risks of mortality after allogeneic HCT. More recent research efforts focused on models that assess health status before HCT. A HCT-specific comorbidity index was designed to assign weights to 17 relevant comorbidities that were shown to independently predict non-relapse mortality. Performance status scales and comprehensive geriatric assessment tools might uncover additional overall health limitations that affect long-term survival among older recipients of allogeneic HCT. Other models include the pretransplantation assessment of mortality score that summarizes the impacts of eight different pretransplantation patient- and disease-specific variables into a 50-point model that predicts survival. The disease-risk index captures the impact of primary diagnoses and disease status on relapse and survival following allogeneic HCT. The values and limitations of each model are discussed herein. We also provide insight on how to use these models in the clinic to decide about offering allogeneic HCT with the most suitable conditioning regimen intensity.

  13. 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.

  14. Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

    PubMed

    van Besien, K; Koshy, M; Anderson-Shaw, L; Talishy, N; Dorn, L; Devine, S; Yassine, M; Kodish, E

    2001-09-01

    Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

  15. 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.

  16. Stimulation of HIV-specific T cell clonotypes using allogeneic HLA.

    PubMed

    Almeida, Coral-Ann; van Miert, Paula; O'Driscoll, Kane; Zoet, Yvonne M; Chopra, Abha; Watson, Mark; de Santis, Dianne; Witt, Campbell; John, Mina; Claas, Frans H J; D'Orsogna, Lloyd J

    2017-03-28

    We hypothesized that HIV-specific CD8 T cell clonotypes can be stimulated by allogeneic HLA molecules. Multiple HIV-specific CD8 T cell clones were derived from 12 individuals with chronic HIV infection, specific for 13 different HIV Gag antigens and restricted to 7 different HLA molecules. The generated T cell clones were assayed for alloreactivity against a panel of single HLA class I expressing cell lines (SALs). HIV-specific T cells recognising at least one allogeneic HLA molecule could be identified from 7 of 12 patients tested. Allorecognition was associated with IFNγ cytokine production, CD137 upregulation and cytotoxicity, suggesting high avidity allo-stimulation. Allo-HLA recognition by HIV-specific T cells was specific to the HIV target peptide/HLA restriction and TCR TRBV usage of the T cells. HIV-specific T cells do crossreact against allogeneic HLA molecules in an epitope and TRBV specific manner. Therefore allo-HLA stimulation could be exploited to induce or augment HIV-specific T cell responses.

  17. 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.

  18. White blood cell recovery after allogeneic hematopoietic cell transplantation predicts clinical outcome.

    PubMed

    Kim, Haesook T; Frederick, David; Armand, Philippe; Andler, Emily; Kao, Grace; Cutler, Corey; Koreth, John; Alyea, Edwin P; Antin, Joseph H; Soiffer, Robert J; Ritz, Jerome; Ho, Vincent T

    2014-06-01

    To determine whether outcome after allogeneic hematopoietic cell transplantation (HCT) could be estimated by using peripheral white blood cell count (WBC) as a metric that integrates several aspects of HCT recovery, we conducted a retrospective study of 1,109 adult patients who underwent first allogeneic HCT from 2003 through 2009. WBC at 1-3 months after HCT was categorized as low (<2), normal (2-10), and high (>10 × 10(9) cells/L). Overall survival (OS) and progression-free survival (PFS) were lower for patients with low or high WBC at 1-3 months after HCT (P < 0.0001). We developed a predictive three-group risk model based on the pattern of WBC recovery early after HCT. Five-year OS was 47, 30, and 15% (P < 0.0001) and 5-year PFS was 39, 22, and 14% for patients in the three different risk groups (P < 0.0001). The pattern of WBC recovery early after HCT provides prognostic information for relapse, nonrelapse mortality, progression-free survival, and overall survival. A scoring system based on the trajectory of the WBC in the first 3 months after HCT can effectively stratify patients into three groups with different PFS and OS. If validated, this system could be useful in the clinical management of patients after HCT, and to stratify patients enrolled on HCT clinical trials.

  19. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7

    PubMed Central

    Wei, Gao; Jie, Yuan; Haibo, Liu; Chaoneng, Wu; Dong, Huang; Jianbing, Zhu; Junjie, Guo; Leilei, Ma; Hongtao, Shi; Yunzeng, Zou; Junbo, Ge

    2017-01-01

    Mature dendritic cells (DCs) home to secondary lymphoid organs through CC chemokine receptor 7 (CCR7). Exosomes derived from DCs (DC-exos) are reported to migrate to spleen and induce inflammation in vivo. In this study, we demonstrated that mature bone marrow DC-exos can activate immature DC and T cells in vitro. Then we intravenously injected DC-exos into C57BL/6 mice, observing that mature DC-exos accumulated more in spleen than immature DC-exos. These DC-exos in spleen could be uptaken by splenetic DCs and T cells and induce an inflammatory response. We further showed that the increased accumulation of mature DC-exos in spleen was regulated by CCR7, whose reduction led to a decrease of accumulation in spleen and attenuated inflammatory response in serum. These data provide us a new perspective to comprehensively understand exosomes, which might inherit some special functions from their parent cells and exert these functions in vivo. PMID:28223684

  20. Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

    PubMed

    Labrador, Jorge; López-Corral, Lucia; Vazquez, Lourdes; Sánchez-Guijo, Fermin; Guerrero, Carmen; Sánchez-Barba, Mercedes; Lozano, Francisco S; Alberca, Ignacio; Del Cañizo, María C; Caballero, Dolores; González-Porras, Jose R

    2015-06-01

    Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P < 0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

  1. Allogeneic Mesenchymal Stem Cells in Combination with Hyaluronic Acid for the Treatment of Osteoarthritis in Rabbits.

    PubMed

    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.

  2. Ex vivo T-cell depletion in allogeneic hematopoietic stem cell transplant: past, present and future.

    PubMed

    Saad, A; Lamb, L S

    2017-03-20

    The most common cause of post-transplant mortality in patients with hematological malignancy is relapse, followed by GvHD, infections, organ toxicity and second malignancy. Immune-mediated complications such as GvHD continue to be challenging, yet amenable to control through manipulation of the T-cell compartment of the donor graft with subsequent immunomodulation after transplant. However, risk of both relapse and infection increase concomitantly with T-cell depletion (TCD) strategies that impair immune recovery. In this review, we discuss the clinical outcome of current and emerging strategies of TCD in allogeneic hematopoietic stem cell transplant that have developed during the modern transplantation era, focusing specifically on ex vivo strategies that target selected T-cell subsets.Bone Marrow Transplantation advance online publication, 20 March 2017; doi:10.1038/bmt.2017.22.

  3. Bulk enrichment of transplantable hemopoietic stem cell subsets from lipopolysaccharide-stimulated murine spleen

    SciTech Connect

    Ploemacher, R.E.; Brons, R.H.; Leenen, P.J.

    1987-02-01

    Counterflow centrifugal elutriation (CCE) in combination with density flotation centrifugation and fluorescence-activated cell sorting on wheat-germ agglutinin-FITC(WGA)-binding cells within the light-scatter ''blast window'' were used consecutively to enrich pluripotent hemopoietic stem cells (HSC) in bulk from lipopolysaccharide-stimulated mouse spleen. The medium-to-strong WGA + ve fraction contained 3.10(6) cells isolated from 3-4 X 10(9) spleen cells, with an average of 126% day-12 CFU-S and 65% day-8 CFU-S as calculated on the basis of their seeding fraction, suggesting that virtually all cells represented in vivo macroscopic colony formers. In view of the large differences reported elsewhere between stem cell subsets differing in reconstitutive capacity and secondary stem cell generation ability, we also studied various isolated cell fractions with respect to spleen colony formation, radioprotective ability, and spleen- and marrow- repopulating ability. Day-8 and day-12 CFU-S copurified when isolated by CCE. Cells from a fraction with high affinity for WGA were most highly enriched for their radioprotective ability (RPA) and their ability to repopulate the cellularity of the spleen and femur of irradiated recipients. This fraction contained virtually pure day-12 CFU-S. However, the ability to generate secondary day-12 CFU-S and CFU-GM in irradiated organs was enriched most in the medium WGA + ve cell fraction. MRA and SRA, according to the latter criteria, could therefore be partly separated from day-12 CFU-S and RPA on the basis of affinity for WGA. The data strongly suggest that at least part of all day-12 CFU-S have a high potential to proliferate and differentiate into mature progeny, but a relatively low self-renewal ability, and may therefore not be representative of the genuine stem cell.

  4. Enhanced Gamma Interferon Responses of Mouse Spleen Cells following Immunotherapy for Tuberculosis Relapse ▿

    PubMed Central

    Gil, Olga; Vilaplana, Cristina; Guirado, Evelyn; Díaz, Jorge; Cáceres, Neus; Singh, Mahavir; Cardona, Pere-Joan

    2008-01-01

    Gamma interferon responses of spleen cells in mice were examined during postchemotherapy relapse of intraperitoneally induced latent tuberculous infection. The mycobacterial extract RUTI, which prevented the relapse, significantly enhanced the immune responses to secreted and structural recombinant mycobacterial antigens, suggesting that RUTI-mediated protection was mediated by activated T cells. PMID:18827194

  5. 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

  6. [Eight years using the "Mexican method" for allogeneic hematopoietic stem cell transplants].

    PubMed

    Ruiz-Argüelles, Guillermo J; Gómez-Almaguer, David; Ruiz-Delgado, Guillermo J; del Carmen Tarin-Arzaga, Luz

    2007-01-01

    In the past eight years, in Mexico and in other developing countries, over 350 patients have undergone allogeneic hematopoietic stem cell transplants using a non-myeloablative conditioning regimen developed in Mexico and based on international standards. The so called "Mexican method" to conduct allogeneic stem cell transplants is endowed with certain advantages which make it affordable and in turn, available to individuals living in resource-poor countries. The best results using this method have been observed among patients with stage 1 chronic myelogenous leukemia and aplastic anemia. The less favourable results have been observed among patients with acute lymphoblastic leukemia; mild to moderate results have been reported among patients with acute myelogenous leukemia. The "Mexican method" to conduct hematopoietic cells allografting has resulted not only in turning this method accessible to patients in developing countries, but also it has witnessed an increase in the academic activities of physicians from these countries involved in the field.

  7. Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy.

    PubMed

    Hensley, Michael Taylor; Tang, Junnan; Woodruff, Kathleen; Defrancesco, Teresa; Tou, Sandra; Williams, Christina M; Breen, Mathew; Meurs, Kathryn; Keene, Bruce; Cheng, Ke

    2017-03-15

    Cardiosphere-derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non-ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c-kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.

  8. Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia.

    PubMed

    Isgrò, Antonella; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2010-08-01

    Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. A risk classes-based approach to transplantation in thalassemia has led to disease-free survival probability of 87, 85, and 80% in classes 1, 2, and 3 patients, respectively. Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging.

  9. The Role of ABO Incompatibility in Allogeneic Peripheral Blood Stem Cell Transplant.

    PubMed

    Arslan, Önder; Coşkun, Hasan Şanol; Arat, Mutlu; Soydan, Ender; Özcan, Muhit; Gürman, Günhan; Çelebi, Harika; Demirer, Taner; Akan, Hamdi; İlhan, Osnman; Konuk, Nahide; Uysal, Akın; Berksaç, Meral; Koç, Haluk

    2002-09-05

    ABO incompatibility is not a contraindication for allogeneic bone marrow transplantation, but this procedure requires an extra effort for erythrocyte or plasma depletion in certain well established conditions. Some acute or delayed immunohematological complications such as acute or chronic hemolysis and pure red cell aplasia may be encountered. In this study the outcome and transplant related complications of ABO incompatible and identical cases, who have received allogeneic peripheral blood stem cells from their HLA identical siblings were compared with each other. Ninety-one patients (CML 36, AML 37, other 18) were analyzed retrospectively including 51 (60.4%) ABO identical patients and 36 (39.6%) ABO mismatched (MM) patients, who have a bi-directional MM (n= 5), major MM (n= 16), minor MM (n= 9) and Rh MM (n= 6). Median follow up was 13 (0.5-43.0) months. We did not observed any significant differences between two groups (identical vs non-identical) in terms of acute hemolysis preceding stem cell infusion, peritransplant transfusion demand, acute- and chronic graft versus host disease. There was no change in estimated disease free survival and overall survival durations. We did not observed any influence of ABO/Rh incompatibility on short term outcome in allogeneic peripheral blood stem cell transplantation in our series and did not recommend further manipulation of the infused stem cells.

  10. Allogeneic Cell Therapy Bioprocess Economics and Optimization: Single-Use Cell Expansion Technologies

    PubMed Central

    Simaria, Ana S; Hassan, Sally; Varadaraju, Hemanthram; Rowley, Jon; Warren, Kim; Vanek, Philip; Farid, Suzanne S

    2014-01-01

    For allogeneic cell therapies to reach their therapeutic potential, challenges related to achieving scalable and robust manufacturing processes will need to be addressed. A particular challenge is producing lot-sizes capable of meeting commercial demands of up to 109 cells/dose for large patient numbers due to the current limitations of expansion technologies. This article describes the application of a decisional tool to identify the most cost-effective expansion technologies for different scales of production as well as current gaps in the technology capabilities for allogeneic cell therapy manufacture. The tool integrates bioprocess economics with optimization to assess the economic competitiveness of planar and microcarrier-based cell expansion technologies. Visualization methods were used to identify the production scales where planar technologies will cease to be cost-effective and where microcarrier-based bioreactors become the only option. The tool outputs also predict that for the industry to be sustainable for high demand scenarios, significant increases will likely be needed in the performance capabilities of microcarrier-based systems. These data are presented using a technology S-curve as well as windows of operation to identify the combination of cell productivities and scale of single-use bioreactors required to meet future lot sizes. The modeling insights can be used to identify where future R&D investment should be focused to improve the performance of the most promising technologies so that they become a robust and scalable option that enables the cell therapy industry reach commercially relevant lot sizes. The tool outputs can facilitate decision-making very early on in development and be used to predict, and better manage, the risk of process changes needed as products proceed through the development pathway. Biotechnol. Bioeng. 2014;111: 69–83. © 2013 Wiley Periodicals, Inc. PMID:23893544

  11. 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.

  12. Effects of Cell-Free Spleen Extract Treatment on the Hematopoietic Tissues of Irradiated Guinea-Pigs

    SciTech Connect

    Ellinger, Friedrigh; Strike, Thomas A.

    2004-07-01

    Guinea pigs were given whole-body Co60 irradiation (650 r) and injected daily thereafter with cell-free extracts of homologous and heterologous spleen. Spleen of irradiated control guinea pigs showed a progressive reduction of alkaline phosphatase staining commencing after the 3rd postirradiation day and reaching a maximum on or about the 9th day. Treatment of the animals with spleen extracts modified the radioinduced changes in alkaline phosphatase staining, so that an almost normal appearance was noted over the entire 14-day observation period. Most of the alkaiine phosphatase-staining spleen elements were mature neutrophils. It was concluded that spleen extract treatment affects apparently various celluiar elements of spleen in a different way. The results support the hypothesis that protection of phosphorylization processes against effects of irradiation represent one of the mechanisms by which the radiation protective effect of spleen extracts is effected.

  13. Resolution of myelofibrosis-associated pulmonary arterial hypertension following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Iliescu, Cezar; Lopez-Mattei, Juan; Patel, Bela; Bashoura, Lara; Popat, Uday

    2016-01-01

    Abstract We present the case of a 62-year-old man with myelofibrosis-associated pulmonary arterial hypertension (PAH) who underwent allogeneic hematopoietic stem cell transplantation with subsequent resolution of disease and PAH. Right heart catheterization was used to guide PAH therapy before and after transplantation. Drug interactions, adverse effects, and renal insufficiency posed clinical challenges for the management of PAH-specific medications after transplantation. PAH improved soon after transplantation, and vasoactive medications were tapered off. Resolution of PAH was confirmed with repeat measurement of pulmonary hemodynamic characteristics. Although the etiology and pathophysiology for the resolution of PAH was unclear, the myelopulmonary pathophysiologic link was likely to have contributed. This is the first report describing resolution of myelofibrosis-associated PAH after allogeneic hematopoietic stem cell transplantation. PMID:28090305

  14. Transplantation immunology of the anterior chamber of the eye. II. Immune response to allogeneic cells.

    PubMed

    Kaplan, H J; Streilein, J W; Stevens, T R

    1975-09-01

    The mechanism by which the anterior chamber of the eye extends immunologic privilege to allogeneic donor tissues has been studied in inbred rats. Inoculation of allogeneic lymphoid cells into the anterior chamber demonstrated that although the site lacks a lymphatic drainage, the afferent limb of the immunologic reflex arc is intact because the recipient can recognize and mount a specific immune response. In addition, host immunity was able to express itself within the anterior chamber when induced systemically, indicating that the efferent limb of the reflex arc is also intact. Therefore, it is suggested that the unique immunologic features of the anterior chamber may result from the obligate intravenous presentation of graft antigen to the host's systemic immunologic apparatus, a route that prejudices the host's response in the direction of tolerance and/or enhancement rather than cell-mediated, tissue destructive immunity.

  15. Interaction of herpesvirus with spleen cell subpopulations comparison of a neurotropic and a lymphotropic virus.

    PubMed

    Chow, T C; Hsiung, G D

    1980-12-01

    We studied the interaction of a neurotropic herpesvirus, herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2), and a lymphotropic herpesvirus, guinea pig herpes-like virus (HLV), with guinea pig spleen cells. Both HSV-1 and HSV-2 and HLV can attach to and penetrate into B- or T-enriched cells. Less than 1.4% of the total B- or T-enriched cell populations were susceptible to infection by HLV and to some degree to HSV-1 or HSV-2 as determined by infectious center assays. After specific antiserum treatment, higher titers of intracellular virus were detected in HLV-infected cells than in HSV-1- or HSV-2-infected cells. Both B-enriched and T-enriched cells could support HLV replication, but not that of HSV-1 or HSV-2. The replication of HSV-1 was demonstrated in guinea pig spleen cells pretreated with lipopolysaccharide but not with phytohemagglutinin. Furthermore, when cells were separated into B- and T-enriched cells, the B- enriched cells prestimulated with lipopolysaccharide were susceptible to HSV-1 replication, whereas the T-enriched cells prestimulated with phytohemagglutinin were not. The differences observed in vitro in the interactions of these two herpesviruses with guinea pig spleen cell subpopulations may provide a basis for understanding the differences observed in vivo in the pathogenesis of these two viruses; i.e., HLV is capable of infecting and persisting in guinea pig lymphocytes, whereas HSV is not.

  16. Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency

    PubMed Central

    Lee, Kiho; Kwon, Deug-Nam; Ezashi, Toshihiko; Choi, Yun-Jung; Park, Chankyu; Ericsson, Aaron C.; Brown, Alana N.; Samuel, Melissa S.; Park, Kwang-Wook; Walters, Eric M.; Kim, Dae Young; Kim, Jae-Hwan; Franklin, Craig L.; Murphy, Clifton N.; Roberts, R. Michael; Prather, Randall S.; Kim, Jin-Hoi

    2014-01-01

    Pigs with severe combined immunodeficiency (SCID) may provide useful models for regenerative medicine, xenotransplantation, and tumor development and will aid in developing therapies for human SCID patients. Using a reporter-guided transcription activator-like effector nuclease (TALEN) system, we generated targeted modifications of recombination activating gene (RAG) 2 in somatic cells at high efficiency, including some that affected both alleles. Somatic-cell nuclear transfer performed with the mutated cells produced pigs with RAG2 mutations without integrated exogenous DNA. Biallelically modified pigs either lacked a thymus or had one that was underdeveloped. Their splenic white pulp lacked B and T cells. Under a conventional housing environment, the biallelic RAG2 mutants manifested a “failure to thrive” phenotype, with signs of inflammation and apoptosis in the spleen compared with age-matched wild-type animals by the time they were 4 wk of age. Pigs raised in a clean environment were healthier and, following injection of human induced pluripotent stem cells (iPSCs), quickly developed mature teratomas representing all three germ layers. The pigs also tolerated grafts of allogeneic porcine trophoblast stem cells. These SCID pigs should have a variety of uses in transplantation biology. PMID:24799706

  17. Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency.

    PubMed

    Lee, Kiho; Kwon, Deug-Nam; Ezashi, Toshihiko; Choi, Yun-Jung; Park, Chankyu; Ericsson, Aaron C; Brown, Alana N; Samuel, Melissa S; Park, Kwang-Wook; Walters, Eric M; Kim, Dae Young; Kim, Jae-Hwan; Franklin, Craig L; Murphy, Clifton N; Roberts, R Michael; Prather, Randall S; Kim, Jin-Hoi

    2014-05-20

    Pigs with severe combined immunodeficiency (SCID) may provide useful models for regenerative medicine, xenotransplantation, and tumor development and will aid in developing therapies for human SCID patients. Using a reporter-guided transcription activator-like effector nuclease (TALEN) system, we generated targeted modifications of recombination activating gene (RAG) 2 in somatic cells at high efficiency, including some that affected both alleles. Somatic-cell nuclear transfer performed with the mutated cells produced pigs with RAG2 mutations without integrated exogenous DNA. Biallelically modified pigs either lacked a thymus or had one that was underdeveloped. Their splenic white pulp lacked B and T cells. Under a conventional housing environment, the biallelic RAG2 mutants manifested a "failure to thrive" phenotype, with signs of inflammation and apoptosis in the spleen compared with age-matched wild-type animals by the time they were 4 wk of age. Pigs raised in a clean environment were healthier and, following injection of human induced pluripotent stem cells (iPSCs), quickly developed mature teratomas representing all three germ layers. The pigs also tolerated grafts of allogeneic porcine trophoblast stem cells. These SCID pigs should have a variety of uses in transplantation biology.

  18. Differential effect of allogeneic versus syngeneic mesenchymal stem cell transplantation in MRL/lpr and (NZB/NZW)F1 mice.

    PubMed

    Gu, Fei; Molano, Ivan; Ruiz, Philip; Sun, Lingyun; Gilkeson, Gary S

    2012-11-01

    MSC are being explored as a promising novel treatment for SLE. In this study, we: 1) assessed the differential effects of allogeneic versus syngeneic MSC transplantation on lupus-like disease, 2) explored the mechanisms by which MSC modulate disease, and 3) investigated whether lupus-derived-MSC have intrinsic immunomodulatory defects. We showed that in MRL/lpr mice and (NZB/NZW)F1 mice, both B6-MSC and lupus-MSC from young mice ameliorated SLE-like disease and reduced splenic CD3+CD4+ T lymphocytes and CD19+CD21+ B lymphocytes. However, lupus-MSC from older (NZB/NZW)F1 mice did not reduce spleen weights, glomerular IgG deposits, renal pathology, interstitial inflammation, CD3+CD4+ T lymphocytes or CD19+CD21+ B lymphocytes significantly. Thus MSC transplantation ameliorates SLE-like disease partly through decreasing CD4+ T cell and naïve mature B cell numbers. Allogeneic MSC may be preferred over syngeneic lupus-derived-MSC given the decreased overall effectiveness of post-lupus-derived-MSC, which appears partially due to disease and not exclusively intrinsic defects in the MSC themselves.

  19. Allogenic iPSC-derived RPE cell transplants induce immune response in pigs: a pilot study.

    PubMed

    Sohn, Elliott H; Jiao, Chunhua; Kaalberg, Emily; Cranston, Cathryn; Mullins, Robert F; Stone, Edwin M; Tucker, Budd A

    2015-07-03

    Stem cell strategies focused on replacement of RPE cells for the treatment of geographic atrophy are under intense investigation. Although the eye has long been considered immune privileged, there is limited information about the immune response to transplanted cells in the subretinal space of large animals. The purpose of this study was to evaluate the survival of allogenic induced pluripotent stem cell-derived RPE cells (iPSC-RPE) delivered to the subretinal space of the pig as well as determine whether these cells induce an immune response in non-diseased eyes. GFP positive iPSC-RPE, generated from outbred domestic swine, were injected into the subretinal space of vitrectomized miniature swine. Control eyes received vehicle only. GFP positive iPSC-RPE cells were identified in the subretinal space 3 weeks after injection in 5 of 6 eyes. Accompanying GFP-negative cells positive for IgG, CD45 and macrophage markers were also identified in close proximity to the injected iPSC-RPE cells. All subretinal cells were negative for GFAP as well as cell cycle markers. We found that subretinal injection of allogenic iPSC-RPE cells into wild-type mini-pigs can induce the innate immune response. These findings suggest that immunologically matched or autologous donor cells should be considered for clinical RPE cell replacement.

  20. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  1. Neural Crest Cells Contribute an Astrocyte-like Glial Population to the Spleen

    PubMed Central

    Barlow-Anacker, Amanda J.; Fu, Ming; Erickson, Christopher S.; Bertocchini, Federica; Gosain, Ankush

    2017-01-01

    Neural crest cells (NCC) are multi-potent cells of ectodermal origin that colonize diverse organs, including the gastrointestinal tract to form the enteric nervous system (ENS) and hematopoietic organs (bone marrow, thymus) where they participate in lymphocyte trafficking. Recent studies have implicated the spleen as an anatomic site for integration of inflammatory signals from the intestine with efferent neural inputs. We have previously observed alterations in splenic lymphocyte subsets in animals with defective migration of NCC that model Hirschsprung’s disease, leading us to hypothesize that there may be a direct cellular contribution of NCC to the spleen. Here, we demonstrate that NCC colonize the spleen during embryogenesis and persist into adulthood. Splenic NCC display markers indicating a glial lineage and are arranged anatomically adjacent to blood vessels, pericytes and nerves, suggesting an astrocyte-like phenotype. Finally, we identify similar neural-crest derived cells in both the avian and non-human primate spleen, showing evolutionary conservation of these cells. PMID:28349968

  2. Appearance of Human Plasma Cells Following Differentiation of Human B Cells in NOD/SCID Mouse Spleen

    PubMed Central

    Kikuchi, Kentaro; Lian, Zhe-Xiong; He, Xiao-Song; Ansari, Aftab A.; Ishibashi, Miyuki; Miyakawa, Hiroshi; Shultz, Leonard D.; Ikehara, Susumu; Gershwin, M. Eric

    2003-01-01

    Relatively little is known for the differentiation and maturation process of human B cells to plasma cells. This is particularly important in reconstitution work involving transfer of autoantibodies. To address this issue, we transplanted human peripheral blood mononuclear cells (PBMC) directly into the spleen of irradiated NOD/SCID mice depleted of natural killer cell activity. Within 6 weeks, naïve B cells differentiated into memory B cells and, importantly, the numbers of human CD138+ plasma cells in spleen increased by 100 fold after transplantation. Plasma cell numbers correlated with the detection of human IgM and IgG in serum, indicating that human B cells had differentiated into mature plasma cells in the murine spleen. In addition to CD19+ plasma cells, a distinct CD19- plasma cell population was detected, suggesting that downregulation of CD19 associated with maturation of plasma cells occurred. When purified human B cells were transplanted, those findings were not observed. Our results indicate that differentiation and maturation of human B cells and plasma cells can be investigated by transplantation of human PBMC into the spleen of NOD/SCID mice. The model will be useful for studying the differentiation of human B cells and generation of plasma cells. PMID:14768952

  3. The flow of red cells through spleen-like filtering slits

    NASA Astrophysics Data System (ADS)

    Freund, Jonathan

    2012-11-01

    It is widely understood that the spleen is the principal site in the body for removal of old red blood cells. As they age during their approximately 120 day lifetimes, red blood cells have increasingly slow relaxation times. This mechanical change is potentially the identifying characteristic for filtering in the spleen, which is thought to occur in particularly narrows slit-like passages (< 1 μ m × ~ 7 μ m). The mechanism of the filtering, however, is unclear. Most simply, increasing cell viscosity with age would slow, rather than stop, cell passage. Similarly, `testing' the cells via significant strains during each passage through the spleen might be expected to accelerate aging through fatigue-like mechanisms. Our detailed simulations of red cells passing trough a model slit geometry suggest that increasing cell viscosity can fundamentally change its passage. The results are suggestive of a bifurcation, such as in the onset of instability, with increasing cell interior viscosity. Higher viscosities (or elastic capillary numbers) are seen in cases to lead to a fingering-like instability, which might be expected to severely damage aged cells, leading to their removal, while leaving younger low viscosity cells relatively unstressed.

  4. Dendritic cell-mediated immune humanization of mice: implications for allogeneic and xenogeneic stem cell transplantation.

    PubMed

    Salguero, Gustavo; Daenthanasanmak, Anusara; Münz, Christian; Raykova, Ana; Guzmán, Carlos A; Riese, Peggy; Figueiredo, Constanca; Länger, Florian; Schneider, Andreas; Macke, Laura; Sundarasetty, Bala Sai; Witte, Torsten; Ganser, Arnold; Stripecke, Renata

    2014-05-15

    De novo regeneration of immunity is a major problem after allogeneic hematopoietic stem cell transplantation (HCT). HCT modeling in severely compromised immune-deficient animals transplanted with human stem cells is currently limited because of incomplete maturation of lymphocytes and scarce adaptive responses. Dendritic cells (DC) are pivotal for the organization of lymph nodes and activation of naive T and B cells. Human DC function after HCT could be augmented with adoptively transferred donor-derived DC. In this study, we demonstrate that adoptive transfer of long-lived human DC coexpressing high levels of human IFN-α, human GM-CSF, and a clinically relevant Ag (CMV pp65 protein) promoted human lymphatic remodeling in immune-deficient NOD.Rag1(-/-).IL-2rγ(-/-) mice transplanted with human CD34(+) cells. After immunization, draining lymph nodes became replenished with terminally differentiated human follicular Th cells, plasma B cells, and memory helper and cytotoxic T cells. Human Igs against pp65 were detectable in plasma, demonstrating IgG class-switch recombination. Human T cells recovered from mice showed functional reactivity against pp65. Adoptive immunotherapy with engineered DC provides a novel strategy for de novo immune reconstitution after human HCT and a practical and effective tool for studying human lymphatic regeneration in vivo in immune deficient xenograft hosts.

  5. 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

  6. Early immunisation with dendritic cells after allogeneic bone marrow transplantation elicits graft vs tumour reactivity

    PubMed Central

    Gigi, V; Stein, J; Askenasy, N; Yaniv, I; Ash, S

    2013-01-01

    Background: Perspectives of immunotherapy to cancer mediated by bone marrow transplantation (BMT) in conjunction with dendritic cell (DC)-mediated immune sensitisation have yielded modest success so far. In this study, we assessed the impact of DC on graft vs tumour (GvT) reactions triggered by allogeneic BMT. Methods: H2Ka mice implanted with congenic subcutaneous Neuro-2a neuroblastoma (NB, H2Ka) tumours were irradiated and grafted with allogeneic H2Kb bone marrow cells (BMC) followed by immunisation with tumour-inexperienced or tumour-pulsed DC. Results: Immunisation with tumour-pulsed donor DC after allogeneic BMT suppressed tumour growth through induction of T cell-mediated NB cell lysis. Early post-transplant administration of DC was more effective than delayed immunisation, with similar efficacy of DC inoculated into the tumour and intravenously. In addition, tumour inexperienced DC were equally effective as tumour-pulsed DC in suppression of tumour growth. Immunisation of DC did not impact quantitative immune reconstitution, however, it enhanced T-cell maturation as evident from interferon-γ (IFN-γ) secretion, proliferation in response to mitogenic stimulation and tumour cell lysis in vitro. Dendritic cells potentiate GvT reactivity both through activation of T cells and specific sensitisation against tumour antigens. We found that during pulsing with tumour lysate DC also elaborate a factor that selectively inhibits lymphocyte proliferation, which is however abolished by humoral and DC-mediated lymphocyte activation. Conclusion: These data reveal complex involvement of antigen-presenting cells in GvT reactions, suggesting that the limited success in clinical application is not a result of limited efficacy but suboptimal implementation. Although DC can amplify soluble signals from NB lysates that inhibit lymphocyte proliferation, early administration of DC is a dominant factor in suppression of tumour growth. PMID:23511628

  7. Fish oil diet affects on oxidative senescence of red blood cells linked to degeneration of spleen cells in mice.

    PubMed

    Oarada, M; Furukawa, H; Majima, T; Miyazawa, T

    2000-08-24

    The effect of dietary polyunsaturated fatty acids and alpha-tocopherol supplementation on erythrocyte lipid peroxidation and immunocompetent cells in mice was studied comparatively using seven dietary oils (15% oil/diet, w/w) including fish oil rich in eicosapentaenoic acid (EPA, 20:5, n-3) and docosahexaenoic acid (DHA, 22:6, n-3). A 43% increase in spleen weight, about twice as many spleen cells and no change in the subpopulations of spleen cells, as well as a significant depression of mitogen-induced blastogenesis of both T and B cells in the spleen were observed in mice fed fish oil for 30 days in comparison with soybean oil diet-fed mice. In the fish oil diet-fed mice, membranous lipid hydroperoxide (hydroperoxides of phosphatidylcholine and phosphatidylethanolamine) accumulation as a marker of oxidative senescence in red blood cells (RBC) was 2.7-3.5 times higher than that in mice fed soybean oil, although there was no difference in the plasma phosphatidylcholine hydroperoxide concentration. In spite of the supplementation of alpha-tocopherol to up to 10 times the level in the basal diet, the degeneration of spleen cells and the stimulated oxidative senescence of RBC found by the fish oil feeding could not be prevented. The results suggest that oral intake of excess polyunsaturated fatty acids, i.e. EPA and DHA, in a fish oil diet can lead to acceleration of membrane lipid peroxidation resulting in RBC senescence linked to the lowering of immune response of spleen cells, and that supplementation of alpha-tocopherol as antioxidant does not always effectively prevent such oxidative degeneration as observed in spleen cells and RBC in vivo.

  8. Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice.

    PubMed

    Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi; Tong, Qing; He, Shan; Liu, Yongnian; Purushe, Janaki; Fung, Henry; Zaidi, M Raza; Zhang, Yanyun; Reshef, Ran; Blazar, Bruce R; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

    2016-06-23

    Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We established a novel platform that produced δ-like ligand 4-positive dendritic cells (Dll4(hi)DCs) from murine bone marrow using Flt3 ligand and Toll-like receptor agonists. Upon allogeneic Dll4(hi)DC stimulation, CD4(+) naïve T cells underwent effector differentiation and produced high levels of interferon γ (IFN-γ) and interleukin-17 in vitro, depending on Dll4 activation of Notch signaling. Following transfer, allogeneic Dll4(hi)DC-induced T cells were unable to mediate severe GVHD but preserved antileukemic activity, significantly improving the survival of leukemic mice undergoing allogeneic HSCT. This effect of Dll4(hi)DC-induced T cells was associated with their impaired expansion in GVHD target tissues. IFN-γ was important for Dll4(hi)DC programming to reduce GVHD toxicities of alloreactive T cells. Absence of T-cell IFN-γ led to improved survival and expansion of Dll4(hi)DC-induced CD4(+) T cells in transplant recipients and caused lethal GVHD. Our findings demonstrate that Dll4(hi)DC programming can overcome GVHD toxicity of donor T cells and produce leukemia-reactive T cells for effective immunotherapy.

  9. Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats

    PubMed Central

    Sun, Yuxin; Lin, Sien; Gu, Weidong; Liu, Yamei; Zhang, Jinfang; Chen, Lin; Li, Gang

    2016-01-01

    Mesenchymal stem cells (MSCs) have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1) Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2) Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX) rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX) and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91). Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn’t show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study

  10. Allogenic human serum, a clinical grade serum supplement for promoting human periodontal ligament stem cell expansion.

    PubMed

    Arpornmaeklong, Premjit; Sutthitrairong, Chotika; Jantaramanant, Piyathida; Pripatnanont, Prisana

    2016-12-13

    Exposing human periodontal ligament stem cells (hPDLSCs) to animal proteins during cell expansion would compromise quality and safety of the hPDLSCs for clinical applications. The current study aimed to evaluate the replacement of animal based serum by human serum for the expansion of hPDLSCs. Human PDLSCs were cultured in culture media supplemented with 4 types of serums, Group A: fetal bovine serum (FBS), Group B: allogeneic human male AB serum (HS) and Group C in-house autologous (Auto-HS) and Group D: in-house allogeneic human serums (Allo-HS). Exhibitions of mesenchymal stem cell (MSC) characteristics of hPDLSCs were examined. Then growth and osteogenic differentiation potential of hPDLSCs in FBS and HS at passages 5 and 15 were compared to investigate effects of serum supplements on growth and expansion stability of the expanded hPDLSCs. After that, growth and osteogenic differentiation of hPDLSCs in Auto- and Allo-HS were investigated. Flow cytometrical analyses, functional differentiations, cell growth kinetic, cytogenetic analysis, alkaline phosphatase (ALP) and calcium content assays and oil red O and von Kossa staining were performed. Results showed that at passage 5, HS promoted growth and osteogenic differentiation of hPDLSCs and extensive cell expansion, decreased growth and differentiation potential of the expanded hPDLSCs, particularly in HS. Growth and osteogenic differentiation of hPDLSCs in Auto-HS and Allo-HS were not different. In summary, allogeneic human serum could be a replacement to FBS for hPDLSC expansion. In vitro cell expansion of hPDLSCs should be minimal to ensure optimal cell quality. This article is protected by copyright. All rights reserved.

  11. Relation between Acute GVHD and NK Cell Subset Reconstitution Following Allogeneic Stem Cell Transplantation

    PubMed Central

    Ullrich, Evelyn; Salzmann-Manrique, Emilia; Bakhtiar, Shahrzad; Bremm, Melanie; Gerstner, Stephanie; Herrmann, Eva; Bader, Peter; Hoffmann, Petra; Holler, Ernst; Edinger, Matthias; Wolff, Daniel

    2016-01-01

    One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56high and mature cytotoxic CD56dim NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56high subset. Notably, the disturbed reconstitution of the CD56high NK cells also correlated with the severity of aGVHD. PMID:28066411

  12. Relation between Acute GVHD and NK Cell Subset Reconstitution Following Allogeneic Stem Cell Transplantation.

    PubMed

    Ullrich, Evelyn; Salzmann-Manrique, Emilia; Bakhtiar, Shahrzad; Bremm, Melanie; Gerstner, Stephanie; Herrmann, Eva; Bader, Peter; Hoffmann, Petra; Holler, Ernst; Edinger, Matthias; Wolff, Daniel

    2016-01-01

    One of the major challenges of allogeneic stem cell transplantation (allo-SCT) is to reduce the risk of graft-versus-host disease (GVHD) while boosting the graft-versus-leukemia (GVL) effect. The reconstitution of natural killer (NK) cells following allo-SCT is of notable interest due to their known capability to induce GVL without GVHD. Here, in this study, we investigate the association between the incidence and severity of acute graft-versus-host disease (aGVHD) and the early reconstitution of NK cell subsets following allo-SCT. We analyzed 342 samples from 107 patients using flow cytometry, with a focus on immature CD56(high) and mature cytotoxic CD56(dim) NK cells. Longitudinal analysis of immune reconstitution after allo-SCT showed that the incidence of aGVHD was associated with a delayed expansion of the entire NK cell population, in particular the CD56(high) subset. Notably, the disturbed reconstitution of the CD56(high) NK cells also correlated with the severity of aGVHD.

  13. Risk for Clostridium difficile Infection After Allogeneic Hematopoietic Cell Transplant Remains Elevated in the Postengraftment Period

    PubMed Central

    Dubberke, Erik R.; Reske, Kimberly A.; Olsen, Margaret A.; Bommarito, Kerry M.; Seiler, Sondra; Silveira, Fernanda P.; Chiller, Tom M.; DiPersio, John; Fraser, Victoria J.

    2017-01-01

    Background Clostridium difficile infection (CDI) is a frequent cause of diarrhea among allogeneic hematopoietic cell transplant (HCT) recipients. It is unknown whether risk factors for CDI vary by time posttransplant. Methods We performed a 3-year prospective cohort study of CDI in allogeneic HCT recipients. Participants were enrolled during their transplant hospitalizations. Clinical assessments were performed weekly during hospitalizations and for 12 weeks posttransplant, and monthly for 30 months thereafter. Data were collected through patient interviews and chart review, and included CDI diagnosis, demographics, transplant characteristics, medications, infections, and outcomes. CDI cases were included if they occurred within 1 year of HCT and were stratified by time from transplant. Multivariable logistic regression was used to determine risk factors for CDI. Results One hundred eighty-seven allogeneic HCT recipients were enrolled, including 63 (34%) patients who developed CDI. 38 (60%) CDI cases occurred during the preengraftment period (days 0-30 post-HCT) and 25 (40%) postengraftment (day >30). Lack of any preexisting comorbid disease was significantly associated with lower risk of CDI preengraftment (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.9). Relapsed underlying disease (OR, 6.7; 95% CI, 1.3-33.1), receipt of any high-risk antimicrobials (OR, 11.8; 95% CI, 2.9-47.8), and graft-versus-host disease (OR, 7.8; 95% CI, 2.0-30.2) were significant independent risk factors for CDI postengraftment. Conclusions A large portion of CDI cases occurred during the postengraftment period in allogeneic HCT recipients, suggesting that surveillance for CDI should continue beyond the transplant hospitalization and preengraftment period. Patients with continued high underlying severity of illness were at increased risk of CDI postengraftment.

  14. The Symptom Experience in the First 100 Days Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

    PubMed Central

    Bevans, Margaret F.; Mitchell, Sandra A.; Marden, Susan

    2010-01-01

    Goals of Work Despite advances in allogeneic hematopoietic stem cell transplantation (HSCT), post-transplant complications are common and patients’ symptom experience has not been well documented. Purpose To characterize the symptom experience of adult patients pre-transplantation and days 0, 30 and 100 after allogeneic HSCT. Methods Data from 76 participants enrolled in a prospective Health-Related Quality of Life (HRQL) study were used. Symptom occurrence, distress, and clusters were determined based on the 11 symptoms of the Symptom Distress Scale (SDS). Results Participants were on average 40 years old (SD ± 13.5). The majority (54%) received reduced intensity conditioning. Prevalent symptoms included fatigue (68%) and worry (68%) at baseline; appetite change (88%) at day 0; and fatigue at days 30 (90%) and 100 (81%). Participants reported the following symptoms as severely distressing: worry (16%) [baseline], insomnia (32%) [Day 0], appetite change (22%) [Day 30] and fatigue (11%) [Day 100]. The total SDS score was highest at day 0 (M = 26.6 ± 7.6) when the highest number of symptoms were reported [Mdn = 8 (1 - 11)]. Symptoms formed clusters comprised of fatigue, appearance change, and worry at baseline, and fatigue, insomnia and bowel changes at days 0 and 30. Compared to those with low symptom distress, participants with moderate/severe symptom distress reported poorer HRQL. Conclusion Allogeneic HSCT patients present for transplantation with low symptom distress yet experience multiple symptoms and high symptom distress after HSCT conditioning. Understanding the symptom experience of allogeneic HSCT patients can guide management strategies and improve HRQL. PMID:18322708

  15. 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.

  16. Allogeneic mesenchymal stem cells, but not culture modified monocytes, improve burn wound healing.

    PubMed

    Clover, Anthony J P; Kumar, Arun H S; Isakson, Matthew; Whelan, Derek; Stocca, Alecia; Gleeson, Birgitta M; Caplice, Noel M

    2015-05-01

    The use of cell therapy to improve burn wound healing is limited as a validated cell source is not rapidly available after injury. Progenitor cells have shown potential to drive the intrinsic wound regeneration. Two sources of cells, allogeneic mesenchymal stem cells (MSC) and autologous culture modified monocytes (CMM), were assessed for their ability to influence burn wound healing. Both could be widely available shortly after injury. Cells were delivered in a fibrin matrix following contact burns in a porcine burns model. Application of MSC significantly decreased the area of unhealed burn compared to CMM or delivery matrix alone (6% MSC, 27% CMM, 24% Matrix, p<0.001). MSC treated wounds showed histological evidence of improved wound healing with increased collagen content (MSC 49%, CMM 42%, p<0.01), increased epidermal area (MSC 8.8%, CMM 6.1%, p<0.01) and dermal thickness (MSC 1108 μm, CMM 1007 μm, p<0.01) compared to CMM treated wounds. Labelled MSC and CMM were identified in the wounds after 2 weeks by immunohistochemistry and FACS. A single application of allogeneic MSC improves the rate of burn wound healing and improves the histological appearance of the burn wound. These cells show potential as a cell therapy that is rapidly available following burn.

  17. Close Vicinity of PrP Expressing Cells (FDC) with Noradrenergic Fibers in Healthy Sheep Spleen

    PubMed Central

    Lezmi, S.; Hunsmann, G.; Baron, T.

    2001-01-01

    In naturally and experimentally occurring scrapie in sheep, prions invade the immune system and replicate in lymphoid organs. Here we analysed immunohistochemically, in seven spleens of 6-month-old healthy sheep, the nature of the cells expressing prion protein (PrP) potentially supporting prion replication, as well as their relationship with autonomic innervation. PrP was identified using either RB1 rabbit antiserum or 4F2 monoclonal antibody directed against AA 108–123 portion of the bovine and AA 79–92 of human prion protein respectively. Using double labelling analysis, we demonstrated that PrPc is expressed by follicular dendritic cells using a specific monoclonal antibody (CNA42). We also showed the close vicinity of these PrP expressing cells with noradrenergic fibers, using a polyclonal tyrosine hydroxylase antibody. Our results may help the study of the cellular requirements for the possible neuroinvasion from the spleen. PMID:11785673

  18. Chronodependent effect of interleukin-2 on mouse spleen cells in the model of cyclophosphamide immunosuppression.

    PubMed

    Shurlygina, A V; Mel'nikova, E V; Trufakin, V A

    2015-02-01

    We studied the chronodependent effect of IL-2 in the experimental model of immunodeficiency, cyclophosphamide-induced immunosuppression in mice. IL-2 in a dose of 100 U/ mouse was administered at 10.00 and 16.00 for 3 days after injection of cyclophosphamide. In contrast to the morning treatment with the cytokine, evening administration produced antiapoptotic effect on splenocytes and stimulated proliferation to a greater extent. This was accompanied by an increase in the number of CD4(+), CD25(+) and CD4(+)25(+) cells in the spleen to a level of intact mice. More pronounced effect of the evening mode of IL-2 administration on the proliferation and subpopulation composition of mouse spleen cells in the studied model can be associated with high blood level of CD25(+) cells at this time of the day.

  19. Functional tooth restoration by allogeneic mesenchymal stem cell-based bio-root regeneration in swine.

    PubMed

    Wei, Fulan; Song, Tieli; Ding, Gang; Xu, Junji; Liu, Yi; Liu, Dayong; Fan, Zhipeng; Zhang, Chunmei; Shi, Songtao; Wang, Songlin

    2013-06-15

    Our previous proof-of-concept study showed the feasibility of regenerating the dental stem cell-based bioengineered tooth root (bio-root) structure in a large animal model. Here, we used allogeneic dental mesenchymal stem cells to regenerate bio-root, and then installed a crown on the bio-root to restore tooth function. A root shape hydroxyapatite tricalcium phosphate scaffold containing dental pulp stem cells was covered by a Vc-induced periodontal ligament stem cell sheet and implanted into a newly generated jaw bone implant socket. Six months after implantation, a prefabricated porcelain crown was cemented to the implant and subjected to tooth function. Clinical, radiological, histological, ultrastructural, systemic immunological evaluations and mechanical properties were analyzed for dynamic changes in the bio-root structure. The regenerated bio-root exhibited characteristics of a normal tooth after 6 months of use, including dentinal tubule-like and functional periodontal ligament-like structures. No immunological response to the bio-roots was observed. We developed a standard stem cell procedure for bio-root regeneration to restore adult tooth function. This study is the first to successfully regenerate a functional bio-root structure for artificial crown restoration by using allogeneic dental stem cells and Vc-induced cell sheet, and assess the recipient immune response in a preclinical model.

  20. 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

  1. Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer-cell neoplasms.

    PubMed

    Murashige, Naoko; Kami, Masahiro; Kishi, Yukiko; Kim, Sung-Won; Takeuchi, Masami; Matsue, Kosei; Kanda, Yoshinobu; Hirokawa, Makoto; Kawabata, Yoshinari; Matsumura, Tomoko; Kusumi, Eiji; Hirabayashi, Noriyuki; Nagafuji, Koji; Suzuki, Ritsuro; Takeuchi, Kengo; Oshimi, Kazuo

    2005-08-01

    The efficacy of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) for natural killer (NK)-cell neoplasms is unknown. We investigated the results of allo-HSCT for NK-cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo-HSCT for malignant lymphoma, 28 had NK-cell neoplasms (World Health Organization classification): extranodal NK/T-cell lymphoma (n=22), blastic NK-cell lymphoma (n=3), and aggressive NK-cell leukaemia (n=3). Twelve were chemosensitive and 16 chemorefractory. Twenty-two had matched-related donors. Stem-cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative (n=23) and non-myeloablative (n=5). Grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno-occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two-year progression-free and overall survivals were 34% and 40% respectively (median follow-up, 34 months). All patients who did not relapse/progress within 10 months achieved progression-free survival (PFS) during the follow-up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3.03), age (>or=40 years vs. <40 years; relative risk 2.85), and diagnoses (extranodal NK/T-cell lymphoma versus others; relative risk 3.94) significantly affected PFS. Allo-HSCT is a promising treatment for NK-cell neoplasms.

  2. Modulation of Human Allogeneic and Syngeneic Pluripotent Stem Cells and Immunological Implications for Transplantation

    PubMed Central

    Sackett, S.D.; Brown, M.E.; Tremmel, D.M.; Ellis, T.; Burlingham, W.J.; Odorico, J.S.

    2016-01-01

    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

  3. 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.

  4. Biomechanics of red blood cells in human spleen and consequences for physiology and disease

    PubMed Central

    Pivkin, Igor V.; Peng, Zhangli; Karniadakis, George E.; Buffet, Pierre A.; Dao, Ming; Suresh, Subra

    2016-01-01

    Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the “physical fitness test” to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria. PMID:27354532

  5. Suppression of hamster lymphocyte reactivity to simian virus 40 tumor surface antigens by spleen cells from pregnant hamsters

    SciTech Connect

    Weppner, W.A.; Adkinson, L.R.; Coggin, J.H.Jr

    1980-09-01

    SV40-transformed tumor cells in hamsters have been found to have cell surface antigens cross-reactive with antigens temporally expressed on fetal tissues. Using a lymphocyte transformation assay, spleen cells from pregnant hamsters were found to be incapable of responding to preparations of either hamster fetal tissue or SV40-transformed cells. However, a suppressor component can be demonstrated in spleen cell populations of both primi-and multiparous hamsters during pregnancy that is capable of reducing the response of lymphocytes sensitized against SV40 tumor-associated antigens. The degree of suppression is proportional to the ratio of responder cells to spleen cells from pregnant animals. These results suggest there is a subpopulation of spleen cells involved in immunoregulation during pregnancy that has the ability to suppress the reactivity of lymphocytes sensitized against SV40-associated oncofetal antigens.

  6. Dynamics of bovine spleen cell populations during the response to acute Babesia bovis infection: an immunohistological study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spleen is the critical organ in defense against hemoparasitic diseases like babesiosis, responding to the pathogen in blood as it passes through the organ. As a lymphoid organ, the spleen is composed of cells whose role it is to orchestrate the engagement of infected erythrocytes and free parasi...

  7. The characteristics of NK cells in Schistosoma japonicum-infected mouse spleens.

    PubMed

    Li, Lu; Cha, Hefei; Yu, Xiuxue; Xie, Hongyan; Wu, Changyou; Dong, Nuo; Huang, Jun

    2015-12-01

    Natural killer (NK) cells are classic innate immune cells that play roles in many types of infectious disease. Recently, some new characteristics of NK cells were discovered. In this study, C57BL/6 mice were infected with Schistosoma japonicum for 5-6 weeks and lymphocytes were isolated from the spleen to detect some of the NK cell characteristics by multiparametric flow cytometry. The results revealed that the S. japonicum infection induced a large amount of NK cells, although the percentage of NK cells was not increased significantly. At the same time, the results showed that infected mouse splenic NK cells expressed increased levels of CD25 and CD69 and produced more IL-2, IL-4, and IL-17 and less IFN-γ after stimulation with PMA and ionomycin. This meant that NK cells played a role in S. japonicum infection. Moreover, decreased NKG2A/C/E (CD94) expression levels were detected on the surface of NK cells from infected mouse spleens, which might serve as a NK cell activation mechanism. Additionally, high levels of IL-10, but not PD-1, were expressed on the infected mouse NK cells, which implied that functional exhaustion might exist in the splenic NK cells from S. japonicum-infected mice. Collectively, our results suggest that NK cells play important roles in the course of S. japonicum infection.

  8. The regulation of allogeneic human cells and tissue products as biomaterials.

    PubMed

    Yano, Kazuo; Tsuyuki, Kenichiro; Watanabe, Natsumi; Kasanuki, Hiroshi; Yamato, Masayuki

    2013-04-01

    The current definition of biomaterials differs vastly from it of just a decade ago. According to advancing technologies, it encompasses unpredictable materials such as engineered human cells and tissue. These biomaterials also have to be approved to use in health care business by regulatory authority, which are defined as drug, medical device, or biologics in the regulation. This Leading Opinion Paper addresses the regulatory issues of engineered human cells and tissue products using allogeneic cells that should have a great possibility to develop therapeutics for life-threating diseases or orphan diseases. Six allogeneic human cells and tissue products derived from neonatal or infant fibroblasts and/or keratinocytes were approved as medical devices or biologics in the United States as well as a hematopoietic cell product. For five of the seven products, well-controlled comparative clinical trials were conducted as pre-approval evaluation followed by post-approval evaluation. Although these products avoid a sterilization process usually used for medical devices, no serious malfunction that would lead to class 1 recall was reported. This article would provide insight for development of the engineered human cells and tissue.

  9. Immune responses to an encapsulated allogeneic islet beta-cell line in diabetic NOD mice.

    PubMed

    Black, Sasha P; 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 (betaTC-tet) in non-obese diabetic mice treated with tetracycline to inhibit cell growth. Relatively low serum levels of tetracycline controlled proliferation of betaTC-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 the 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.

  10. VH1 Family Immunoglobulin Repertoire Sequencing after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sethi, Maya K.; Thol, Felicitas; Stadler, Michael; Heuser, Michael; Ganser, Arnold

    2017-01-01

    After allogeneic hematopoietic stem cell transplantation (HSCT), recovery of humoral immunity is essential to protect from life-threatening infections. However, monitoring the humoral immune system after transplantation with standard techniques in the clinical routine is imprecise. Here, we performed sequencing of mononuclear bone marrow cells to characterize the VH1-repertoire of switched B cells of healthy volunteers and patients undergoing HSCT. Analysis of healthy bone marrow donors and patients showed virtually no clonally related sequences between individuals. Interestingly, clonally related sequences were present in pre- and post-transplantation bone marrow of patients undergoing HSCT for acute myeloid leukemia treatment. We consistently observed such related B cell clones, irrespective of conditioning regimen, donor source or time post transplantation. In general, repertoire diversity was lower in post-HSCT as compared to pre-HSCT samples. However, post-HSCT repertoires retained highly mutated sequences, despite immunosuppressive therapy and presence of T cell deficiency after HSCT. These observations identify key properties of the recovering B cell compartment and provide a conceptual framework for the surveillance of humoral immunity after allogeneic transplantation. PMID:28095438

  11. 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

  12. The Reed-Sternberg cell/lymphocyte rosette. I. Properties of rosettes formed between Hodgkin's cell lines and allogeneic lymphocytes.

    PubMed

    Flavell, D J; Wright, D H

    1989-02-01

    The properties of rosettes formed between the Hodgkin's cell lines, L428 and L591, and allogeneic peripheral blood mononuclear cell populations have been investigated. Immunocytochemical analysis showed that the majority of adherent cells were T-cells of both the CD4 and CD8 subsets. Only relatively few B-cells and monocytes were seen to adhere. However, when peripheral blood mononuclear cell populations were fractionated, it was found that monocytes were as good as T-cells at forming rosettes with both L428 and L591, though B-cells were shown to be poor at forming such associations. Treatment of both L428 and L591 with neuraminidase resulted in a significant reduction (P less than 0.01) in the mean number of adherent lymphocytes and in the numbers of Hodgkin's tumour cells which formed rosettes. Smaller, less significant effects were observed for Cytochalasin B and trypsin. EDTA (10(-2) M) at pH 7.2 had no significant effect on rosetting for L428 or L591. Adherence of allogeneic lymphocytes to L428 or L591 was pH dependent but did not appear to correlate with cell surface charge. Treatment of L428 cells with Fab fragments prepared from the IgG fraction of a hyperimmune rabbit anti-L428 antiserum, significantly (P less than 0.05) inhibited the adherence of allogeneic lymphocytes, but only when used at high concentration. The binding requirements of the Hodgkin's cell lines with allogeneic peripheral blood lymphocytes, as described in this study, appear to be quite different from those described for freshly isolated Hodgkin's tumour cells with autologous intratumoral lymphocytes. This suggests that the two phenomena may be unrelated. There would appear to be an absolute requirement for cell surface sialic acid for allogeneic lymphocyte attachment to the HD cell lines. This might suggest that the receptor-ligand system involved contains sialic acid as an integral part of the cell surface receptor structure involved in recognition of the appropriate ligand.

  13. 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

  14. Nutritional risk in allogeneic stem cell transplantation: rationale for a tailored nutritional pathway.

    PubMed

    Aoyama, Takashi; Imataki, Osamu; Mori, Keita; Yoshitsugu, Kanako; Fukaya, Masafumi; Okamura, Ikue; Enami, Terukazu; Tatara, Raine; Ikeda, Takashi

    2017-04-01

    Hematopoietic stem cell transplantation carries nutrition-related risks. Therefore, nutritional therapy needs to be initiated before transplantation even takes place. We assessed nutritional risk among patients who underwent allogeneic stem cell transplantation. We assessed nutrient supply (calorie supply and protein supply) by chart review. Assessments were made from the pretreatment phase of transplantation to after the end of parenteral nutrition in 51 patients who underwent allogeneic stem cell transplantation at Shizuoka Cancer Center between 2007 and 2012. We compared nutrition-related adverse events and parameters between two groups: those in whom % loss of body weight was ≥7.5 and those in whom % loss of body weight was <7.5. A correlation was observed between changes in weight and skeletal muscle mass (r = 0.89; P < 0.0001). A weak correlation was observed between % loss of body weight and nutrient supply of calories (r = 0.517; P = 0.0001). There were significant differences between the % loss of body weight ≥7.5 group and the % loss of body weight <7.5 group in the following variables: % loss of body weight, nutrient supply from calories and protein; orally ingested nutrient supply from calories and protein; start day of oral intake; and acute graft-versus-host disease. Orally ingested calories were negatively correlated with nutrition-related adverse events in both groups. Early and customized nutritional intervention may be optimal for all patients who undergo allogeneic stem cell transplantation to ameliorate body weight loss associated with nutrition-related adverse events.

  15. Secondary monoclonal gammopathy of undetermined significance after allogeneic stem cell transplantation in multiple myeloma.

    PubMed

    Schmitz, Marian F; Otten, Henny G; Franssen, Laurens E; van Dorp, Suzanne; Strooisma, Theo; Lokhorst, Henk M; van de Donk, Niels W C J

    2014-12-01

    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.).

  16. Visceral leishmaniasis in congenic mice of susceptible and resistant phenotypes: immunosuppression by adherent spleen cells.

    PubMed Central

    Nickol, A D; Bonventre, P F

    1985-01-01

    Visceral leishmaniasis is one of several parasitic diseases of humans characterized by immune suppression. A murine model of disseminated leishmaniasis utilizing inbred strains of specific genetic constitution was used to study the mechanisms of immunosuppression elicited during the course of infection. Resistant (Lshr) and susceptible (Lshs) strains of mice were challenged with amastigotes of Leishmania donovani and evaluated as to immune status at intervals between 2 and 40 weeks after challenge. The proliferative responses of splenic lymphocytes to T-cell mitogens, a B-cell mitogen, and parasite antigens were measured to evaluate the relative immune status of parasitized mice and noninfected control mice. Lymphocytes from resistant C3Heb/FeJ (C3H) mice responded normally to concanavalin A and phytohemagglutinin throughout the course of infection. Parasite antigen responses appeared 2 weeks after challenge of C3H mice and remained vigorous for periods up to 6 months. In contrast, immune suppression during infection was profound in both the curing (C57B1/10) and noncuring (B10.D2) phenotypes of Lshs congenic mice. Both Lshs strains developed severe infection as evidenced by high parasite burdens in the liver and spleen 4 to 5 weeks after challenge; splenic lymphocytes taken from these mice between 2 and 8 weeks became increasingly unresponsive to the T-cell mitogens as well as to parasite antigens. The noncuring B10.D2 mice which suffered chronic infection continued to be suppressed for as long as 40 weeks. C57B1/10 (curing) mice, in contrast, cleared infection between 12 and 16 weeks. After spontaneous recovery or elimination of parasites by antimonial drug therapy, the response of spleen cells to T-cell mitogens or parasite antigens were restored to normal. The spleen cells from the Lshs strains of mice obtained during the height of infection suppressed the proliferative responses of spleen cells from their uninfected counterparts upon cocultivation in vitro

  17. Luteinizing Hormone-Releasing Hormone Enhances T Cell Recovery following Allogeneic Bone Marrow Transplantation1

    PubMed Central

    Goldberg, Gabrielle L.; King, Christopher G.; Nejat, Rebecca A.; Suh, David Y.; Smith, Odette M.; Bretz, Jamison C.; Samstein, Robert M.; Dudakov, Jarrod A.; Chidgey, Ann P.; Chen-Kiang, Selina; Boyd, Richard L.; van den Brink, Marcel R. M.

    2009-01-01

    Posttransplant immunodeficiency, specifically a lack of T cell reconstitution, is a major complication of allogeneic bone marrow transplantation. This immunosuppression results in an increase in morbidity and mortality from infections and very likely contributes to relapse. In this study, we demonstrate that sex steroid ablation using leuprolide acetate, a luteinizing hormone-releasing hormone agonist (LHRHa), increases the number of lymphoid and myeloid progenitor cells in the bone marrow and developing thymocytes in the thymus. Although few differences are observed in the peripheral myeloid compartments, the enhanced thymic reconstitution following LHRHa treatment and allogeneic bone marrow transplantation leads to enhanced peripheral T cell recovery, predominantly in the naive T cell compartment. This results in an increase in T cell function in vivo and in vitro. Graft-versus-host-disease is not exacerbated by LHRHa treatment and graft-versus-tumor activity is maintained. Because LHRHa allows for reversible (and temporary) sex steroid ablation, has a strong safety profile, and has been clinically approved for diseases such as prostate and breast cancer, this drug treatment represents a novel therapeutic approach to reversal of thymic atrophy and enhancement of immunity following immunosuppression. PMID:19380833

  18. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: 'whom, when and how'.

    PubMed

    Freed, J; Talano, J; Small, T; Ricci, A; Cairo, M S

    2012-12-01

    Sickle cell disease (SCD) is an autosomal recessive inherited hematological disorder characterized by chronic hemolysis and vaso-occlusion, resulting in multiorgan dysfunction and premature death. The only known curative therapy for patients with severe SCD is myeloablative conditioning and allo-SCT from HLA-matched sibling donors. In this state of the art review, we discuss current and future considerations including patient selection/eligibility, intensity of conditioning regimens, allogeneic graft sources, graft manipulation, mixed donor chimerism, organ function and stability and autologous gene correction stem cell strategies. Recent novel approaches to promote mixed donor chimerism have included the use of matched unrelated adult donors, umbilical cord blood donors, haploidentical familial donors and the utilization of nonmyeloablative, such as reduced intensity and reduced toxicity conditioning regimens. Future strategies will include gene therapy and autologous gene correction stem cell designs. Prospects are bright for novel stem and cellular approaches for patients with severe SCD, and we are currently at the end of the beginning for utilizing cellular therapeutics for the curative treatment of this chronic and debilitating condition.

  19. Pure red cell aplasia after ABO major-mismatched allogeneic peripheral blood stem cell transplantation successfully treated with plasma exchange and low-dose steroid: two case reports.

    PubMed

    Tsai, Hui-Jen; Lin, Sheng-Fung; Liu, Ta-Chih; Chang, Chao-Sung; Hsiao, Hui-Hua; Chen, Tyen-Po

    2004-03-01

    Pure red cell aplasia (PRCA) is a complication of ABO-incompatible allogeneic stem cell transplantation. The mechanism is not well known, although the isoagglutinin titer before transplantation or cyclosporine use is considered to be the cause. Patients with this complication require more blood transfusions than those without it. There is no standard treatment. We report two cases of PRCA after allogeneic peripheral blood stem cell transplantation that were successfully treated with plasma exchange and low-dose steroid.

  20. Th2 cells are essential for modulation of vascular repair by allogeneic endothelial cells

    PubMed Central

    Methe, Heiko; Nanasato, Mamoru; Spognardi, Anna-Maria; Groothuis, Adam; Edelman, Elazer R.

    2009-01-01

    Background Endothelial cells (EC) embedded within three-dimensional matrices (MEEC) when placed in the vascular adventitia control lumenal inflammation and intimal hyperplasia. Matrix-embedding alters endothelial immunogenicity in vitro. T helper (Th) driven host immunity is a major impediment for of allogeneic grafts. We therefore aimed to identify if modulation of T helper balance would affect immune compatibility and endothelial regulation of vascular repair in vivo. Methods Pigs (n=4/group) underwent balloon injury of both carotid arteries and were left alone (group 1) or received perivascular implants of porcine MEEC (group 2), a 12 days course of cyclosporine A (CsA) (group 3), or a combination of MEEC and CsA (group 4). Host immune reactivity (EC-specific antibodies, activation of splenocytes) was analyzed after 28 and 90 days in 2 pigs/group respectively. Results MEEC treatment alone induced formation of EC-specific IgG1-antibodies (41±6 mean fluorescence intensity (MFI)) and differentiation of host splenocytes into Th2, but not Th1, cytokine-producing cells (IL-4: 242±102, IL-10: 273±114 number of spots). Concomitant CsA-therapy reduced the frequency of IgG1-antibodies (25±2 MFI; p<0.02) and Th2-cytokine producing splenocytes upon MEEC treatment (IL-4: 157±19, IL-10: 124±26 number of spots; p< 0.05). MEEC significantly inhibited luminal occlusion 28 and 90 days after balloon injury compared to untreated controls (12±7 vs. 68±14%; p<0.001) but to a lesser extent in the face of immunomodulation with concomitant CsA-treatment (34±13%; p<0.02 vs. group 2). Conclusions MEEC do not induce a significant Th1-driven immune response expected from alloimplants, but do enhance differentiation of splenocytes into Th2-cytokine producing cells. Reduction in this Th2 response reduces the vasoregulatory effects of allogeneic EC after injury. PMID:20036161

  1. Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient.

    PubMed

    Neemann, K; Eichele, D D; Smith, P W; Bociek, R; Akhtari, M; Freifeld, A

    2012-12-01

    We present a case of severe Clostridium difficile infection (CDI) in a non-neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso-jejunal instillation of donor stool, the patient's symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

  2. Suspected Pulmonary Infection with Trichoderma longibrachiatum after Allogeneic Stem Cell Transplantation

    PubMed Central

    Akagi, Tomoaki; Kawamura, Chizuko; Terasawa, Norio; Yamaguchi, Kohei; Kubo, Kohmei

    2017-01-01

    Aspergillus and Candida species are the main causative agents of invasive fungal infections in immunocompromised human hosts. However, saprophytic fungi are now increasingly being recognized as serious pathogens. Trichoderma longibrachiatum has recently been described as an emerging pathogen in immunocompromised patients. We herein report a case of isolated suspected invasive pulmonary infection with T. longibrachiatum in a 29-year-old man with severe aplastic anemia who underwent allogeneic stem cell transplantation. A direct microscopic examination of sputum, bronchoaspiration, and bronchoalveolar lavage fluid samples revealed the presence of fungal septate hyphae. The infection was successfully treated with 1 mg/kg/day liposomal amphotericin B. PMID:28090056

  3. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens

    PubMed Central

    Fujii, Nobuharu; Akatsuka, Yoshiki; Chaney, Colette N.; Mito, Jeffrey K.; Loeb, Keith R.; Gooley, Ted A.; Brown, Michele L.; Koo, Kevin K. W.; Rosinski, Kellie V.; Ogawa, Seishi; Matsubara, Aiko; Appelbaum, Frederick R.; Riddell, Stanley R.

    2010-01-01

    The adoptive transfer of donor T cells that recognize recipient minor histocompatibility antigens (mHAgs) is a potential strategy for preventing or treating leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). A total of 7 patients with recurrent leukemia after major histocompatibility complex (MHC)–matched allogeneic HCT were treated with infusions of donor-derived, ex vivo–expanded CD8+ cytotoxic T lymphocyte (CTL) clones specific for tissue-restricted recipient mHAgs. The safety of T-cell therapy, in vivo persistence of transferred CTLs, and disease response were assessed. Molecular characterization of the mHAgs recognized by CTL clones administered to 3 patients was performed to provide insight into the antileukemic activity and safety of T-cell therapy. Pulmonary toxicity of CTL infusion was seen in 3 patients, was severe in 1 patient, and correlated with the level of expression of the mHAg-encoding genes in lung tissue. Adoptively transferred CTLs persisted in the blood up to 21 days after infusion, and 5 patients achieved complete but transient remissions after therapy. The results of these studies illustrate the potential to selectively enhance graft-versus-leukemia activity by the adoptive transfer of mHAg-specific T-cell clones and the challenges for the broad application of this approach in allogeneic HCT. This study has been registered at http://clinicaltrials.gov as NCT00107354. PMID:20071660

  4. Spleen cells from young but not old immunized mice eradicate large established cancers

    PubMed Central

    Schreiber, Karin; Arina, Ainhoa; Engels, Boris; Spiotto, Michael T.; Sidney, John; Sette, Alessandro; Karrison, Theodore; Weichselbaum, Ralph R.; Rowley, Donald A.; Schreiber, Hans

    2017-01-01

    Purpose Solid tumors that have grown two weeks or longer in mice and have diameters larger than 1 cm are histologically indistinguishable from autochthonous human cancers. When experimental tumors reach this clinically relevant size, they are usually refractory to most immunotherapies but may be destroyed by adoptive T cell transfer. However, TCR-transgenic T cells and/or tumor cells overexpressing antigens are frequently used in these experiments. Here we studied the requirements for destroying clinical size, unmanipulated 8101 tumors by adoptive cell therapy. Experimental Design 8101 arose in an old mouse after chronic exposure to UV light. A cancer line was established, which was never serially transplanted. The immunodominant CD8+ T cell-recognized antigen of this tumor is caused by a somatic tumor-specific mutation in the RNA helicase p68. 8101 tumors were treated with spleen cells from young naïve, or young and old immunized mice to ascertain the characteristics of immune cells that lead to rejection. Results Here we show that the mutant p68 peptide has an exceptionally high affinity to the presenting MHC class I molecule Kb and that spleen cells from immunized young syngeneic mice adoptively transferred to Rag-/- or cancer-suppressed euthymic mice eradicate 8101 tumors larger than 1 cm in average diameter and established for several weeks. Spleen cells from naïve young mice or from old and boosted (re-immunized) mice were ineffective. Conclusions Relapse-free destruction of large and long-established tumors expressing a genuine very high-affinity tumor-specific antigen can be achieved by using adoptive transfer of lymphocytes from immunized young individuals. PMID:22415314

  5. Pure red cell aplasia following major ABO-incompatible allogeneic hematopoietic stem cell transplantation.

    PubMed

    Zhu, Kang-Er; Xu, Yang; Wu, Dong; Zhong, Juan

    2002-02-01

    Six out of 20 patients undergoing a major ABO-incompatible allogeneic stem cell transplantation (allo-HSCT) developed pure red cell aplasia (PRCA), which did not show any effects on granulocyte and platelet engraftment, and incidence of grade II-IV aGVHD. All the 6 cases of PRCA were in blood group O recipients of grafts from blood group A donors (n = 5) or blood group B donor (n = 1), suggesting that donor/recipient pair (A/O) is associated with a high risk of PRCA after major ABO-incompatible allo-HSCT. Erythroid engraftment occurred spontaneously in four cases without specific intervention other than the RBC transfusion, which coincided with the decrease of isoagglutinin titers below 8, and the remaining 2 patients with prolonged erythroid aplasia( > 300 days) despite therapy with erythropoietin (EPO) were successfully treated by plasma exchange with donor-type plasma replacement. Cyclosporine did not appear to have played any role in causing PRCA in our patients, however, the occurrence of GVHD may facilitate the recovery of erythropoiesis.

  6. Inflammatory pseudotumour-like follicular dendritic cell tumour of the spleen

    PubMed Central

    Nishiyama, Raisuke; Baba, Satoshi; Watahiki, Yoichi; Maruo, Hirotoshi

    2015-01-01

    We describe an unusual case of a 73-year-old woman presenting with a solitary splenic mass 8 cm in diameter and an elevation of serum soluble interleukin-2 receptor level. The preoperative diagnosis was primary malignant lymphoma of the spleen. Splenectomy was conducted. Histological analysis confirmed an inflammatory pseudotumour-like follicular dendritic cell tumour that showed different clinicopathological features from those of the classic follicular dendritic cell tumour. Only 33 cases of inflammatory pseudotumour-like follicular dendritic cell tumour have so far been reported. We discuss the incidence, presentation and management of this rare disease. PMID:25766434

  7. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease.

    PubMed

    Gluckman, Eliane

    2013-01-01

    Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Despite antenatal counseling and neonatal screening programs implemented in higher income countries, SCD is still associated with multiple morbidities and early mortality. To date, the only curative approach to SCD is hematopoietic stem cell transplantation, but this therapy is not yet established worldwide. The registries of the European Blood and Marrow Transplant (EBMT) and the Centre for International Blood and Marrow Transplant Research (CIBMTR) account, respectively, for 611 and 627 patients receiving transplantations for SCD. Most of these patients were transplanted with grafts from an HLA-identical sibling donor. The main obstacles to increasing the number of transplantations are a lack of awareness on the part of physicians and families, the absence of reliable prognostic factors for severity, and the perceived risk that transplantation complications may outweigh the benefits of early transplantation. Results show that more than 90% of patients having undergone an HLA-identical sibling transplantation after myeloablative conditioning are cured, with very limited complications. Major improvement is expected from the use of new reduced-toxicity conditioning regimens and the use of alternative donors, including unrelated cord blood transplantations and related haploidentical bone marrow or peripheral blood stem cell transplantations.

  8. MHC Universal Cells Survive in an Allogeneic Environment after Incompatible Transplantation

    PubMed Central

    Figueiredo, Constança; Wedekind, Dirk; Müller, Thomas; Vahlsing, Stefanie; Horn, Peter A.; Seltsam, Axel; Blasczyk, Rainer

    2013-01-01

    Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting β2-microglobulin (RN_shβ2m) was delivered into fibroblasts derived from LEW/Ztm (RT1l) (RT1-Al) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats (RT1l) and MHC-congenic LEW.1W rats (RT1u), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A-silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine. PMID:24350288

  9. MHC universal cells survive in an allogeneic environment after incompatible transplantation.

    PubMed

    Figueiredo, Constança; Wedekind, Dirk; Müller, Thomas; Vahlsing, Stefanie; Horn, Peter A; Seltsam, Axel; Blasczyk, Rainer

    2013-01-01

    Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting β2-microglobulin (RN_shβ2m) was delivered into fibroblasts derived from LEW/Ztm (RT1(l)) (RT1-A(l)) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats (RT1(l)) and MHC-congenic LEW.1W rats (RT1(u)), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1 α , IL-1 β , IL-6, TNF- α , and IFN- γ were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A-silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine.

  10. De novo purine biosynthesis by two pathways in Burkitt lymphoma cells and in human spleen.

    PubMed

    Reem, G H

    1972-05-01

    This study was designed to answer the question whether human lymphocytes and spleen cells were capable of de novo purine biosynthesis. Experiments were carried out in cell-free extracts prepared from human spleen, and from a cell line established from Burkitt lymphoma. Burkitt lymphoma cells and human spleen cells could synthesize the first and second intermediates of the purine biosynthetic pathway. Cell-free extracts of all cell lines studied contained the enzyme systems which catalyze the synthesis of phosphoribosyl-1-amine, the first intermediate unique to the purine biosynthetic pathway and of phosphoribosyl glycinamide, the second intermediate of this pathway. Phosphoribosyl-1-amine could be synthesized in cell-free extracts from alpha-5-phosphoribosyl-1-pyrophosphate (PRPP) and glutamine, from PRPP and ammonia, and by an alternative pathway, directly from ribose-5-phosphate and ammonia. These findings suggest that extrahepatic tissues may be an important source for the de novo synthesis of purine ribonucleotide in man. They also indicate that ammonia may play an important role in purine biosynthesis. The alternative pathway for the synthesis of phosphoribosyl-1-amine from ribose-5-phosphate and ammonia was found to be subject to inhibition by the end products of the purine synthetic pathway, particularly by adenylic acid and to a lesser degree by guanylic acid. The alternative pathway for phosphoribosyl-1-amine synthesis from ribose-5-phosphate and ammonia may contribute significantly towards the regulation of the rate of de novo purine biosynthesis in the normal state, in metabolic disorders in which purines are excessively produced and in myeloproliferative diseases.

  11. Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy.

    PubMed

    Blau, Olga; Blau, Igor Wolfgang

    2014-01-01

    Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders. MDS remains a disease of elderly patients; moreover, the incidence of high risk MDS is proportionally greater in elderly patients, with increased frequency of secondary acute myeloid leukemia, as well as adverse cytogenetic abnormalities. Allogeneic stem cell transplantation is a therapeutic approach with known curative potential for patients with MDS that allows the achievement of long-term disease control. Numerous controversies still exist regarding transplantation in MDS: timing of transplantation, disease status at transplantation and comorbidity, conditioning intensity, pretransplant therapy, and stem cell source. Various transplant modalities of different intensities and alternative donor sources are now in use. Current advances in transplant technology are allowing the consideration of older patients. This should result in a greater number of older patients benefiting from this potentially curative treatment modality. Despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reduced early mortality, transplant numbers in MDS patients have significantly increased. Moreover, recent new developments with innovative drugs, including hypomethylating agents, have extended the therapeutic alternatives for MDS patients. Hypomethylating agents allow the delay of allogeneic stem cell transplantation by serving as an effective and well-tolerated means to reduce disease burden.

  12. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis.

    PubMed

    Wang, Li; Han, Qin; Chen, Hua; Wang, Ke; Shan, Guang-liang; Kong, Fang; Yang, Yun-jiao; Li, Yong-zhe; Zhang, Xuan; Dong, Fen; Wang, Qian; Xu, Dong; Hu, Zhao-jun; Wang, Shi-hua; Keating, Armand; Bi, Ya-lan; Zhang, Feng-chun; Zhao, Robert Chun-hua

    2014-10-15

    The objective of this study was to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal stromal/stem cell transplantation (BM-MSCT) for patients with ursodeoxycholic acid (UDCA)-resistant primary biliary cirrhosis (PBC). Ten patients were enrolled in this trial of BM-MSCT. All patients were permitted to concurrently continue their previous UDCA treatment. The efficacy of BM-MSCT in UDCA-resistant PBC was assessed at various time points throughout the 12-month follow up. No transplantation-related side effects were observed. The life quality of the patients was improved after BM-MSCT as demonstrated by responses to the PBC-40 questionnaire. Serum levels of ALT, AST, γ-GT, and IgM significantly decreased from baseline after BM-MSCT. In addition, the percentage of CD8+ T cells was reduced, while that of CD4+CD25+Foxp3+ T cells was increased in peripheral lymphocytic subsets. Serum levels of IL-10 were also elevated. Notably, the optimal therapeutic outcome was acquired in 3 to 6 months and could be maintained for 12 months after BM-MSCT. In conclusion, allogeneic BM-MSCT in UDCA-resistant PBC is safe and appears to be effective.

  13. Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study.

    PubMed

    Saglio, Francesco; Cena, Silvia; Berger, Massimo; Quarello, Paola; Boccasavia, Viola; Ferrando, Federica; Pittana, Laura; Bruno, Benedetto; Fagioli, Franca

    2015-06-01

    Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities.

  14. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  15. [Wandering spleen].

    PubMed

    Burcharth, Jakob; Parvaiz, Imran; Moesgaard, Flemming A

    2005-08-15

    The spleen is well fixed below the left side of the diaphragm. Wandering spleen is a rare condition of unknown pathogenesis. The wandering spleen is most often localized in the lower abdomen or pelvis. The diagnosis may be difficult if wandering spleen is not suspected. Often a wandering spleen can be palpated in the lower abdomen. In the rare cases of torsion of the splenic vascular pedicle, wandering spleen becomes symptomatic, and splenectomy should be performed. We report a case of a 20-year-old female treated with splenectomy because of torsion of the vascular pedicle.

  16. Current Status of Allogeneic Hematopoietic Cell Transplantation for MDS

    PubMed Central

    Xu, Feng; Deeg, H. Joachim

    2011-01-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for patients with myelodysplastic syndromes (MDS). However, as most patients with MDS are in the 7th or 8th decade of life, only few of these were transplanted in the past, using high-dose conditioning regimens. The development of reduced-intensity conditioning has allowed to offer HCT also to older patients and those with clinically relevant comorbid conditions. Dependent upon disease status and the type of clonal chromosomal abnormalities present at the time of HCT, some 25%–75% of patients will be cured of their disease and survive long-term. Recent results with HLA matched unrelated donors are comparable to those with HLA genotypically identical siblings. The increasing use of cord blood and HLA haploidentical donors is expected to make HCT available to a growing number of patients. However, post-transplant relapse and graft-versus-host disease remain problems requiring further investigation. PMID:22571701

  17. Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

    PubMed Central

    Hocine, Hocine R.; Costa, Hicham E. L.; Dam, Noemie; Giustiniani, Jerome; Palacios, Itziar; Loiseau, Pascale; Benssusan, Armand; Borlado, Luis R.; Charron, Dominique; Suberbielle, Caroline; Jabrane-Ferrat, Nabila; Al-Daccak, Reem

    2017-01-01

    Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are currently under clinical investigation for cardiac repair. While cellular immune response against allogeneic hCPC could be part of their beneficial-paracrine effects, their humoral immune response remains largely unexplored. Donor-specific HLA antibodies (DSA-HLA-I/DSA-HLA-II), primary elements of antibody-mediated allograft injury, might present an unidentified risk to allogeneic hCPC therapy. Here we established that the binding strength of anti-HLA monoclonal antibodies delineates hCPC proneness to antibody-mediated injury. In vitro modeling of clinical setting demonstrated that specific DSA-HLA-I of high/intermediate binding strength are harmful for hCPC whereas DSA-HLA-II are benign. Furthermore, the Luminex-based solid-phase assays are suitable to predict the DSA-HLA risk to therapeutic hCPC. Our data indicate that screening patient sera for the presence of HLA antibodies is important to provide an immune-educated choice of allogeneic therapeutic cells, minimize the risk of precipitous elimination and promote the allogeneic reparative effects. PMID:28117403

  18. 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

  19. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now.

    PubMed

    Hsieh, Matthew M; Fitzhugh, Courtney D; Tisdale, John F

    2011-08-04

    Although sickle cell disease (SCD) has a variable clinical course, many patients develop end-organ complications that are associated with significant morbidity and early mortality. Myeloablative allogeneic HSCT (allo-HSCT) is curative but has been historically performed only in children younger than 16 years of age. Modest modifications in the conditioning regimen and supportive care have improved outcome such that the majority of children with a suitable HLA-matched sibling donor can expect a cure from this approach. However, adult patients have been excluded from myeloablative allo-HSCT because of anticipated excess toxicity resulting from accumulated disease burden. Efforts to use nonmyeloablative transplantation strategies in adults logically followed but were initially met with largely disappointing results. Recent results, however, indicate that nonmyeloablative allo-HSCT in adult patients with SCD allows for stable mixed hematopoietic chimerism with associated full-donor erythroid engraftment and normalization of blood counts, and persistence in some without continued immunosuppression suggests immunologic tolerance. The attainment of tolerance should allow extension of these potentially curative approaches to alternative donor sources. Efforts to build on these experiences should increase the use of allo-HSCT in patients with SCD while minimizing morbidity and mortality.

  20. Activating receptor NKG2D targets RAE-1-expressing allogeneic neural precursor cells in a viral model of multiple sclerosis.

    PubMed

    Weinger, Jason G; Plaisted, Warren C; Maciejewski, Sonia M; Lanier, Lewis L; Walsh, Craig M; Lane, Thomas E

    2014-10-01

    Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2(b) ) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1(+) NPCs were susceptible to NK cell-mediated killing whereas RAE-1(-) cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2(d) ) mice resulted in infiltration of NKG2D(+) CD49b(+) NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1(-) allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway.

  1. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again.

    PubMed

    Toubert, A; Glauzy, S; Douay, C; Clave, E

    2012-02-01

    Assessment of the host immune status is becoming a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persistent immune defects. In allo-HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required to generate naive recent T-cell emigrants (RTE). These cells account for a durable T-cell reconstitution, generating a diverse T-cell receptor (TCR) repertoire and robust response to infections. It is now possible to quantify the production of RTE by measuring thymic T-cell receptor excision circles or 'TREC' which are small circular DNA produced during the recombination of the genomic segments encoding the TCR alpha chain. Here we discuss the role of thymic function in allo-HSCT. The pre-transplant recipient thymic function correlates with clinical outcome in terms of survival and occurrence of severe infections. Post-transplant, TREC analysis showed that the thymus is a sensitive target to the allogeneic acute graft-versus-host disease (GvHD) reaction but is also prone to recovery in young adult patients. In all, thymus is a key player for the quality of immune reconstitution and clinical outcome after allo-HSCT. Thymic tissue is plastic and it is a future challenge to halt or reverse thymic GVHD therapeutically by acting at the level of T-cell progenitors generation, thymic homing and/or epithelial thymic tissue preservation.

  2. 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.

  3. 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.

  4. Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.

    PubMed

    Faraci, Maura; Zecca, Marco; Pillon, Marta; Rovelli, Attilio; Menconi, Maria Cristina; Ripaldi, Mimmo; Fagioli, Franca; Rabusin, Marco; Ziino, Ottavio; Lanino, Edoardo; Locatelli, Franco; Daikeler, Thomas; Prete, Arcangelo

    2014-02-01

    Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab.

  5. Multispectral Imaging of T and B Cells in Murine Spleen and Tumor

    PubMed Central

    Feng, Zipei; Jensen, Shawn M.; Messenheimer, David J.; Farhad, Mohammed; Neuberger, Michael; Bifulco, Carlo B.

    2016-01-01

    Recent advances in multiplex immunohistochemistry techniques allow for quantitative, spatial identification of multiple immune parameters for enhanced diagnostic and prognostic insight. However, applying such techniques to murine fixed tissues, particularly sensitive epitopes, such as CD4, CD8α, and CD19, has been difficult. We compared different fixation protocols and Ag-retrieval techniques and validated the use of multiplex immunohistochemistry for detection of CD3+CD4+ and CD3+CD8+ T cell subsets in murine spleen and tumor. This allows for enumeration of these T cell subsets within immune environments, as well as the study of their spatial distribution. PMID:26994219

  6. Displacement of the Spleen Mimicking Renal Cell Cancer Recurrence Post-Nephrectomy: A Case Report

    PubMed Central

    Emanuels, Carolina S.; Timmerman, Krista D.; Aijaz, Tabish; Nguyen, Thu-Cuc; Jest, Nathaniel; Drane, Walter E.; Gilbert, Scott M.; Crispen, Paul L.; Su, Li-Ming; Deitte, Lori A.

    2015-01-01

    Local regional recurrence of renal cell cancer post-nephrectomy most often occurs within three years after surgery. Post-nephrectomy, many processes may mimic RCC recurrence. We present the case of a 75 year-old Caucasian male patient with a mass in his renal fossa post-nephrectomy for renal cell cancer, suggesting local recurrence. Use of the technetium-99m sulfur colloid scan showed that the mass was his spleen which had been displaced into the renal fossa. With high index of suspicion, characterization of these processes as splenic in origin would prevent subjecting patients to risks of biopsy or even surgery.

  7. A critical role for the TLR4/TRIF pathway in allogeneic hematopoietic cell rejection by innate immune cells.

    PubMed

    Xu, Hong; Yan, Jun; Zhu, Ziqiang; Hussain, Lala-Rukh; Huang, Yiming; Ding, Chuanlin; Bozulic, Larry D; Wen, Yujie; Ildstad, Suzanne T

    2013-01-01

    We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMCs as organ allografts are rejected mainly via MyD88 signaling. Using T- or T-/B-cell-deficient mice, we found that BMC allorejection occurred early before T-cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not in MyD88 or TLR3. The restored cytotoxicity in TRIF-deficient recipients transferred with wild-type F4/80(+) or NK1.1(+) cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T- and B-cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating the rejection of allogeneic BMCs. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation.

  8. Delivering nanoparticles to lungs while avoiding liver and spleen through adsorption on red blood cells.

    PubMed

    Anselmo, Aaron C; Gupta, Vivek; Zern, Blaine J; Pan, Daniel; Zakrewsky, Michael; Muzykantov, Vladimir; Mitragotri, Samir

    2013-12-23

    Nanoparticulate drug delivery systems are one of the most widely investigated approaches for developing novel therapies for a variety of diseases. However, rapid clearance and poor targeting limit their clinical utility. Here, we describe an approach to harness the flexibility, circulation, and vascular mobility of red blood cells (RBCs) to simultaneously overcome these limitations (cellular hitchhiking). A noncovalent attachment of nanoparticles to RBCs simultaneously increases their level in blood over a 24 h period and allows transient accumulation in the lungs, while reducing their uptake by liver and spleen. RBC-adsorbed nanoparticles exhibited ∼3-fold increase in blood persistence and ∼7-fold higher accumulation in lungs. RBC-adsorbed nanoparticles improved lung/liver and lung/spleen nanoparticle accumulation by over 15-fold and 10-fold, respectively. Accumulation in lungs is attributed to mechanical transfer of particles from the RBC surface to lung endothelium. Independent tracing of both nanoparticles and RBCs in vivo confirmed that RBCs themselves do not accumulate in lungs. Attachment of anti-ICAM-1 antibody to the exposed surface of NPs that were attached to RBCs led to further increase in lung targeting and retention over 24 h. Cellular hitchhiking onto RBCs provides a new platform for improving the blood pharmacokinetics and vascular delivery of nanoparticles while simultaneously avoiding uptake by liver and spleen, thus opening the door for new applications.

  9. Acellular allogeneic nerve grafting combined with bone marrow mesenchymal stem cell transplantation for the repair of long-segment sciatic nerve defects: biomechanics and validation of mathematical models

    PubMed Central

    Li, Ya-jun; Zhao, Bao-lin; Lv, Hao-ze; Qin, Zhi-gang; Luo, Min

    2016-01-01

    We hypothesized that a chemically extracted acellular allogeneic nerve graft used in combination with bone marrow mesenchymal stem cell transplantation would be an effective treatment for long-segment sciatic nerve defects. To test this, we established rabbit models of 30 mm sciatic nerve defects, and treated them using either an autograft or a chemically decellularized allogeneic nerve graft with or without simultaneous transplantation of bone marrow mesenchymal stem cells. We compared the tensile properties, electrophysiological function and morphology of the damaged nerve in each group. Sciatic nerves repaired by the allogeneic nerve graft combined with stem cell transplantation showed better recovery than those repaired by the acellular allogeneic nerve graft alone, and produced similar results to those observed with the autograft. These findings confirm that a chemically extracted acellular allogeneic nerve graft combined with transplantation of bone marrow mesenchymal stem cells is an effective method of repairing long-segment sciatic nerve defects. PMID:27651781

  10. Histological Lesions, Cell Cycle Arrest, Apoptosis and T Cell Subsets Changes of Spleen in Chicken Fed Aflatoxin-contaminated Corn

    PubMed Central

    Peng, Xi; Zhang, Keying; Bai, Shiping; Ding, Xuemei; Zeng, Qiufeng; Yang, Jun; Fang, Jing; Chen, Kejie

    2014-01-01

    The purpose of this study was to evaluate the effects of corn naturally contaminated with aflatoxin B1 and aflatoxin B2 on pathological lesions, apoptosis, cell cycle phases and T lymphocyte subsets of spleen, and to provide an experimental basis for understanding the mechanism of aflatoxin-induced immunosuppression. A total of 900 COBB500 male broilers were randomly allocated into five groups with six replicates per group and 30 birds per replicate. The experiment lasted for 6 weeks and the five dietary treatments consisted of control, 25% contaminated corn, 50% contaminated corn, 75% contaminated corn and 100% contaminated corn groups. The histopathological spleen lesions from the contaminated corn groups was characterized as congestion of red pulp, increased necrotic cells and vacuoles in the splenic corpuscle and periarterial lymphatic sheath. The contaminated corn intake significantly increased relative weight of spleen, percentages of apoptotic splenocytes, induced cell cycle arrest of splenocytes, increased the percentages of CD3+CD8+ T cells and decreased the ratios of CD3+CD4+ to CD3+CD8+. The results suggest that AFB-induced immunosuppression maybe closely related to the lesions of spleen. PMID:25141002

  11. Adoptive transfer of allogeneic liver sinusoidal endothelial cells specifically inhibits T-cell responses to cognate stimuli.

    PubMed

    Banshodani, Masataka; Onoe, Takashi; Shishida, Masayuki; Tahara, Hiroyuki; Hashimoto, Shinji; Igarashi, Yuka; Tanaka, Yuka; Ohdan, Hideki

    2013-01-01

    Although it is well known that liver allografts are often accepted by recipients, leading to donor-specific tolerance of further organ transplants, the underlying mechanisms remain unclear. We had previously used an in vitro model and showed that mouse liver sinusoidal endothelial cells (LSECs) selectively suppress allospecific T-cells across major histocompatibility complex (MHC) barriers. In the present study, we established an in vivo model for evaluating the immunomodulatory effects of allogeneic LSECs on corresponding T-cells. Allogeneic BALB/cA LSECs were injected intraportally into recombination activating gene 2 γ-chain double-knockout (RAG2/gc-KO, H-2(b)) mice lacking T, B, and natural killer (NK) cells. In order to facilitate LSEC engraftment, the RAG2/gc-KO mice were injected intraperitoneally with monocrotaline 2 days before the adoptive transfer of LSECs; this impaired the host LSECs, conferring a proliferative advantage to the transplanted LSECs. After orthotopic allogeneic LSEC engraftment, the RAG2/gc-KO mice were immune reconstituted intravenously with C57BL/6 splenocytes. After immune reconstitution, mixed lymphocyte reaction (MLR) assay using splenocytes from the recipients revealed that specific inhibition of host CD4(+) and CD8(+) T-cell proliferation was greater in response to allostimulation with irradiated BALB/cA splenocytes rather than to stimulation with irradiated third party SJL/jorllco splenocytes. This inhibitory effect was attenuated by administering anti-programmed death ligand 1 (PD-L1) monoclonal antibody during immune reconstitution in the above-mentioned mice, but not in RAG2/gc-KO mice engrafted with Fas ligand (FasL)-deficient BALB/cA LSECs. Furthermore, engraftment of allogeneic BALB/cA LSECs significantly prolonged the survival of subsequently grafted cognate allogeneic BALB/cA hearts in RAG2/gc-KO mice immune reconstituted with bone marrow transplantation from C57BL/6 mice. In conclusion, murine LSECs have been proven

  12. Follicular B cell trafficking within the spleen actively restricts humoral immune responses

    PubMed Central

    Hoek, Kristen L.; Gordy, Laura E.; Collins, Patrick L.; Parekh, Vrajesh V.; Aune, Thomas M.; Joyce, Sebastian; Thomas, James W.; Van Kaer, Luc; Sebzda, Eric

    2010-01-01

    Summary Follicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor, Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naïve FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens. PMID:20691614

  13. T Cell Receptor Excision Circle (TREC) Monitoring after Allogeneic Stem Cell Transplantation; a Predictive Marker for Complications and Clinical Outcome

    PubMed Central

    Gaballa, Ahmed; Sundin, Mikael; Stikvoort, Arwen; Abumaree, Muhamed; Uzunel, Mehmet; Sairafi, Darius; Uhlin, Michael

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment modality for a variety of malignant diseases as well as for inborn errors of the metabolism or immune system. Regardless of disease origin, good clinical effects are dependent on proper immune reconstitution. T cells are responsible for both the beneficial graft-versus-leukemia (GVL) effect against malignant cells and protection against infections. The immune recovery of T cells relies initially on peripheral expansion of mature cells from the graft and later on the differentiation and maturation from donor-derived hematopoietic stem cells. The formation of new T cells occurs in the thymus and as a byproduct, T cell receptor excision circles (TRECs) are released upon rearrangement of the T cell receptor. Detection of TRECs by PCR is a reliable method for estimating the amount of newly formed T cells in the circulation and, indirectly, for estimating thymic function. Here, we discuss the role of TREC analysis in the prediction of clinical outcome after allogeneic HSCT. Due to the pivotal role of T cell reconstitution we propose that TREC analysis should be included as a key indicator in the post-HSCT follow-up. PMID:27727179

  14. Ethanol extract of fermented soybean, Chungkookjang, inhibits the apoptosis of mouse spleen, and thymus cells.

    PubMed

    Kim, Han Bok; Lee, Hye Sung; Kim, Sook Jin; Yoo, Hyung Jae; Hwang, Jae Sung; Chen, Gang; Youn, Hyun Joo

    2007-06-01

    Apoptosis is a step of the cell cycle which is important in the regulation of immune cell populations. Chungkookjang is a Korean traditional fermented soybean containing microorganisms, enzymes, and bioactive compounds which was used in the treatment of mouse spleen as well as thymus cells (CH1-fermented soybean containing barley, wormwood, and sea tangle; CH2-fermented soybean) and was found to exhibit substantially reduced small DNA fragmentation. An MTT assay showed that the treatment of CH1 and CH2 into the mouse splenocytes and thymocytes sharply increased their survival. Moreover, a FACS analysis also showed that CH1 and CH2 are effective at suppressing the apoptosis of splenocytes and thymocytes. The fermented soybean isoflavone concentrations, which are implicated in lowering breast and prostate cancers, lowering the risk of cardiovascular diseases, and improving bone health, were determined using Capillary Electrophoresis-Electrochemical Detection (CE-ED). The amount of Daidzein in fermented soybean significantly increased by 44-fold dramatically, compared with those in unfermented soybean. In this study, we demonstrated that ethanol extracts of Chungkookjang promote the survival of the mouse spleen and thymus cells in culture by suppressing their apoptotic death. Future studies should investigate which genes are related to apoptosis of the immune cells.

  15. 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

  16. Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy

    PubMed Central

    Yamamoto, Wataru; Ogusa, Eriko; Matsumoto, Kenji; Maruta, Atsuo; Ishigatsubo, Yoshiaki; Kanamori, Heiwa

    2016-01-01

    Objective: The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy. Materials and Methods: We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010. Results: The median age was 43 years (minimum-maximum: 17-65 years). Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis. Conclusion: These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration. PMID:27094383

  17. Cognitive function in the acute course of allogeneic hematopoietic stem cell transplantation for hematological malignancies.

    PubMed

    Schulz-Kindermann, F; Mehnert, A; Scherwath, A; Schirmer, L; Schleimer, B; Zander, A R; Koch, U

    2007-06-01

    The aim of the study was to assess cognitive performance in patients with hematological malignancies before, and 3 months after, allogeneic hematopoietic stem cell transplant (HSCT). A consecutive sample of 39 patients was assessed before admission with a comprehensive neuropsychological test battery and health-related quality-of-life (HRQoL) questionnaires; 19 of these patients were retested around 100 days post HSCT. Test results were compared with normative data and revealed minimal differences at both time points in the level of group-means. One parameter - simple reaction time - was significantly worse (prolonged) at second measurement after HSCT. According to the definition of an impairment score (more than three impaired functions), 26% of patients were classified as impaired before as well as after HSCT. Neuropsychological test results did not vary systematically according to medical variables such as extent of pretreatment, graft-versus-host-disease (GvHD) and kind of conditioning protocol. As a dimension of HRQoL, self-rated cognitive function was in the normal range before and after HSCT. Significant correlations between HRQoL and neuropsychological parameters were related to symptom scales. This study showed impairments of neuropsychological performance for a subgroup of patients before and after allogeneic HSCT. Systematic effects of conditioning, medical variables or self-rated HRQoL could not be observed.

  18. Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients.

    PubMed

    Lengliné, E; Chevret, S; Moreau, A-S; Pène, F; Blot, F; Bourhis, J-H; Buzyn, A; Schlemmer, B; Socié, G; Azoulay, E

    2015-06-01

    Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits.

  19. YKL-40 in allogeneic hematopoietic cell transplantation after acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Kornblit, Brian; Wang, Tao; Lee, Stephanie J.; Spellman, Stephen R.; Zhu, Xiaochun; Fleischhauer, Katharina; Müller, Carlheinz; Verneris, Michael R.; Müller, Klaus; Johansen, Julia S.; Vindelov, Lars; Garred, Peter

    2016-01-01

    YKL-40, also called chitinase3-like-1 protein, is an inflammatory biomarker which has been associated with disease severity in inflammatory and malignant diseases, including acute myeloid leukemia (AML), multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pre-transplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (MDS) (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ≥5 (p=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age adjusted 95th percentile a trend towards increased grade II-IV acute graft versus host disease in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00–1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available. PMID:27427920

  20. Second allogeneic hematopoietic cell transplantation for Patients with Fanconi anemia and Bone Marrow Failure

    PubMed Central

    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

    2015-01-01

    Second allogeneic hematopoietic cell transplantation (HCT) is the only salvage option for those for develop graft failure after their first HCT. Data on outcomes after second HCT in Fanconi anemia (FA) are scarce. We report outcomes after second allogeneic HCT for FA (n=81). The indication for second HCT was graft failure after the first HCT. Transplants occurred between 1990 and 2012. The timing of second transplantation predicted subsequent graft failure and survival. Graft failure was high when the second transplant occurred less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between first and second transplant was less than 3 months compared to 23% when the interval was longer (p<0.001). Consequently, survival rates were substantially lower when the interval between first and second transplant was less than 3 months, 23% at 1-year compared to 58%, when the interval was longer (p=0.001). The corresponding 5-year probabilities of survival were 16% and 45%, respectively (p=0.006). Taken together, these data suggest that fewer than half of FA patients undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to lower graft failure after first HCT. PMID:26116087

  1. Is ABO mismatch another risk factor for allogeneic hematopoietic stem cell transplantation in pediatric thalassemic patients?

    PubMed

    Atay, Didem; Erbey, Fatih; Akcay, Arzu; Ozturk, Gulyuz

    2015-09-01

    The ABO incompatibility between donor and recipient is not considered a barrier to successful allogeneic HSCT. Nevertheless, conflicting data still exist about the influence of ABO incompatibility on transplant outcome in pediatric patients with thalassemia. Fifty-one children with beta-thalassemia major who underwent allogeneic HSCT were enrolled this study. Twenty-three of them (45%) received an ABO-incompatible transplant [minor ABO mismatch: six (26%), major ABO mismatch: fourteen (61%), and bidirectional mismatch: three (13%)]. In this study, ABO incompatibility did not significantly impair GVHD, VOD, neutrophil and platelet engraftment, TRM, OS and TFS. Particularly in major and bidirectional ABO-mismatched patients, a delayed erythroid recovery was recorded as compared to the group receiving an ABO-compatible graft (median time, 31 and 38 days vs. 19.5 days; p: 0.02 and p: 0.03). Median time to red cell transfusion independence was significantly longer in major ABO-incompatible patients (median time, 87 days vs. 32 days; p: 0.001). Therefore, whenever feasible, major ABO-mismatched donors should be avoided in HSCT recipients, to prevent delayed erythroid recovery with prolonged RBC transfusion needs and impaired quality of life.

  2. Neural signaling in the spleen controls B-cell responses to blood-borne antigen.

    PubMed

    Mina-Osorio, Paola; Rosas-Ballina, Mauricio; Valdes-Ferrer, Sergio I; Al-Abed, Yousef; Tracey, Kevin J; Diamond, Betty

    2012-05-09

    Entry of blood-borne pathogens into the spleen elicits a series of changes in cellular architecture that culminates in the systemic release of protective antibodies. Despite an abundance of work that has characterized these processes, the regulatory mechanisms that coordinate cell trafficking and antibody production are still poorly understood. Here, marginal zone (MZ) B cells responding to streptococcus in the blood were observed to migrate along splenic nerves, arriving at the red pulp venous sinuses where they become antibody-secreting cells. Electrical stimulation of the vagus nerve, which in turn regulates the splenic nerve, arrested B-cell migration and decreased antibody secretion. Thus, neural circuits regulate the first wave of antibody production following B-cell exposure to blood-borne antigen.

  3. Effects of several salt marsh plants on mouse spleen and thymus cell proliferation using mtt assay

    NASA Astrophysics Data System (ADS)

    Seo, Youngwan; Lee, Hee-Jung; Kim, You Ah; Youn, Hyun Joo; Lee, Burm-Jong

    2005-12-01

    In the present study, we have tested the effects of 21 salt marsh plants on cell proliferation of mouse immune cells (spleen and thymus) using MTT assay in culture. The methanolic extracts of six salt marsh plants ( Rosa rugosa, Ixeris tamagawaensis, Artemisia capillaris, Tetragonia tetragonoides, Erigeron annus, and Glehnia littoralis) showed very powerful suppressive effects of mouse immune cell death and significant activities of cell proliferation in vitro. Especially, the methanolic extract of Rosa rugosa was found to have fifteen times compared to the control treatment, demonstrating that Rosa rugosa may have a potent stimulation effect on immune cell proliferation. These results suggest that several salt marsh plants including Rosa rugosa could be useful for further study as an immunomodulating agent.

  4. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study

    PubMed Central

    Ferreira, Érika Elias; Guerra, Daiane Cristina; Baluz, Kátia; de Resende Furtado, Wander; da Silva Bouzas, Luis Fernando

    2014-01-01

    Objective This study aimed to describe and compare the nutritional status of adult patients submitted to allogeneic hematopoietic stem cell transplantation at two different time points (admission and discharge). Methods A retrospective, descriptive and quantitative study was performed based on clinical, laboratory and nutritional data obtained from medical records of adult patients of both genders submitted to allogeneic hematopoietic stem cell transplantation in a bone marrow transplantation reference center in Rio de Janeiro in the period from 2010 to 2013. Statistical analysis was performed using the SPSS software (version 22.0). Results Sixty-four patients were evaluated. The mean age was 42.1 ± 3.2 years and the most prevalent disease was acute myeloid leukemia (39%). There was a high prevalence of gastrointestinal symptoms including nausea (100%), vomiting (97%) and mucositis (93%). Between admission and discharge there was a significant decrease in the median weight (−2.5 kg; 71.5 vs. 68.75 kg; p-value < 0.001), body mass index (−0.9 kg/m2; 24.8 vs. 24.4 kg/m2; p-value < 0.001), and serum albumin levels (−0.2 g/dL; 3.7 vs. 3.6 g/dL; p-value = 0.024). The survival time after hematopoietic stem cell transplantation correlated negatively with C-reactive protein at discharge (CC = −0.72; p-value < 0.001) and positively with serum albumin levels (CC = 0.56; p-value = 0.004) and with high total protein level at discharge (CC = 0.53; p-value = 0.006). Conclusion Our results suggest that patients submitted to allogeneic hematopoietic stem cell transplantation have compromised nutritional status during the hospital stay for transplantation. PMID:25453651

  5. Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient.

    PubMed

    Osthoff, M; Chew, E; Bajel, A; Kelsey, G; Panek-Hudson, Y; Mason, K; Szer, J; Ritchie, D; Slavin, M

    2013-02-01

    Toxoplasmosis is increasingly diagnosed after hematopoietic stem cell transplantation (HSCT) and is associated with considerable morbidity and mortality. In the majority of cases, reactivation of latent disease secondary to impaired cellular and humoral immunity after HSCT is believed to be the main pathogenetic mechanism. Hence, primary toxoplasmosis is rarely considered in the differential diagnosis of infections after HSCT in a recipient who is seronegative for Toxoplasma gondii pre-transplant. We herein report a seronegative patient with acute T-cell lymphoblastic leukemia, who developed primary disseminated toxoplasmosis 5 months after HSCT from a seronegative unrelated donor. A review of all reported cases of primary toxoplasmosis after HSCT revealed significantly increased morbidity and mortality. Patients with negative pre-transplant Toxoplasma serology should therefore be considered at risk for toxoplasmosis after allogeneic HSCT. Possible prevention and monitoring strategies for seronegative recipients are reviewed and discussed in detail.

  6. BK virus-hemorrhagic cystitis following allogeneic stem cell transplantation: Clinical characteristics and utility of leflunomide treatment.

    PubMed

    Park, Young Hoon; Lim, Joo Han; Yi, Hyeon Gyu; Lee, Moon Hee; Kim, Chul Soo

    2016-04-18

    BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC.

  7. 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.

  8. Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

    PubMed Central

    Kashiyama, Noriyuki; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kawamura, Ai; Yoshida, Shohei; Harada, Akima; Watabe, Tadashi; Kanai, Yasukazu; Toda, Koichi; Hatazawa, Jun; Sawa, Yoshiki

    2016-01-01

    Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of

  9. Durable Scar Size Reduction Due to Allogeneic Mesenchymal Stem Cell Therapy Regulates Whole‐Chamber Remodeling

    PubMed Central

    Williams, Adam R.; Suncion, Viky Y.; McCall, Frederic; Guerra, Danny; Mather, Jacques; Zambrano, Juan P.; Heldman, Alan W.; Hare, Joshua M.

    2013-01-01

    Background Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. Methods and Results Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post‐MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3‐dimensional cardiac magnetic resonance imaging angiography–derived anatomy to accurately target infarct border zone injections. MSC‐treated animals had a 19.62±2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09±2.31% from 3 to 6 months postinjection (P<0.0001). MSC‐treated animals had unchanged end‐diastolic volume (EDV; P=0.08) and end‐systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC‐treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69±1.68% to 35.85±2.74% at 3 months post‐MSC injection and progressed to 39.02±2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow‐up (P=0.33). Conclusion Intramyocardial injection of allogeneic MSCs leads to a sustained and

  10. Interferon-gamma associated cytokines and chemokines produced by spleen cells from Brucella-immune mice.

    PubMed

    Paranavitana, Chrysanthi; Zelazowska, Elzbieta; Izadjoo, Mina; Hoover, David

    2005-04-21

    It is known that interferon (IFN)-gamma plays a critical role in protection against brucellosis. In this study we have investigated several cytokines and chemokines that are associated with IFN-gamma for potential in vitro correlates of protection. We cultured spleen cells in vitro from mice immunized orally with a live, attenuated Brucella melitensis vaccine candidate (WR201) and stimulated these cells with a lysate of B. melitensis. Differential gene expression of several cytokines and chemokines in stimulated spleen cells was analysed by real-time PCR, and secreted proteins were determined by ELISA. Immunized mice produced higher levels of both protein and gene transcripts for IFN-gamma, interleukin (IL)-2, IL-18 and MIP1-alpha. Immunized mice also had elevated gene expression levels for IL12-p40, IL23-p19, IP-10, MIG and MCP-1 when compared to normal mice. In this study we have identified new cytokines and chemokines as potential immune correlates in responses to protection in Brucella-vaccinated mice.

  11. Varying Dietary Levels of Molybdenum Inducing Cell Apoptosis of Spleen Under Cadmium Stress in Caprine.

    PubMed

    Xiao, Qingyang; Zhang, Caiying; Gu, Xiaolong; Zhuang, Yu; Luo, Junrong; Liu, Ping; Guo, Xiaoquan; Hu, Guoliang; Cao, Huabin

    2016-07-01

    The present experiment aims at evaluating chronic toxic effects of the combination of cadmium (Cd) and molybdenum (Mo) according to residual element contents, apoptosis gene expression, and ultrastructure and histopathology changes of caprine spleen. In total, 36 Boer goats were randomly divided into four groups with the equal number in each group. The control group was orally administered with deionized water while the experimental groups I, II, and III were administered with the equal quantity of CdCl2 (1 mg kg(-1) BW) and (NH4)6·Mo7O24·4H2O including 15, 30, and 45 mg·Mo kg(-1) BW, respectively. Three individuals from each group were treated with euthanasia on days 0, 25, and 50. The data showed that the content of splenic residual Mo and Cd increased (P < 0.05) in the experimental groups on days 25 and 50, while no significant difference was observed in the content of Cu. The apoptosis-related gene expression levels including Bcl-2, Bax, Caspase-3, Smac, and ceruloplasmin (CP) were also determined. Results showed that significant reductions were observed in Bcl-2 and CP expressions (P < 0.01), while Caspase-3 gene was up-regulated (P < 0.05). However, no significant difference was observed in Smac and Bax expressions. Furthermore, on day 50, spleen tissues were presented to observe ultrastructural changes in lesions by means of transmission electron microscopy, with fragmentized nucleus, vesiculation of cytoplasm, mitochondria hyperplasia, and increasing lysosomes included. In addition, histopathology results corroborated the toxicity by showing cell hemorrhage, thickening central arteries, and enhanced capsule thickness. To sum up, our study revealed that the combination of Cd and Mo could induce remarkable damage to the spleen of goats by promoting cell apoptosis in the mitochondrial pathway and affecting the deposition of Mo and Cd.

  12. Cell apoptosis of caprine spleen induced by toxicity of cadmium with different levels of molybdenum.

    PubMed

    Gu, Xiaolong; Chen, Rongrong; Hu, Guoliang; Zhuang, Yu; Luo, Junrong; Zhang, Caiying; Guo, Xiaoquan; Huang, Aiming; Cao, Huabin

    2015-07-01

    In order to clarify the effects of the combination of Mo and Cd on goat and relationship between the two elements, combined chronic toxicity of cadmium with different levels of molybdenum in vivo on apoptosis gene and ultrastructure of spleen was evaluated with the methods of RT-qPCR and transmission electron microscopy. A total of thirty-six goats were randomly distributed in equal number into four groups. These groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mgCd kg(-1)) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1), group I; 30 mg Mo kg(-1), group II; 45 mg Mo kg(-1), group III), while the control group received deionized water. Spleen tissues were taken from individual goat at different time intervals to measure the levels of apoptosis genes including Bcl-2, Bax, Cyt c, Caspase-3, Smac and ceruloplasmin (Cp). The results revealed that a significant suppression in Bcl-2 expression and increase in Cyt c, Caspase-3 and Cp expression in splenic cells. The Bax expression in group I and II was up-regulated, however, it displayed reduction in group III, whereas no statistical significance was observed on Smac expression. In addition, histopathologic injury revealed remarkable morphplogical changes on the splenocytes in the means of apoptosis including fragmentized nucleus, apoptotic body and vesiculation of cytoplasma and mitochondria. Taken together, combined chronic toxicity of cadmium with different levels of molybdenum induce goat spleen cell apoptosis associated with mitochondrial intrinsic pathway, and the two elements showed possible antergic relationship.

  13. Disorder of G2-M Checkpoint Control in Aniline-Induced Cell Proliferation in Rat Spleen.

    PubMed

    Wang, Jianling; Wang, Gangduo; Khan, M Firoze

    2015-01-01

    Aniline, a toxic aromatic amine, is known to cause hemopoietic toxicity both in humans and animals. Aniline exposure also leads to toxic response in spleen which is characterized by splenomegaly, hyperplasia, fibrosis and the eventual formation of tumors on chronic in vivo exposure. Previously, we have shown that aniline exposure leads to iron overload, oxidative DNA damage, and increased cell proliferation, which could eventually contribute to a tumorigenic response in the spleen. Despite our demonstration that cell proliferation was associated with deregulation of G1 phase cyclins and increased expression of G1 phase cyclin-dependent kinases (CDKs), molecular mechanisms, especially the regulation of G2 phase and contribution of epigenetic mechanisms in aniline-induced splenic cellular proliferation remain largely unclear. This study therefore, mainly focused on the regulation of G2 phase in an animal model preceding a tumorigenic response. Male Sprague-Dawley rats were given aniline (0.5 mmol/kg/day) in drinking water or drinking water only (controls) for 30 days, and expression of G2 phase cyclins, CDK1, CDK inhibitors and miRNAs were measured in the spleen. Aniline treatment resulted in significant increases in cell cycle regulatory proteins, including cyclins A, B and CDK1, particularly phosphor-CDK1, and decreases in CDK inhibitors p21 and p27, which could promote the splenocytes to go through G2/M transition. Our data also showed upregulation of tumor markers Trx-1 and Ref-1 in rats treated with aniline. More importantly, we observed lower expression of miRNAs including Let-7a, miR-15b, miR24, miR-100 and miR-125, and greater expression of CDK inhibitor regulatory miRNAs such as miR-181a, miR-221 and miR-222 in the spleens of aniline-treated animals. Our findings suggest that significant increases in the expression of cyclins, CDK1 and aberrant regulation of miRNAs could lead to an accelerated G2/M transition of the splenocytes, and potentially to a

  14. Antigen Presenting Properties of a Myeloid Dendritic-Like Cell in Murine Spleen.

    PubMed

    Hey, Ying-Ying; O'Neill, Helen C

    This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named "L-DC" since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11bhiCD11cloMHCII-CD43+Ly6C-Ly6G-Siglec-F- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4+ T cells, they are capable of antigen cross-presentation for activation of CD8+ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8- cDC and CD8+ cDC are quite distinct from L-DC. CD8+ cDC are distinguishable from the other two subsets by expression of CD24a, Clec9a, Xcr1 and Tlr11, while CD8- cDC are distinguished by expression of Ccnd1 and H-2Eb2. L-DC are distinct from the two cDC subsets through upregulated expression of Clec4a3, Emr4, Itgam, Csf1r and CD300ld. The L-DC gene profile is quite distinct from that of cDC, confirming a myeloid cell type with distinct antigen presenting properties.

  15. Long Term Incidence of Secondary Malignancies Following Allogeneic Hematopoietic Cell Transplantation: a Single Center Experience.

    PubMed

    Michelis, Fotios V; Kotchetkov, Rouslan; Grunwald, Rebecca M; Azeem, Aamir; Atenafu, Eshetu G; Lipton, Jeffrey H; Loach, David; Gupta, Vikas; Kuruvilla, John; Kim, Dennis D; Viswabandya, Auro; Deotare, Uday; Messner, Hans A

    2017-02-27

    To review the emergence of secondary malignancies (SM) in recipients of allogeneic hematopoietic cell transplantation (HCT). We documented the occurrence of SM in 2415 allogeneic HCT recipients, ages 18-71, in a single center over four decades. SM was seen in 209 patients, including 58 with non-metastatic squamous cell (SCC) and basal cell carcinoma (BCC) of the skin. Cumulative incidence of SM was 6.3% at 10 years, 13.5% at 20 years and 17.6% at 30 years post-HCT. Median age at diagnosis of SM was 61 years (range 21-85). By multivariable analysis, older age at HCT was the only independent prognostic factor for SM (HR=1.39 for age 41-55 and HR=1.92 for age >55 compared to age ≤40, p=0.001). The rate of SM (excluding non-metastatic SCC/BCC of skin) after HCT was 2.07 times higher (p=0.01) compared to the general population. Overall survival (OS) following diagnosis of SM (excluding non-metastatic SCC/BCC of skin) was 58% at 5 years and 50% at 10 years post-diagnosis. ECOG score was the only independent predictor of OS on multivariable analysis, with over 2 fold increased risk of death for patients with an ECOG score of 1 and over 6 fold for ECOG 2-4, compared to ECOG score 0 (p<0.0001). Forty (19%) of the 209 patients diagnosed with SM subsequently developed another new malignancy. OS was 68% and 51% at 5 and 10 years, respectively. The survival of SM patients post-HCT is favorable, thus warranting diligent long-term cancer screening and standard of care treatment. ECOG status of these patients is a predominant prognostic factor.

  16. Cryptozoospermia with normal testicular function after allogeneic stem cell transplantation: a case report.

    PubMed

    Tauchmanovà, L; Alviggi, C; Foresta, C; Strina, I; Garolla, A; Colao, A; Lombardi, G; De Placido, G; Rotoli, B; Selleri, C

    2007-02-01

    One of the most frequent consequences of allogeneic haemopoietic stem cell transplantation (allo-SCT) in both males and females is gonadal insufficiency. We report the case of a 27-year-old myelodysplastic male who developed azoospermia after allogeneic transplantation of haemopoietic stem cells from his HLA-identical sister. Post-transplant azoospermia was alternated with intermittent severe oligospermia. The patient had a normal endocrine pattern and evidence of mild chronic graft-versus-host disease (cGVHD). Normal intratesticular spermatogenesis was revealed by bilateral fine needle aspiration (FNA) cytology. Inflammation was evident at semen analysis, but no infection was detected by microbiological examination and sperm culture. These findings, together with the re-appearance of sperm cells at semen analysis after a low-dose immunosuppressive treatment, suggested the presence of cGVHD of the urogenital tract, causing a reversible obstruction of the spermatic tract and cryptozoospermia. This is the first case report documenting a severe impairment of sperm count because of a reversible obstruction of the seminal tract, likely caused by cGVHD, in a long-term survivor of allo-SCT with normal endocrine pattern. An important practical consequence of this case report is the fact that azoospermia was cured using low-dose immunosuppressive therapy, and this allowed us to avoid expensive stimulatory treatments with gonadotrophins, which remain, however, ineffective if the obstruction of spermatic tracts is not removed. A spontaneous uncomplicated pregnancy occurred in the partner of the patient 3 months after the corticosteroid treatment withdrawal.

  17. High frequency of donor chimerism after allogeneic transplantation of CD34+-selected peripheral blood cells.

    PubMed

    Briones, J; Urbano-Ispizua, A; Lawler, M; Rozman, C; Gardiner, N; Marín, P; Salgado, C; Féliz, P; McCann, S; Montserrat, E

    1998-05-01

    Ex vivo T cell depletion of allogeneic grafts is associated with a high (up to 80%) rate of mixed chimerism (MC) posttransplantation. The number of transplanted progenitor cells is an important factor in achieving complete donor chimerism in the T cell depletion setting. Use of granulocyte colony-stimulating factor (G-CSF) peripheral blood allografts allows the administration of large numbers of CD34+ cells. We studied the chimeric status of 13 patients who received allogeneic CD34+-selected peripheral blood progenitor cell transplants (allo-PBPCTs/CD34+) from HLA-identical sibling donors. Patients were conditioned with cyclophosphamide (120 mg/kg) and total-body irradiation (13 Gy in four fractions). Apheresis products were T cell-depleted by the immunoadsorption avidin-biotin method. The median number of CD34+ and CD3+ cells infused was 2.8x10(6)/kg (range 1.9-8.6x10(6)/kg) and 0.4x10(6)/kg (range 0.3-1x10(6)/kg), respectively. Molecular analysis of the engraftment was performed using polymerase chain reaction (PCR) amplification of highly polymorphic short tandem repeat (PCR-STR) sequences in peripheral blood samples. MC was detected in two (15%) of 13 patients. These two patients relapsed at 8 and 10 months after transplant, respectively. The remaining 11 patients showed complete donor chimerism and were in clinical remission after a maximum follow-up period of 24 months (range 6-24 months). These results were compared with those obtained in 10 patients who were treated with T cell-depleted bone marrow transplantation by means of elutriation and who received the same conditioning treatment and similar amounts of CD3+ cells (median 0.45x10(6)/kg; not significant) but a lower number of CD34+ cells (median 0.8x10(6)/kg; p = 0.001). MC was documented in six of 10 patients (60%), which was significantly higher than in the allo-PBPCT/CD34+ group (p = 0.04). We conclude that a high frequency of complete donor chimerism is achieved in patients receiving allo-PBPCT/CD34

  18. Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen.

    PubMed

    Wang, Jianling; Wang, Gangduo; Ma, Huaxian; Khan, M Firoze

    2011-01-15

    Aniline exposure is associated with toxicity to the spleen leading to splenomegaly, hyperplasia, fibrosis and a variety of sarcomas of the spleen on chronic exposure. In earlier studies, we have shown that aniline exposure leads to iron overload, oxidative stress and activation of redox-sensitive transcription factors, which could regulate various genes leading to a tumorigenic response in the spleen. However, molecular mechanisms leading to aniline-induced cellular proliferation in the spleen remain largely unknown. This study was, therefore, undertaken on the regulation of G1 phase cell cycle proteins (cyclins), expression of cyclin-dependent kinases (CDKs), phosphorylation of retinoblastoma protein (pRB) and cell proliferation in the spleen, in an experimental condition preceding a tumorigenic response. Male SD rats were treated with aniline (0.5 mmol/kg/day via drinking water) for 30 days (controls received drinking water only), and splenocyte proliferation, protein expression of G1 phase cyclins, CDKs and pRB were measured. Aniline treatment resulted in significant increases in splenocyte proliferation, based on cell counts, cell proliferation markers including proliferating cell nuclear antigen (PCNA), nuclear Ki67 protein (Ki67) and minichromosome maintenance (MCM), MTT assay and flow cytometric analysis. Western blot analysis of splenocyte proteins from aniline-treated rats showed significantly increased expression of cyclins D1, D2, D3 and E, as compared to the controls. Similarly, real-time PCR analysis showed significantly increased mRNA expression for cyclins D1, D2, D3 and E in the spleens of aniline-treated rats. The overexpression of these cyclins was associated with increases in the expression of CDK4, CDK6, CDK2 as well as phosphorylation of pRB protein. Our data suggest that increased expression of cyclins, CDKs and phosphorylation of pRB protein could be critical in cell proliferation, and may contribute to aniline-induced tumorigenic response in

  19. Enhanced expression of cyclins and cyclin-dependent kinases in aniline-induced cell proliferation in rat spleen

    SciTech Connect

    Wang Jianling; Wang Gangduo; Ma Huaxian; Khan, M. Firoze

    2011-01-15

    Aniline exposure is associated with toxicity to the spleen leading to splenomegaly, hyperplasia, fibrosis and a variety of sarcomas of the spleen on chronic exposure. In earlier studies, we have shown that aniline exposure leads to iron overload, oxidative stress and activation of redox-sensitive transcription factors, which could regulate various genes leading to a tumorigenic response in the spleen. However, molecular mechanisms leading to aniline-induced cellular proliferation in the spleen remain largely unknown. This study was, therefore, undertaken on the regulation of G1 phase cell cycle proteins (cyclins), expression of cyclin-dependent kinases (CDKs), phosphorylation of retinoblastoma protein (pRB) and cell proliferation in the spleen, in an experimental condition preceding a tumorigenic response. Male SD rats were treated with aniline (0.5 mmol/kg/day via drinking water) for 30 days (controls received drinking water only), and splenocyte proliferation, protein expression of G1 phase cyclins, CDKs and pRB were measured. Aniline treatment resulted in significant increases in splenocyte proliferation, based on cell counts, cell proliferation markers including proliferating cell nuclear antigen (PCNA), nuclear Ki67 protein (Ki67) and minichromosome maintenance (MCM), MTT assay and flow cytometric analysis. Western blot analysis of splenocyte proteins from aniline-treated rats showed significantly increased expression of cyclins D1, D2, D3 and E, as compared to the controls. Similarly, real-time PCR analysis showed significantly increased mRNA expression for cyclins D1, D2, D3 and E in the spleens of aniline-treated rats. The overexpression of these cyclins was associated with increases in the expression of CDK4, CDK6, CDK2 as well as phosphorylation of pRB protein. Our data suggest that increased expression of cyclins, CDKs and phosphorylation of pRB protein could be critical in cell proliferation, and may contribute to aniline-induced tumorigenic response in

  20. Allogeneic Hematopoietic Cell Transplantation for Myeloma: When and in Whom Does It Work.

    PubMed

    Bashir, Qaiser; Qazilbash, Muzaffar H

    2017-03-11

    The growing list of available therapies for patients with multiple myeloma has resulted in tremendously high response rates and prolonged survival. However, the cure remains elusive. A continued effort at developing strategies to utilize all available treatment modalities in the most effective manner is needed. Allogeneic hematopoietic cell transplantation (allo-HCT) is a robust platform, associated with high response rates, and provides a unique foundation on which immune therapies and novel agents can be employed to improve clinical outcomes. Patients with high-risk myeloma and those relapsing after novel agent-based therapies or early after an autologous HCT should be considered for allo-HCT, ideally in a clinical trial setting. Results from several ongoing studies are expected to provide important information that will help determine the place of allo-HCT in the myeloma treatment algorithm.

  1. How I treat late effects in adults after allogeneic stem cell transplantation

    PubMed Central

    Griffith, Michelle L.; Jagasia, Shubhada; Lee, Stephanie J.

    2011-01-01

    More than 25 000 allogeneic hematopoietic stem cell transplantations (allo-HCTs) are expected to be performed worldwide in 2010, a number that has been increasing yearly. With broadening indications, more options for allo-HCT, and improvement in survival, by 2020 there may be up to half a million long-term survivors after allo-HCT worldwide. These patients have increased risks for various late complications, which can cause morbidity and mortality. Most long-term survivors return to the care of their local hematologists/oncologists or primary care physicians, who may not be familiar with specialized monitoring recommendations for this patient population. The purpose of this article is to describe practical approaches to screening for and managing these late effects, with the goal of reducing preventable morbidity and mortality associated with allo-HCT. PMID:21193694

  2. Inhibition of adenylate cyclase by delta 9-tetrahydrocannabinol in mouse spleen cells: a potential mechanism for cannabinoid-mediated immunosuppression.

    PubMed

    Schatz, A R; Kessler, F K; Kaminski, N E

    1992-01-01

    The ability of delta 9-Tetrahydrocannabinol (delta 9-THC) to modulate adenylate cyclase activity in mouse spleen cells was investigated. These studies were prompted by the recent identification and cloning of a G-protein coupled cannabinoid receptor localized in certain regions of the brain and the potential for a common mechanism between cannabinoid-mediated CNS effects and immunosuppression. Temporal addition studies were initially performed to identify the period of time when spleen cells in culture were most susceptible to the inhibitory effects of delta 9-THC, as measured by the day 5 IgM antibody forming cell response. delta 9-THC was only inhibitory when added to spleen cell cultures during the first 2 hr following antigen sensitization. In light of this time course, adenylate cyclase activity was measured in spleen cells incubated in the presence of 22 microM delta 9-THC for 5 min and subsequently stimulated with forskolin. delta 9-THC treated spleen cells demonstrated a 33% inhibition and a 66% inhibition in intracellular cAMP after a 5 or 15 min stimulation with forskolin, respectively. These studies suggest that inhibition of immune function by delta 9-THC may be mediated through the inhibition of intracellular cAMP early after antigen stimulation.

  3. Comparison of autogenic and allogenic bone marrow derived mesenchymal stem cells for repair of segmental bone defects in rabbits.

    PubMed

    Udehiya, Rahul Kumar; Amarpal; Aithal, H P; Kinjavdekar, P; Pawde, A M; Singh, Rajendra; Taru Sharma, G

    2013-06-01

    Autogenic and allogenic bone marrow derived mesenchymal stem cells (BM-MSCs) were compared for repair of bone gap defect in rabbits. BM-MSCs were isolated from bone marrow aspirates and cultured in vitro for allogenic and autogenic transplantation. A 5mm segmental defect was created in mid-diaphysis of the radius bone. The defect was filled with hydroxyapatite alone, hydroxyapatite with autogeneic BM-MSCs and hydroxyapatite with allogenic BM-MSCs in groups A, B and C, respectively. On an average 3.45×10(6) cells were implanted at each defect site. Complete bridging of bone gap with newly formed bone was faster in both treatment groups as compared to control group. Histologically, increased osteogenesis, early and better reorganization of cancellous bone and more bone marrow formation were discernible in treatment groups as compared to control group. It was concluded that in vitro culture expanded allogenic and autogenic BM-MSCs induce similar, but faster and better healing as compared to control.

  4. Immunogenicity of Decidual Stromal Cells in an Epidermolysis Bullosa Patient and in Allogeneic Hematopoietic Stem Cell Transplantation Patients

    PubMed Central

    Carlson, Lena-Maria; Erkers, Tom; Nava, Silvia; Molldén, Pia; Gustafsson, Britt; Qian, Hua; Li, Xiaoguang; Hashimoto, Takashi; Sadeghi, Behnam; Alheim, Mats; Ringdén, Olle

    2015-01-01

    Allogeneic mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but little is known about their immunogenicity. In this study, we monitored the therapeutic and immunogenic effects of decidual stromal cells (DSCs) from term placentas when used as a therapy for generalized severe junctional epidermolysis bullosa (JEB) (previously termed Herlitz JEB), a lethal condition caused by the lack of functional laminin-332. An 11-month-old JEB patient was treated with five infusions of allogeneic DSCs within a 3-month period. Amniotic membranes (AMs) were applied to severe wounds. After the treatment, wounds started to heal in the middle of the blisters, but the improvements were transient. After two infusions of DSCs, the JEB patient had developed multispecific anti-HLA class-I antibodies. No antibodies to laminin-332 were detected, but the patient had high levels of anti-bovine serum albumin antibodies, which could bind to DSCs. Peripheral blood mononuclear cells (PBMCs) from the patient had a higher proliferative response to DSCs than to third-party PBMCs, which contrasts with the pattern observed in healthy donors. Human DSCs and MSCs induced similar xenoreactivity in mice. Two of 16 allogeneic stem cell-transplanted patients, treated with DSCs for graft-versus-host disease or hemorrhagic cystitis, showed a positive flow cytometric crossmatch test. One patient had anti-HLA antibodies before DSC infusion, whereas the other had no anti-HLA antibodies at any time. AM and DSC infusions may have improved the healing process in the JEB patient, but DSCs appeared to induce anti-HLA antibodies. The risk of alloimmunization by DSCs seems to be low in immunocompromised patients. PMID:25658253

  5. Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.

    PubMed

    Besser, Michal J; Shoham, Tsipi; Harari-Steinberg, Orit; Zabari, Naama; Ortenberg, Rona; Yakirevitch, Arkadi; Nagler, Arnon; Loewenthal, Ron; Schachter, Jacob; Markel, Gal

    2013-01-01

    Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.

  6. Correlation of Pain and Fluoride Concentration in Allogeneic Hematopoietic Stem Cell Transplant Recipients on Voriconazole.

    PubMed

    Barajas, Megan R; McCullough, Kristen B; Merten, Julianna A; Dierkhising, Ross A; Bartoo, Gabriel T; Hashmi, Shahrukh K; Hogan, William J; Litzow, Mark R; Patnaik, Mrinal M; Wilson, John W; Wolf, Robert C; Wermers, Robert A

    2016-03-01

    Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase

  7. Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients.

    PubMed

    Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu; Stednick, Zach; Callais, Cheryl; Leisenring, Wendy M; Englund, Janet A; Chien, Jason W; Boeckh, Michael

    2016-05-01

    Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P < .0001) at day 80 and r = .931 (P < .0001) at 1 year when the handheld and laboratory tests were performed within 1 day of each other. Correlation for handheld forced expiratory volume in 6 seconds (FEV6) with laboratory forced vital capacity was r = .914 (P < .0001) at day 80 and r = .826 (P < .0001) at 1 year. The bias, or the mean difference (handheld minus laboratory), for FEV1 at day 80 and 1 year was -.13 L (limits of agreement, -.63 to .37) and -.10 L (limits of agreement, -.77 to .56), respectively. FEV6 showed greater bias at day 80 (-.51 L [limits of agreement, -1.44 to .42]) and 1 year (-.40 L [limits of agreement, -1.81 to 1.01]). Handheld spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction.

  8. Absolute lymphocyte count recovery after allogeneic hematopoietic stem cell transplantation predicts clinical outcome.

    PubMed

    Kim, Haesook T; Armand, Philippe; Frederick, David; Andler, Emily; Cutler, Corey; Koreth, John; Alyea, Edwin P; Antin, Joseph H; Soiffer, Robert J; Ritz, Jerome; Ho, Vincent T

    2015-05-01

    Immune reconstitution is critical for clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT). To determine the impact of absolute lymphocyte count (ALC) recovery on clinical outcomes, we conducted a retrospective study of 1109 adult patients who underwent a first allogeneic HSCT from 2003 through 2009, excluding patients who died or relapsed before day 30. The median age was 51 years (range, 18 to 74) with 52% undergoing reduced-intensity conditioning and 48% undergoing myeloablative conditioning HSCT with T cell-replete peripheral blood stem cells (93.7%) or marrow (6.4%) grafts. The median follow-up time was 6 years. To determine the threshold value of ALC for survival, the entire cohort was randomly split into a training set and a validation set in a 1:1 ratio, and then a restricted cubic spline smoothing method was applied to obtain relative hazard estimates of the relationship between ALC at 1 month and log hazard of progression-free survival (PFS). Based on this approach, ALC was categorized as ≤.2 × 10(9) cells/L (low) or >.2 × 10(9) cells/L. For patients with low ALC at 1, 2, or 3 months after HSCT, the overall survival (OS) (P ≤ .0001) and PFS (P ≤ .0002) were significantly lower and nonrelapse mortality (NRM) (P ≤ .002) was significantly higher compared with patients with ALC > .2 × 10(9) cells/L at each time point. When patients who had low ALC at 1, 2, or 3 months after HSCT were grouped together and compared, their outcomes were inferior to those of patients who had ALC > .2 × 10(9) cells/L at 1, 2, and 3 months after HSCT: the 5-year OS for patients with low ALC was 28% versus 46% for patients with ALC > .2 × 10(9) cells/L, P < .0001; the 5-year PFS was 21% versus 39%, P < .0001, respectively and 5-year NRM was 40% versus 18%, P < .0001, respectively. This result remained consistent when other prognostic factors, including occurrence of grade II to IV acute graft-versus-host disease (GVHD), were adjusted for in

  9. Major non-ABO incompatibility caused by anti-Jk(a) in a patient before allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kim, M Y; Chaudhary, P; Shulman, I A; Pullarkat, V

    2013-01-01

    A 49-year-old white man with blood group AB, D+ was found to have alloanti-Jk(a) and -K when he developed a delayed hemolytic transfusion reaction before allogeneic hematopoietic stem cell transplant (HSCT). Given that his stem cell donor was blood group O, D+, Jk(a+), K-, rituximab was added to his conditioning regimen of fludarabine and melphalan to prevent hemolysis of engrafting Jk(a+) donor red blood cells. The patient proceeded to receive a peripheral blood stem cell transplant from a matched unrelated donor with no adverse events. To our knowledge, this is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature.

  10. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma.

    PubMed

    Schilling, G; Hansen, T; Shimoni, A; Zabelina, T; Pérez-Simón, J-A; Simon-Perez, J-A; Gutierrez, N C; Bethge, W; Liebisch, P; Schwerdtfeger, R; Bornhäuser, M; Otterstetter, S; Penas, E M M; Dierlamm, J; Ayuk, F; Atanackovic, D; Bacher, U; Bokemeyer, C; Zander, A; San Miguel, J; Miguel, J S; Nagler, A; Kröger, N

    2008-06-01

    We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.

  11. Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia.

    PubMed

    Menon, Neethu N; Jenkins, Lydia M; Cui, Haiyan; Jenkins, Craig; Anwer, Faiz; Yeager, Andrew M; Katsanis, Emmanuel

    2016-03-01

    A second allogeneic (allo) hematopoietic cell transplant (HCT) is an important therapeutic consideration for patients relapsing after their first. We conducted a retrospective review of 41 pediatric patients with leukemia that underwent a second allo-HCT at our institution. Overall, 53.7 and 43.9 % of patients were alive and disease-free at 1 and 5 years, respectively, after the second allo-HCT. The factors affecting outcome by both univariate and multivariate analysis were interval between transplants and the use of a myeloablative conditioning (MAC) regimen prior to second transplant. Outcomes were inferior in patients who received their second transplant <6 months from their first HCT when compared to patients in whom the interval between HCTs was 6-12 or more than 12 months. Interval between HCTs was also significant when each type of leukemia (acute lymphoblastic leukemia (ALL) n = 21, acute myelogenous leukemia (AML) n = 11, and chronic myelogenous leukemia (CML) n = 7) was analyzed separately. In univariate analysis, use of the same donor and use of a matched sibling donor resulted in significant improved outcome. There was not a significant association between disease-free survival (DFS) and age, remission status, use of total body irradiation (TBI) before second HCT, or type of leukemia. Second allogeneic HCT can be a curative therapeutic option for leukemia patients relapsing after their first transplant. As more targeted therapies have become available, patients that relapse after first HCT are more likely to achieve remission. Therefore, it is anticipated that there will be more candidates for second HCT with improved performance and remission status, ultimately leading to a better outcome with the second HCT.

  12. Toxoplasmosis after allogeneic stem cell transplantation--a single centre experience.

    PubMed

    Busemann, Christoph; Ribback, Silvia; Zimmermann, Kathrin; Sailer, Verena; Kiefer, Thomas; Schmidt, Christian A; Schulz, Katrin; Steinmetz, Ivo; Dombrowski, Frank; Dölken, Gottfried; Krüger, William H

    2012-07-01

    Toxoplasmosis is a rare but possibly underestimated complication following allogeneic stem cell transplantation with a high mortality rate. One reason might be the limitation of the diagnostic instruments relying mainly on imaging and molecular-based techniques. In this report, we present three cases of toxoplasmosis identified among 155 allograft recipients treated at Greifswald University Hospital. Widely disseminated toxoplasmosis was detected post-mortem in two patients allografted for high-risk multiple myeloma. Clinical signs suspicious for toxoplasmosis occurred after days +32 and +75, respectively. In one case, serology and conventional Toxoplasma gondii PCR, targeting the B1 gene, revealed negative results, while in the other patient, toxoplasmosis was not investigated. Both patients received pentamidine for Pneumocystis jirovecii pneumonia (PcP) prophylaxis. The third patient, a 68-year-old woman allografted for AML, developed cerebral toxoplasmosis from day +395 after allogeneic SCT with typical signs in magnetic resonance tomography. Toxoplasma DNA was amplified from one of two samples of cerebrospinal fluid. The patient died of disseminated toxoplasmosis despite immediate initiation of therapy. Retrospective comparative testing of clinical specimens by the conventional T. gondii PCR and by a real-time PCR targeting a 529-bp genomic fragment suggests a higher sensitivity of the latter method in our patients. In conclusion, we suggest a rigorous real-time PCR monitoring for high-risk patients or patients with signs of infections suspicious for toxoplasmosis, even though low-copy results are presently difficult to interpret. Our reported cases might also encourage the use of trimethoprim-sufmethoxazole instead of pentamidine for PcP prophylaxis in those patients.

  13. The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population

    PubMed Central

    Lee, Hyo-Jin; Lee, Dong-Gun; Choi, Su-Mi; Park, Sun Hee; Cho, Sung-Yeon; Choi, Jae-Ki; Kim, Si-Hyun; Choi, Jung-Hyun; Yoo, Jin-Hong; Cho, Byung-Sik; Eom, Ki-Seong; Lee, Seok; Kim, Yoo-Jin; Kim, Hee-Je; Min, Chang-Ki; Kim, Dong-Wook; Lee, Jong-Wook; Min, Woo-Sung; Jung, Jung Im

    2017-01-01

    Background The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT. Methods From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea. Results TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49–886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59–14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis. Conclusion Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed. PMID:28278166

  14. The Outcomes of Hypertransfusion in Major ABO Incompatible Allogeneic Stem Cell Transplantation

    PubMed Central

    Park, Se Hoon; Lee, Se Hoon; Lee, Kyung-Eun; Park, Jinny; Park, Joon Oh; Kim, Kihyun; Kim, Won Seog; Jung, Chul Won; Im, Young-Hyuk; Kang, Won Ki; Park, Keunchil; Kim, Seon Woo; Lee, Kyoo Hyung; Lee, Je Hwan

    2004-01-01

    Major ABO incompatibility may be potentially associated with immediate or delayed hemolysis and delayed onset of erythropoiesis in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). To determine if hemolysis can be prevented by the inhibition of graft erythropoiesis, we performed hypertransfusion and assessed red cell transfusion requirement and independence. Between October 1995 and December 2001, 28 consecutive patients receiving major ABO incompatible HSCT at Samsung Medical Center were hypertransfused to maintain their hemoglobin levels at 15 g/dL or more. We retrospectively compared the outcomes of these patients with those of 47 patients at Asan Medical Center whose target hemoglobin levels were 10 g/dL. Reticulocyte engraftment was significantly delayed in hypertransfused group (51 days vs. 23 days; p=.001). There was no significant difference in the total amount of red cells transfused within 90 days post-HSCT (25 units vs. 26 units; p=.631). No significant difference in the time to red cell transfusion independence was observed between the two groups (63 days vs. 56 days; p=.165). In conclusion, we failed to improve red cell transfusion requirement and independence in major ABO incompatible HSCT with hypertransfusion. PMID:14966346

  15. Immunogenicity of allogeneic mesenchymal stem cells transplanted via different routes in diabetic rats

    PubMed Central

    Gu, Le-Hui; Zhang, Tian-Tian; Li, Yang; Yan, Hong-Jie; Qi, Hui; Li, Fu-Rong

    2015-01-01

    Due to their hypoimmunogenicity and unique immunosuppressive properties, mesenchymal stem cells (MSCs) are considered one of the most promising adult stem cell types for cell therapy. Although many studies have shown that MSCs exert therapeutic effects on several acute and subacute conditions, their long-term effects are not confirmed in chronic diseases. Immunogenicity is a major limitation for cell replacement therapy, and it is not well understood in vivo. We evaluated the immunogenicity of allogeneic MSCs in vivo by transplanting MSCs into normal and diabetic rats via the tail vein or pancreas and found that MSCs exhibited low immunogenicity in normal recipients and even exerted some immunosuppressive effects in diabetic rats during the initial phase. However, during the later stage in the pancreas group, MSCs expressed insulin and MHC II, eliciting a strong immune response in the pancreas. Simultaneously, the peripheral blood mononuclear cells in the recipients in the pancreas group were activated, and alloantibodies developed in vivo. Conversely, in the tail vein group, MSCs remained immunoprivileged and displayed immunosuppressive effects in vivo. These data indicate that different transplanting routes and microenvironments can lead to divergent immunogenicity of MSCs. PMID:25242276

  16. 131I-Anti-CD45 Antibody Plus Busulfan and Cyclophosphamide before Allogeneic Hematophoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia in First Remission

    SciTech Connect

    Pagel, John M.; Appelbaum, Frederick R.; Eary, Janet F.; Rajendran, Joseph G.; Fisher, Darrell R.; Gooley, Ted; Ruffner, Katherine; Nemecek, Eneida; Sickle, Eileen; Durack, Larry; Carreras, Jeanette; Horowitz, Mary; Press, Oliver W.; Gopal, Ajay K.; Martin, Paul J.; Bernstein, Irwin D.; Matthews, Dana C.

    2006-03-01

    In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a Phase I/II study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/ml) and cyclophosphamide (CY; 120 mg/kg). Fifty-two of 59 patients (88%) receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102-298 mCi 131I delivering an estimated 5.3-19 (mean 11.3) Gy to marrow, 17-72 (mean 29.7) Gy to spleen, and 3.5 Gy (n=4) to 5.25 Gy (n=42) to the liver. The estimated 3-year non-relapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared to those from 509 similar International Bone Marrow Transplant Registry patients transplanted using BU/CY alone. After adjusting for differences in age and cytogenetics-risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; p=.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and Phase II results are sufficiently encouraging to warrant further study.

  17. Increased maternal T cell microchimerism in the allogeneic fetus during LPS-induced preterm labor in mice.

    PubMed

    Wegorzewska, Marta; Le, Tom; Tang, Qizhi; MacKenzie, Tippi C

    2014-01-01

    Fetal surgery is a promising strategy to treat fetuses with severe congenital abnormalities but its clinical applications are often limited by preterm labor. In normal pregnancy, multiple mechanisms protect the semi-allogeneic fetus from attack by maternal T cells. Maternal microchimerism (the presence of maternal cells in the fetus) has been suggested to be one mechanism of maternal-fetal tolerance in that it exposes the fetus to non-inherited maternal antigens and leads to the generation of fetal regulatory T cells that can suppress a maternal T cell response. Preterm labor may represent a breakdown of this robust tolerance network. We hypothesized that during inflammation-associated preterm labor, maternal leukocytes cross the maternal-fetal interface and enter the fetal circulation. Consistent with this hypothesis, we found that during preterm labor in mice, the percentage of maternal microchimerism in fetal blood increased and the frequency of fetuses with high levels of trafficking (greater than 0.5%) also increased. Finally, we showed that the maternal leukocytes trafficking into the fetus are primarily Gr-1(+) cells in both syngeneic and allogeneic pregnancy, while T cell trafficking into the fetus specifically increases during allogeneic pregnancies. Our results demonstrate that trafficking of maternal leukocytes during pregnancy is altered during preterm labor. Such alterations may be clinically significant in affecting maternal-fetal tolerance.

  18. Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

    PubMed Central

    Pareek, Tej K.; Eid, Saada; Ganguly, Sudipto; Tyler, Megan; Huang, Alex Y.; Letterio, John J.

    2017-01-01

    Molecular intermediates in T-cell activation pathways are crucial targets for the therapy and prevention of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We recently identified an essential role for cyclin-dependent kinase 5 (Cdk5) in T-cell activation and effector function, but the contribution of Cdk5 activity to the development of GVHD has not been explored. Using an established, preclinical, murine, GVHD model, we reveal that Cdk5 activity is increased in key target organs early after allo-HCT. We then generated chimeric mice (Cdk5+/+C or Cdk5−/−C) using hematopoietic progenitors from either embryonic day 16.5 Cdk5+/+ or Cdk5−/− embryos to enable analyses of the role of Cdk5 in GVHD, as germ line Cdk5 gene deletion is embryonically lethal. The immunophenotype of adult Cdk5−/−C mice is identical to control Cdk5+/+C mice. However, transplantation of donor Cdk5−/−C bone marrow and T cells dramatically reduced the severity of systemic and target organ GVHD. This phenotype is attributed to decreased T-cell migration to secondary lymphoid organs (SLOs), reduced in vivo proliferation within these organs, and fewer cytokine-producing donor T cells during GVHD development. Moreover, these defects in Cdk5−/− T-cell function are associated with altered CCR7 signaling following ligation by CCL19, a receptor:ligand interaction critical for T-cell migration into SLOs. Although Cdk5 activity in donor T cells contributed to graft-versus-tumor effects, pharmacologic inhibition of Cdk5 preserved leukemia-free survival. Collectively, our data implicate Cdk5 in allogeneic T-cell responses after HCT and as an important new target for therapeutic intervention. PMID:28064242

  19. [Spontaneous rupture of the spleen in a patient treated with chemotherapy and growth factors for stem cell mobilization].

    PubMed

    Rossitto, M; Versaci, A; Barbera, A; Broccio, M; Lepore, V; Ciccolo, A

    1998-05-01

    The Authors report a case of spontaneous spleen rupture in a woman with breast cancer treated with chemotherapy and growth factors for stem cell mobilization. After a wide review of the literature, they suppose this therapy, causing a considerable increase of immature cells, that promote the stasis of the splenic microcirculation, can sometime elicit a spontaneous rupture of the organ.

  20. Cure for thalassemia major – from allogeneic hematopoietic stem cell transplantation to gene therapy

    PubMed Central

    Srivastava, Alok; Shaji, Ramachandran V.

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation has been well established for several decades as gene replacement therapy for patients with thalassemia major, and now offers very high rates of cure for patients who have access to this therapy. Outcomes have improved tremendously over the last decade, even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent, with a >90% survival rate, but for the best results, hematopoietic stem cell transplantation should be offered early, before any end organ damage occurs. However, access to this therapy is limited in more than half the patients by the lack of suitable donors. Inadequate hematopoietic stem cell transplantation services and the high cost of therapy are other reasons for this limited access, particularly in those parts of the world which have a high prevalence of this condition. As a result, fewer than 10% of eligible patients are actually able to avail of this therapy. Other options for curative therapies are therefore needed. Recently, gene correction of autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β-globin mutation or disrupt the BCL11A gene to increase fetal hemoglobin production has also been reported, and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world will remain a challenge. PMID:27909215

  1. Primary Graft Failure after Myeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

    PubMed Central

    Olsson, Richard F.; Logan, Brent R.; Chaudhury, Sonali; Zhu, Xiaochun; Akpek, Görgün; Bolwell, Brian J.; Bredeson, Christopher N.; Dvorak, Christopher C.; Gupta, Vikas; Ho, Vincent T.; Lazarus, Hillard M.; Marks, David I.; Ringdén, Olle T.H.; Pasquini, Marcelo C.; Schriber, Jeffrey R.; Cooke, Kenneth R.

    2015-01-01

    Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1,278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared to bone marrow grafts (2.5 vs. 7.3%; P<0.001). A 4-fold increase of PGF was observed in myeloproliferative disorders compared to acute leukemia (P<0.001). Other risk factors for PGF included recipient age below 30, HLA-mismatch, male recipients of female donor grafts, ABO-incompatibility, busulfan/cyclophosphamide conditioning, and cryopreservation. In bone marrow transplants, total nucleated cell doses ≤2.4 × 108/kg were associated with PGF (OR 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post-transplant may provide the rationale for an early request for additional hematopoietic stem cells. PMID:25772027

  2. MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice.

    PubMed

    Hirata, Yuichi; Li, Hao-Wei; Takahashi, Kazuko; Ishii, Hiroshi; Sykes, Megan; Fujisaki, Joji

    2015-01-01

    NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs.

  3. MHC Class I Expression by Donor Hematopoietic Stem Cells Is Required to Prevent NK Cell Attack in Allogeneic, but Not Syngeneic Recipient Mice

    PubMed Central

    Hirata, Yuichi; Li, Hao-Wei; Takahashi, Kazuko; Ishii, Hiroshi; Sykes, Megan; Fujisaki, Joji

    2015-01-01

    NK cells resist engraftment of syngeneic and allogeneic bone marrow (BM) cells lacking major histocompatibility (MHC) class I molecules, suggesting a critical role for donor MHC class I molecules in preventing NK cell attack against donor hematopoietic stem and progenitor cells (HSPCs), and their derivatives. However, using high-resolution in vivo imaging, we demonstrated here that syngeneic MHC class I knockout (KO) donor HSPCs persist with the same survival frequencies as wild-type donor HSPCs. In contrast, syngeneic MHC class I KO differentiated hematopoietic cells and allogeneic MHC class I KO HSPCs were rejected in a manner that was significantly inhibited by NK cell depletion. In vivo time-lapse imaging demonstrated that mice receiving allogeneic MHC class I KO HSPCs showed a significant increase in NK cell motility and proliferation as well as frequencies of NK cell contact with and killing of HSPCs as compared to mice receiving wild-type HSPCs. The data indicate that donor MHC class I molecules are required to prevent NK cell-mediated rejection of syngeneic differentiated cells and allogeneic HSPCs, but not of syngeneic HSPCs. PMID:26544200

  4. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  5. Large volume leukapheresis maximizes the progenitor cell yield for allogeneic peripheral blood progenitor donation.

    PubMed

    Kobbe, G; Soehngen, D; Heyll, A; Fischer, J; Thiele, K P; Aul, C; Wernet, P

    1997-04-01

    We have investigated the efficiency and safety of large volume leukapheresis (LVL) for the collection of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPCs) from healthy donors. In six apheresis sessions in four healthy individuals on a COBE-BCT Spectra cell separator (median processed volume 3.5 X total blood volume, TBV, range 3.3-4.4 X TBV), harvested cells were collected sequentially into three single bags. The collection bags were changed after processing 33%, 66%, and 100% of the prospective apheresis volume, allowing analysis of PBPCs collected at different periods during one harvest. Mononuclear cells (MNCs), CD34+ cells, CD34+ subsets, and lymphocyte subsets were determined in each bag. Substantially more PBPCs were harvested than were in the circulation before G-CSF administration preceding LVL (median 171%, range 69-267%), reflecting progenitor release during the procedure. In donors 1 and 3, the CD34+ cell yields decreased in the third bag to 53% and 42% of that collected in the first bag, whereas the progenitor cell yields in donors 2 and 4 were stable or rose during the procedure, achieving in the third bag 157% and 105% of the number of CD34+ cells collected in the first bag. Minor changes were found in the subsets of CD34+ cells, lymphocytes, and monocytes collected at different periods during a single harvest. LVL was well tolerated. Reversible thombocytopenia developed in all cases. No late effects attributable to LVL or G-CSF were found in the 4 donors and 16 other healthy individuals who have undergone LVL in our institution. We conclude that LVL is safe and maximizes PBPC yields for allogeneic transplantation.

  6. Effect of synthetic compound B 58 on natural killer and cytostatic cell activity in the mouse spleen

    SciTech Connect

    Malaitsev, V.V.; Bogdanova, I.M.; Spivak, N.Ya.; Bogdashin, I.V.; Zueva, V.S.

    1987-11-01

    The authors study the effect of compound B 58, a synthetic interferon inducer, on activity of natural killer cells (NKC) and cytostatic effectors in the mouse spleen. NKC activity in the spleen was determined in the 4-hour microtoxicity test against VAC-1 target cells labeled with /sup 51/Cr. /sup 3/H-thymidine was added to the effectors and targets. An increase in activity of the cellular mechanisms of natural antitumor resistance arising under the influence of compound B 58 is shown.

  7. Human spleen contains phenotypic subsets of macrophages and dendritic cells that occupy discrete microanatomic locations.

    PubMed Central

    Buckley, P. J.; Smith, M. R.; Braverman, M. F.; Dickson, S. A.

    1987-01-01

    Macrophages (M phi s) are an important component of the immune response and mediate numerous other functions. Phenotypic and functional subsets of circulating monocytes have been described, but few similar studies have analyzed M phi s in human tissues. By use of immunohistochemical techniques and a large number of monoclonal antibodies, the presence and distribution of phenotypic subpopulations of M phi s and dendritic cells in human spleen were assessed. The results of this study show that different subsets of M phi s and dendritic cells are present in the spleen and that some of these occupy discrete microanatomic locations. In the red pulp (RP) certain groups of antigens are expressed by different proportions of uniformly distributed M phi s in the cords. On the other hand, some antigens are present on M phi s that form clusters of variable size within the red pulp. M phi s in the splenic marginal zone (MZ) share some antigens with red pulp M phi s, but in addition express CR3, Mo-2, 61D3, and 63D3. These antigens are found on only a few RP M phi s. MZ cells expressing one antigen shared with RP M phi s (Leu-3a,b) and one present largely on the MZ cells (63D3) form clusters around small vessels; these structures resemble the so-called splenic ellipsoids that may play a role in the trapping of circulating antigens. Phagocytic M phi s (tingible body M phi s) of the white pulp follicular germinal centers were also shown to differ from RP and MZ cels with respect to the expression of the antigens detected by anti-FcR, Leu-M3, Mo-2, 25F9, and anti-CR3. The unique topographical and surface antigenic features of dendritic cells were confirmed by this study. Furthermore, these cells were found to share a number of antigens with RP, MZ, and white pulp M phi s, which suggests that they may be derived from a common progenitor. The presence of phenotypic subpopulations and variation in distribution among human splenic phagocytic cells and dendritic cells may be indicative

  8. Patients with mantle-cell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation.

    PubMed

    Martínez, C; Carreras, E; Rovira, M; Urbano-Ispizua, A; Esteve, J; Perales, M; Fernández, F; Montserrat, E

    2000-09-01

    Two patients with disseminated mantle-cell lymphoma relapsed 24 and 13 months, respectively, after high-dose chemotherapy and autologous stem cell transplantation (autoSCT). Both patients had an HLA-identical sibling and received an allogeneic stem cell transplant (alloSCT) 32 and 18 months after autologous transplant, after conditioning with fractionated 12 Gy total body irradiation plus cyclophosphamide 120 mg/kg. They are both alive and in complete remission 24 months after transplant. Both patients have developed chronic graft-versus-host disease and their Karnofsky performance status is 90%. AlloSCT may offer a useful approach in a subgroup of patients with mantle-cell lymphoma who have relapsed after autologous transplantation.

  9. Allogeneic cellular gene therapy in hemoglobinopathies--evaluation of hematopoietic SCT in sickle cell anemia.

    PubMed

    Lucarelli, G; Gaziev, J; Isgrò, A; Sodani, P; Paciaroni, K; Alfieri, C; De Angelis, G; Marziali, M; Simone, M D; Gallucci, C; Roveda, A; Saltarelli, F; Torelli, F; Andreani, M

    2012-02-01

    Many patients with thalassemia have been cured with BMT since the first successful transplant in 1981. Allogeneic stem cell gene therapy is the only treatment option for patients with sickle cell anemia (SCA). A total of 11 patients with a median age of 12 years (range, 2-16), affected by SCA, received hematopoietic SCT from HLA-identical, related donors following a myeloablative-conditioning regimen. Indications for transplantation were vaso-occlusive crisis, acute chest syndrome, avascular bone necrosis, chronic RBC transfusions, or hemorrhagic stroke. All patients had sustained engraftment. One patient became a stable mixed chimera with 25% of donor cells at 4 years after transplantation. One patient died at 1 year after transplantation. The probability of survival, SCA-free survival and TRM at 5 years after transplant were 90, 90 and 10%, respectively. All 10 surviving patients remained free of any SCA-related events after transplantation. In conclusion, these data confirm SCT from a suitable HLA-matched, related donor should become the primary option for curing children with SCA. There is an excellent survival rate and a return to normal life, free of SCA-related events.

  10. Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Morin-Zorman, Sarah; Loiseau, Pascale; Taupin, Jean-Luc; Caillat-Zucman, Sophie

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field. PMID:27570526

  11. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

    PubMed Central

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T.; Bhatt, Vijaya Raj

    2016-01-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  12. Adverse Late and Long-Term Treatment Effects in Adult Allogeneic Hematopoietic Stem Cell Transplant Survivors.

    PubMed

    Mosesso, Kara

    2015-11-01

    Hematopoietic stem cell transplantation (HSCT) has become the standard of care for many malignant and nonmalignant hematologic diseases that don't respond to traditional therapy. There are two types: autologous transplantation (auto-HSCT), in which an individual's stem cells are collected, stored, and infused back into that person; and allogeneic transplantation (allo-HSCT), in which healthy donor stem cells are infused into a recipient whose bone marrow has been damaged or destroyed. There have been numerous advancements in this field, leading to marked increases in the number of transplants performed annually. This article--the first of several on cancer survivorship--focuses on the care of adult allo-HSCT survivors because of the greater complexity of their posttransplant course. The author summarizes potential adverse late and long-term treatment-related effects, with special focus on the evaluation and management of several cardiovascular disease risk factors that can occur either independently or concurrently as part of the metabolic syndrome. These risk factors are potentially modifiable with appropriate nursing interventions and lifestyle modifications.

  13. Erythrocyte antigen and reticulocyte engraftment after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Yildirim, I; Ozer, Y; Yüksel, M K; Arat, M; Arslan, O

    2004-08-01

    The aim of this study was to study the usefulness of erythrocyte antigen (EA) measurement to study engraftment after allogeneic HSCT. In all, 31 consecutive patients receiving HLA-identical bone marrow (BM) (n=13) or peripheral blood stem cells (n=18) were investigated. Apart from the ABO group, 15 EAs representing six minor blood groups were followed by the simple tube agglutination technique. A total of 20 (64.5%) patients received ABO-identical, eight (25.8%) received ABO minor and three (9.7%) received ABO major mismatched grafts. In all, 29 patients were followed for a median of 12 (6-16) months; 65% of the patients expressed donor type EA 1 month and almost all did so 6 months after transplant. Reticulocyte engraftment was significantly shorter than EA engraftment (median 18 vs 35 days) (P=0.001). Patients who received PB stem cells showed significantly faster EA and reticulocyte engraftment than patients who received BM stem cells (P=0.038 and 0.025). ABO compatibility did not have an impact on reticulocyte and EA engraftment (P=0.4 and 0.55). The earliest donor type EA detected was from the Rh and Kidd system. These data suggest that EA and reticulocyte assays are useful in monitoring engraftment.

  14. Control of Immune Response to Allogeneic Embryonic Stem Cells by CD3 Antibody-Mediated Operational Tolerance Induction.

    PubMed

    Calderon, D; Prot, M; You, S; Marquet, C; Bellamy, V; Bruneval, P; Valette, F; de Almeida, P; Wu, J C; Pucéat, M; Menasché, P; Chatenoud, L

    2016-02-01

    Implantation of embryonic stem cells (ESCs) and their differentiated derivatives into allogeneic hosts triggers an immune response that represents a hurdle to clinical application. We established in autoimmunity and in transplantation that CD3 antibody therapy induces a state of immune tolerance. Promising results have been obtained with CD3 antibodies in the clinic. In this study, we tested whether this strategy can prolong the survival of undifferentiated ESCs and their differentiated derivatives in histoincompatible hosts. Recipients of either mouse ESC-derived embryoid bodies (EBs) or cardiac progenitors received a single short tolerogenic regimen of CD3 antibody. In immunocompetent mice, allogeneic EBs and cardiac progenitors were rejected within 20-25 days. Recipients treated with CD3 antibody showed long-term survival of implanted cardiac progenitors or EBs. In due course, EBs became teratomas, the growth of which was self-limited. Regulatory CD4(+)FoxP3(+) T cells and signaling through the PD1/PDL1 pathway played key roles in the CD3 antibody therapeutic effect. Gene profiling emphasized the importance of TGF-β and the inhibitory T cell coreceptor Tim3 to the observed effect. These results demonstrate that CD3 antibody administered alone promotes prolonged survival of allogeneic ESC derivatives and thus could prove useful for enhancing cell engraftment in the absence of chronic immunosuppression.

  15. Acupoint Injection of Autologous Stromal Vascular Fraction and Allogeneic Adipose-Derived Stem Cells to Treat Hip Dysplasia in Dogs

    PubMed Central

    Marx, Camila; Silveira, Maiele Dornelles; Selbach, Isabel; da Silva, Ariel Silveira; Braga, Luisa Maria Gomes de Macedo; Camassola, Melissa; Nardi, Nance Beyer

    2014-01-01

    Stem cells isolated from adipose tissue show great therapeutic potential in veterinary medicine, but some points such as the use of fresh or cultured cells and route of administration need better knowledge. This study aimed to evaluate the effect of autologous stromal vascular fraction (SVF, n = 4) or allogeneic cultured adipose-derived stem cells (ASCs, n = 5) injected into acupuncture points in dogs with hip dysplasia and weak response to drug therapy. Canine ASCs have proliferation and differentiation potential similar to ASCs from other species. After the first week of treatment, clinical evaluation showed marked improvement compared with baseline results in all patients treated with autologous SVF and three of the dogs treated with allogeneic ASCs. On days 15 and 30, all dogs showed improvement in range of motion, lameness at trot, and pain on manipulation of the joints, except for one ASC-treated patient. Positive results were more clearly seen in the SVF-treated group. These results show that autologous SVF or allogeneic ASCs can be safely used in acupoint injection for treating hip dysplasia in dogs and represent an important therapeutic alternative for this type of pathology. Further studies are necessary to assess a possible advantage of SVF cells in treating joint diseases. PMID:25180040

  16. A Review of Myeloablative vs Reduced Intensity/Non-Myeloablative Regimens in Allogeneic Hematopoietic Stem Cell Transplantations

    PubMed Central

    Atilla, Erden; Ataca Atilla, Pınar; Demirer, Taner

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment option for both malignant and some benign hematological diseases. During the last decade, many of the newer high-dose regimens in different intensity have been developed specifically for patients with hematologic malignancies and solid tumors. Today there are three main approaches used prior to allogeneic transplantation: Myeloablative (MA), Reduced Intensity Conditioning (RIC) and Non-MA (NMA) regimens. MA regimens cause irreversible cytopenia and there is a requirement for stem cell support. Patients who receive NMA regimen have minimal cytopenia and this type of regimen can be given without stem cell support. RIC regimens do not fit the criteria of MA and NMA: the cytopenia is reversible and the stem cell support is necessary. NMA/RIC for Allo-HSCT has opened a new era for treating elderly patients and those with comorbidities. The RIC conditioning was used for 40% of all Allo-HSCT and this trend continue to increase. In this paper, we will review these regimens in the setting of especially allogeneic HSCT and our aim is to describe the history, features and impact of these conditioning regimens on specific diseases. PMID:28251017

  17. Influence of spaceflight on the production of interleukin-3 and interleukin-6 by rat spleen and thymus cells

    NASA Technical Reports Server (NTRS)

    Miller, Edwin S.; Koebel, D. Anne; Sonnefeld, Gerald

    1995-01-01

    Six adult male Sprague-Dawley rats were flown on the 7-day US space shuttle mission STS-54. After flight, the spleen and thymus from each animal were assayed for the capacity to secrete the cytokines interleukin-3 (IL-3) and IL-6. Spleen and thymus cells were incubated for 48 h in the presence of 5 microgram/ml of concanavalin A or 2 microgram/ml of bacterial lipopolysaccharide to stimulate the production of IL-3 and IL-6. IL-3 activity was measured using the IL-3/colony-stimulating-factor-dependent cell line 32D. IL-6 activity was measured using the IL-6-dependent cell line 7TD1. Spleen and thymus cells harvested from flown rats secreted significantly higher titers of biologically active IL-3 compared with ground control rats. Spaceflight significantly enhanced IL-6 production by thymus, but not spleen, cells. The results of this study demonstrate that spaceflight can enhance the production of certain cytokines by cells of the immune system.

  18. Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium

    PubMed Central

    Weil, Brian R.; Suzuki, Gen; Leiker, Merced M.; Fallavollita, James A.; Canty, John M.

    2015-01-01

    Rationale Allogeneic bone marrow-derived mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs) have each entered clinical trials but a direct comparison of these cell types has not been performed in a large animal model of hibernating myocardium. Objective Using completely blinded methodology, compare the efficacy of global intracoronary allogeneic MSCs (icMSCs, ~35×106) and CDCs (icCDCs, ~35×106) vs. vehicle in cyclosporine-immunosuppressed swine with a chronic LAD stenosis (n=26). Methods and Results Studies began 3-months after instrumentation when wall-thickening (%WT) was reduced (LAD%WT 38±11% (mean ± SD) vs. 83±26% in remote, p<0.01) and similar among groups. Four-weeks after treatment, LAD%WT increased similarly following icCDCs and icMSCs, while it remained depressed in vehicle-treated controls (icMSCs: 51±13%; icCDCs: 51±17%; vehicle: 34±3%, treatments p<0.05 vs. vehicle). There was no change in myocardial perfusion. Both icMSCs and icCDCs increased LAD myocyte nuclear density (icMSCs: 1601±279 nuclei/mm2, icCDCs: 1569±294 nuclei/mm2, vehicle: 973±181 nuclei/mm2, treatments p<0.05 vs. vehicle) and reduced myocyte diameter (icMSCs: 16.4±1.5 μm, icCDCs: 16.8±1.2 μm, vehicle: 20.2±3.7 μm, treatments p<0.05 vs. vehicle) to the same extent. Similar changes in myocyte nuclear density and diameter were observed in the remote region of cell-treated animals. Cell fate analysis using Y-FISH demonstrated rare cells from sex-mismatched donors. Conclusions Allogeneic icMSCs and icCDCs exhibit comparable therapeutic efficacy in a large animal model of hibernating myocardium. Both cell types produced equivalent increases in regional function and stimulated myocyte regeneration in ischemic and remote myocardium. The activation of endogenous myocyte proliferation and regression of myocyte cellular hypertrophy support a common mechanism of cardiac repair. PMID:26271689

  19. The role of NK cells in HIV-1 protection: autologous, allogeneic or both?

    PubMed

    Hens, Jef; Jennes, Wim; Kestens, Luc

    2016-01-01

    Natural killer (NK) cells specialize in killing virally infected- or tumor cells and are part of the innate immune system. The activational state of NK cells is determined by the balance of incoming activating and inhibitory signals mediated by receptor-ligand binding with the target cell. These receptor-ligand bonds mainly consist of the killer immunoglobulin-like receptors (KIR), which are expressed at the cell surface of NK cells, and their ligands: the highly variable human leukocyte antigen -class I molecules (HLA). Absence of an inhibitory receptor-ligand bond lowers the NK cell activation threshold, whereas an activating receptor-ligand bond stimulates the cell, potentially overcoming this threshold and triggering NK cell activation. NK cells influence the course of infection as well as the acquisition of HIV-1. Several lines of evidence relate the activating NK cell receptor KIR3DS1, in the presence or absence of its putative ligand HLA-Bw4, with slower disease progression as well as resistance to HIV-1 infection. Overall, resistance to HIV-1 infection predominantly correlates with activating KIR/HLA profiles, consisting of e.g. activating KIRs, group B haplotypes, or inhibitory KIRs in absence of their ligands. Such a conclusion is less evident for studies of HIV-1 disease progression, with studies reporting beneficial as well as detrimental effects of activating KIR/HLA genotypes. It is likely that KIR/HLA association studies are complicated by the complexity of the KIR and HLA loci and their mutual interactions, as well as by additional factors like route of HIV exposure, immune activation, presence of co-infections, and the effect of anti-HIV-1 antibodies. One newly discovered NK cell activation pathway associated with resistance to HIV-1 infection involves the presence of an iKIR/HLA mismatch between partners. The absence of such an iKIR/HLA bond renders donor-derived allogeneic HIV-1 infected cells vulnerable to NK cell responses during HIV-1

  20. Cell death and phagocytosis of haematopoietic elements at the onset of haematopoiesis in the mouse spleen: an ultrastructural study.

    PubMed Central

    Sasaki, K; Iwatsuki, H; Suda, M; Itano, C

    1993-01-01

    The spleen in fetal and early postnatal mice contains a variety of proliferating haematopoietic cells as well as 2 kinds of phagocytes, scavenger macrophages and mast cells, laden with large heterogeneous inclusions. Their phagocytotic activity is directed towards extruded erythrocyte nuclei, erythrocytes and dying haematopoietic cells. The splenic cords after 18 d of gestation become filled with proliferating haematopoietic cells, and the cords contain a small number of free haematopoietic cells undergoing degeneration. The early signs of cell death can be observed in the nuclear structures: hyperchromasia of the nuclear membrane or nuclear dissolution. Erythroblast nuclei are amongst the most frequent elements engulfed. Phagocytes also take up and digest degenerating blood cells, i.e. erythrocytes, erythroblasts and neutrophil granulocytes. Since the digestion processes are ultrastructurally different for the various haematopoietic elements, the origins of heterolysosomes enclosed by phagocytes can be identified by electron microscopy. Mast cells, originally classified as secretory cells, phagocytose erythroid line cells in the spleen. Cell death in several haematopoietic cell lines is discussed in relation to programmed cell death in the developing spleen. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8270466

  1. Killing of Targets by CD8+ T Cells in the Mouse Spleen Follows the Law of Mass Action

    PubMed Central

    Ganusov, Vitaly V.; Barber, Daniel L.; De Boer, Rob J.

    2011-01-01

    It has been difficult to correlate the quality of CD8 T cell responses with protection against viral infections. To investigate the relationship between efficacy and magnitude of T cell responses, we quantify the rate at which individual CD8 effector and memory T cells kill target cells in the mouse spleen. Using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (LCMV) in mouse spleens with varying numbers of epitope-specific CD8 T cells. We find that the killing of targets follows the law of mass-action, i.e., the death rate of individual target cells remains proportional to the frequency (or the total number) of specific CD8 T cells in the spleen despite the fact that effector cell densities and effector to target ratios vary about a 1000-fold. The killing rate of LCMV-specific CD8 T cells is largely independent of T cell specificity and differentiation stage. Our results thus allow one to calculate the critical T cell concentration at which growth of a virus with a given replication rate can be prevented from the start of infection by memory CD8 T cell response. PMID:21283669

  2. Regression of the tumor after withdrawal of cyclosporine in relapsed extranodal natural killer/T cell lymphoma following allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kako, Shinichi; Izutsu, Koji; Oshima, Kumi; Sato, Hiroyuki; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2007-10-01

    The prognosis of patients with advanced-stage extranodal natural killer/T cell lymphoma, nasal type (ENKL) has been generally poor, and several anecdotal reports have suggested the role of allogeneic hematopoietic stem cell transplantation (HSCT). A potential advantage of allogeneic HSCT may be the graft-versus-lymphoma (GVL) effect. The susceptibility to the GVL effect, however, has been shown to vary according to histologic subtypes, and it has been hardly documented yet whether ENKL is susceptible to the GVL effect. Here we report a patient with advanced-stage ENKL who underwent allogeneic HSCT from an HLA one-allele mismatched related donor, whose clinical course after HSCT suggested the potent GVL effect against ENKL. A 43-year-old female underwent allogeneic HSCT for advanced-stage, chemorefractory ENKL, and achieved complete response. In 4 months after the transplantation, however, the ENKL relapsed in multiple sites. These lesions markedly responded to the discontinuation of immunosuppressive agents and disappeared. Except for a temporal exacerbation of bronchiolitis obliterans organizing pneumonia, she has been free from disease for more than a year without other treatments against lymphoma. The clinical course of the current patient suggests the potent GVL effect against ENKL. Allogeneic HSCT, including that with reduced-intensity regimens, is a promising treatment option for high-risk ENKL.

  3. The rapid rejection of allogeneic lymphocytes by a non-adaptive, cell-mediated mechanism (NK activity).

    PubMed Central

    Rolstad, B; Fossum, S; Bazin, H; Kimber, I; Marshall, J; Sparshott, S M; Ford, W L

    1985-01-01

    The fate of allogeneic lymphocytes (AO or DA) transferred to non-immune PVG recipients was studied in the light of previous evidence (Heslop & McNeilage, 1983; Rolstad & Ford, 1983) that allogeneic lymphocytes can be rapidly destroyed in certain strain combinations of rats and mice by a mechanism that is distinct from either T-cell mediated immunity or an alloantibody response. AO lymphocytes injected into PVG recipients were discriminated from syngeneic lymphocytes within 15-30 min of i.v. injection, as testified by the excess release of 51Cr into the lymph plasma of the recipient. The following experiments were intended to distinguish between natural antibody and natural killer (NK) cells as the mechanism responsible for the allogeneic lymphocyte cytotoxicity (ALC) displayed by PVG rats. Nude rats treated from birth with anti-mu chain serum and shown to be lacking B and T lymphocytes, as well as being profoundly deficient in immunoglobulin, displayed more aggressive ALC than did control nude rats which, in turn, showed stronger ALC than did euthymic rats. Serum from PVG nude rats exerted no inhibitory or destructive effect on allogeneic lymphocytes in an antibody-dependent cellular cytotoxicity system, an assay of graft-versus-host activity, or when injected into 3-4-week-old PVG rats which had not yet developed ALC. Treatment of nude rats with anti-asialo GM 1 antiserum depressed ALC and NK activity in parallel, thus adding to a wide range of circumstances in which ALC and NK activity are closely correlated. In conclusion, ALC is implemented by a non-adaptive, cell-mediated mechanism independent of immunoglobulin, but the precise identity of the effector cell in the recipients' lymphatic tissues remains to be settled. Images Figure 2 PMID:3972430

  4. Has allogeneic stem cell cryopreservation been given the 'cold shoulder'? An analysis of the pros and cons of using frozen versus fresh stem cell products in allogeneic stem cell transplantation.

    PubMed

    Frey, N V; Lazarus, H M; Goldstein, S C

    2006-09-01

    Donor stem cells for allogeneic transplant traditionally are collected and transfused 'fresh' into the recipient on the day of transplant; alternatively such cells can be collected in advance and cryopreserved until needed. Most centers favor the former approach based on theoretical concerns that cryopreservation and thawing may worsen clinical outcomes. Limited published data from single institution retrospective studies show no significant impairment of engraftment or reduced day 100 survival for cryopreserved bone marrow recipients. There are no reported outcomes for recipients of cryopreserved peripheral blood allografts. Use of cryopreserved stem cells is associated with a higher incidence of adverse events (transfusion reactions, bacterial graft contamination and collection of grafts which are not utilized). Conversely, use of cryopreserved grafts introduces a greater flexibility into a stressed healthcare system and results in a more streamlined experience for the donor. Some data suggest that transplantation with a cryopreserved product may lower the incidence of acute graft-versus-host disease. We compare the pros and cons of using 'fresh' versus cryopreserved stem cell products for allogeneic transplantation and suggest that the current standard of using 'fresh' products may not be warranted. We also suggest future areas of exploration to better elucidate this issue.

  5. Regulation of human aortic endothelial cell-derived mesenchymal growth factors by allogeneic lymphocytes in vitro. A potential mechanism for cardiac allograft vasculopathy.

    PubMed Central

    Wagner, C R; Morris, T E; Shipley, G D; Hosenpud, J D

    1993-01-01

    Cardiac allograft vasculopathy is thought to be triggered by an alloreactive response to the donor coronary vasculature, resulting in smooth muscle cell proliferation and ultimate occlusion of the donor coronary arteries. To determine whether allogeneic lymphocytes are capable of regulating endothelial-derived smooth muscle cell (SMC) growth factors, human aortic endothelial cells (HAECs) were exposed to allogeneic lymphocytes. The HAEC-lymphocyte co-cultures were assessed for (a) lymphocyte proliferation in response to the allogeneic HAECs; (b) release of soluble factors that stimulate human aortic SMC proliferation; and (c) alteration of HAEC mRNA levels for a panel of known SMC growth factors. Co-culture conditioned medium increased SMC proliferation, compared to medium conditioned by HAECs alone. HAECs exposed to allogeneic lymphocytes increased their expression of mRNA for basic fibroblast growth factor, transforming growth factors alpha and beta, and platelet derived growth factor A and B chains. These results demonstrate that allogeneic lymphocytes are capable of inducing HAECs to increase mRNA levels for several mesenchymal growth factors and to release bioactive products capable of stimulating SMC cell proliferation in vitro. Additionally, the data support the hypothesis that alloreactive lymphocytes can stimulate allogeneic donor endothelial cells to produce growth factors that may contribute to the intimal thickening seen in cardiac allograft vasculopathy. Images PMID:8376585

  6. Spleen removal

    MedlinePlus

    ... Splenic artery aneurysm (rare) Trauma to the spleen Risks Risks for anesthesia and surgery in general are: ... urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows ...

  7. Effects of Bu-Shen-Ning-Xin Decoction on immune cells of the spleen and bone marrow in ovariectomized mice.

    PubMed

    Qiu, Xuemin; Gui, Yuyan; Zhang, Na; Xu, Yingping; Li, Dajin; Wang, Ling

    2016-11-15

    Osteoimmunology is a new discipline that focuses on the interaction between the bones and the immune system. Immune cells play an important role in bone metabolism. The aim of this study was to illustrate the effect of Bu-Shen-Ning-Xin Decoction (BSNXD) on lymphocytes in the spleen and bone marrow to explore the potential role on the bone. C57BL/6 mice were divided into four groups: sham, ovariectomized (OVX), OVX+BSNXD, and OVX+ estrogen. The sham and OVX groups were treated with saline, the OVX+BSNXD group was treated with BSNXD, and the OVX+ estrogen group was treated with estrogen. After mice were sacrificed, the spleens and bones were collected, and the lymphocytes in the spleen and bone marrow were analyzed. We found that BSNXD lessened the extent of the increase of CD4(+) and bone marrow. In contrast, these numbers were both increased in the OVX group. BSNXD had no influence on the percentage of γδ T cells. However, it increased the proportion of NK cells in the spleen and bone marrow. BSNXD lessened the extent of the increase of monocytes by ovariectomy. In vitro experiment, we found Tregs can decrease osteoclastogenesis when co-cultured with osteoclast precursor cells. This study suggests that BSNXD changes the immune environment and immune cells have a role in bone metabolism in OVX mice.

  8. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease.

    PubMed

    Staffas, Anna; Burgos da Silva, Marina; van den Brink, Marcel R M

    2017-02-23

    Hematopoietic cell transplantation (HCT) is a critical treatment of patients with high-risk hematopoietic malignancies, hematological deficiencies, and other immune diseases. In allogeneic HCT (allo-HCT), donor-derived T cells recognize host tissues as foreign, causing graft-versus-host disease (GVHD) which is a main contributor to morbidity and mortality. The intestine is one of the organs most severely affected by GVHD and research has recently highlighted the importance of bacteria, particularly the gut microbiota, in HCT outcome and in GVHD development. Loss of intestinal bacterial diversity is common during the course of HCT and is associated with GVHD development and treatment with broad-spectrum antibiotics. Loss of intestinal diversity and outgrowth of opportunistic pathogens belonging to the phylum Proteobacteria and Enterococcus genus have also been linked to increased treatment-related mortality including GVHD, infections, and organ failure after allo-HCT. Experimental studies in allo-HCT animal models have shown some promising results for prebiotic and probiotic strategies as prophylaxis or treatment of GVHD. Continuous research will be important to define the relation of cause and effect for these associations between microbiota features and HCT outcomes. Importantly, studies focused on geographic and cultural differences in intestinal microbiota are necessary to define applicability of new strategies targeting the intestinal microbiota.

  9. Menstrual patterns, fertility and main pregnancy outcomes after allogeneic haematopoietic stem cell transplantation.

    PubMed

    Chiodi, Sandra; Spinelli, Simonetta; Bruzzi, Paolo; Anserini, Paola; Di Grazia, Carmen; Bacigalupo, Andrea

    2016-08-01

    Two-hundred and sixty-nine females aged ≤42 and undergoing an allogeneic stem cell transplant were retrospectively studied to assess the effect of age, conditioning regimen and chronic graft-versus-host disease (cGVHD) on resumption of stable menstrual cyclicity. Overall, a stable menstrual cyclicity was observed in 22% of cases. The cumulative probability of menses resumption was significantly age and conditioning regimen related. A statistically significant inverse correlation between cGVHD severity and menses resumption was observed only in univariate analysis. In patients with residual ovarian function, infertility was found in 43% and early menopause in 45%. An increased incidence of prematurity and low birth weight (LBW) was observed among the single spontaneous pregnancies. Follicle-stimulating hormone (FSH) and 17 beta-oestradiol levels were found to be inadequate to detect both early signs of menses resumption and menstrual stability. Our study confirms the crucial role of full dose total body irradiation (TBI) and age on menses recovery and fertility after haematopoietic stem cell transplantation (HSCT). The impact of severe cGVHD remains unclear.

  10. Successful treatment with low-dose nivolumab in refractory Hodgkin lymphoma after allogeneic stem cell transplantation.

    PubMed

    Onizuka, Makoto; Kojima, Minoru; Matsui, Keiko; Machida, Shinichiro; Toyosaki, Masako; Aoyama, Yasuyuki; Kawai, Hidetsugu; Amaki, Jun; Hara, Ryujiro; Ichiki, Akifumi; Ogawa, Yoshiaki; Kawada, Hiroshi; Nakamura, Naoya; Ando, Kiyoshi

    2017-01-17

    Previous studies have reported that an antibody that blocks programmed cell death 1 (PD-1) has therapeutic activity in patients with refractory/relapsed Hodgkin lymphoma (HL). However, the safety and efficacy of these agents in the post-allogeneic stem cell transplantation (allo-SCT) setting are not well known. Here, we describe a patient who was diagnosed as classical HL and treated with five regimens of chemotherapies with autologous SCT. Complete remission (CR) was not achieved following this initial treatment, so we performed allo-SCT from an HLA-matched sibling donor. Since his disease progressed at day 403 after allo-SCT, we decided to use nivolumab in the treatment of his refractory disease. To prevent the worsening of his chronic graft-versus-host disease (GVHD), we reduced the initial dose and frequency of nivolumab compared with the previous report. After four courses of 0.5 mg/kg of nivolumab every three weeks, FDG-PET imaging showed partial response (PR) to the treatment, a remarkable result. However, since the escalated dose of 2 mg/kg resulted in worsening of dyspnea and skin sclerosis, we initiated systemic administration of prednisolone and reduced nivolumab to 1 mg/kg. At the time of this report, his HL is in stable PR with three weekly administration of nivolumab and steroid controlled mild chronic GVHD.

  11. Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

    2015-01-01

    Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials.

  12. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy. PMID:27610174

  13. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Jenq, Robert R.; Perales, Miguel-Angel; Littmann, Eric R.; Morjaria, Sejal; Ling, Lilan; No, Daniel; Gobourne, Asia; Viale, Agnes; Dahi, Parastoo B.; Ponce, Doris M.; Barker, Juliet N.; Giralt, Sergio; van den Brink, Marcel; Pamer, Eric G.

    2014-01-01

    Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. PMID:24939656

  14. Administration of Hydrogen-Rich Saline in Mice with Allogeneic Hematopoietic Stem-Cell Transplantation

    PubMed Central

    Yuan, Lijuan; Chen, Xiaoping; Qian, Liren; Shen, Jianliang; Cai, Jianming

    2015-01-01

    Background Hydrogen, as a novel antioxidant, has been shown to selectively reduce the level of hydroxyl radicals and alleviate acute oxidative stress in many animal experiments. Hydrogen-rich saline provides a high concentration of hydrogen that can be easily and safely applied. Allogeneic hematopoietic stem-cell transplantation (HSCT) has been the most curative therapy for hematological malignancies. However, acute graft-versus-host disease (aGVHD) is the main cause of death in post-transplantation patients. In this study, we examined whether hydrogen-rich saline would show favorable effects on acute GVHD in mice. Material/Methods After lethal irradiation, BALB/c mice received bone marrow transplantation from C57BL/6 mice. Hydrogen-rich saline (5 ml/kg) was given to recipient mice in the hydrogen group once a day by intraperitoneal injection, and saline (5 ml/kg) was given to recipient mice in the saline group. Survival rates were monitored, clinical and pathological scores of aGVHD were determined after bone marrow transplantation (BMT), and the serum cytokine levels were examined on the 7th day after BMT. Result This study proves that hydrogen-rich saline increased the survival rate, reduced clinical and histopathological scores of aGVHD, promoted the recovery of white blood cells, reduced the serum cytokine levels, and reversed tissue damage after transplantation in mice. Conclusions Hydrogen has potential as an effective and safe therapeutic agent in aGVHD. PMID:25763677

  15. Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation.

    PubMed

    Schmitt, Michael; Publicover, Amy; Orchard, Kim H; Görlach, Matthias; Wang, Lei; Schmitt, Anita; Mani, Jiju; Tsirigotis, Panagiotis; Kuriakose, Reeba; Nagler, Arnon

    2014-01-01

    The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen (®) ) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.

  16. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases.

    PubMed

    Krivit, William

    2004-11-01

    This is a review of the clinical responses and prospectus of new therapies following use of allogeneic hematopoietic stem cell transplantation for the treatment of the following disorders: Hurlers syndrome (MPS 1-H), globoid cell leukodystrophy (GLD; Krabbes disease), adrenoleukodystrophy, metachromatic leukodystrophy, Wolmans disease, I-cell disease (mucolipidosis II; MLS-II), alpha-mannosidosis, fucosidosis, Niemann-Pick B/A disease, Slys disease (MPS VII), Gauchers disease (Gaucher-II-III), Battens disease, Farbers disease, Sanfilippo syndrome (MPS-III), Hunters disease (MPS-II), Maroteaux-Lamy syndrome (MPS-VI), and aspartylglucosaminuria (AGU). Over 500 patients with lysosomal and peroxisomal metabolic storage diseases due to deficiency of primary enzymes have been treated with hematopoietic stem cell transplantation since the initial patient was treated a quarter of century ago. Normal enzymatic activity has been robust and continuous over these years without the need for any medication. Proof of principle has been reported for multiple positive effects including that of the reconstruction of the central nervous system. Furthermore, the excellent engraftment rate along with significantly diminished graft-vs-host-disease needs to be emphasized. The genetic diseases enumerated above have remarkable differences from those discussed elsewhere in this issue of Seminars in Immunopathology. Each has a greater genetic heterogeneity. Misdiagnosis resulting in delay of treatment and further decline of function and ultimate quality of life occurs almost all the time. Neonatal screening of these diseases will be mandatory to vastly improve outcomes. Plans are being implemented to use dried blood spots on filter paper, as is commonly done for many other genetic diseases. Many new therapies are being adopted which should enhance positivity and acceptance of treatment by hematopoietic stem cell transplantation.

  17. Allogeneic Transplantation of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets in Canine Critical-Size Supra-Alveolar Periodontal Defect Model

    PubMed Central

    Tsumanuma, Yuka; Iwata, Takanori; Kinoshita, Atsuhiro; Washio, Kaoru; Yoshida, Toshiyuki; Yamada, Azusa; Takagi, Ryo; Yamato, Masayuki; Okano, Teruo; Izumi, Yuichi

    2016-01-01

    Abstract Periodontitis is a chronic inflammatory disease that induces the destruction of tooth-supporting tissues, followed by tooth loss. Although several approaches have been applied to periodontal regeneration, complete periodontal regeneration has not been accomplished. Tissue engineering using a combination of cells and scaffolds is considered to be a viable alternative strategy. We have shown that autologous transplantation of periodontal ligament-derived multipotent mesenchymal stromal cell (PDL-MSC) sheets regenerates periodontal tissue in canine models. However, the indications for autologous cell transplantation in clinical situations are limited. Therefore, this study evaluated the safety and efficacy of allogeneic transplantation of PDL-MSC sheets using a canine horizontal periodontal defect model. Canine PDL-MSCs were labeled with enhanced green fluorescent protein (EGFP) and were cultured on temperature-responsive dishes. Three-layered cell sheets were transplanted around denuded root surfaces either autologously or allogeneically. A mixture of β-tricalcium phosphate and collagen gel was placed on the bone defects. Eight weeks after transplantation, dogs were euthanized and subjected to microcomputed tomography and histological analyses. RNA and DNA were extracted from the paraffin sections to verify the presence of EGFP at the transplantation site. Inflammatory markers from peripheral blood sera were quantified using an enzyme-linked immunosorbent assay. Periodontal regeneration was observed in both the autologous and the allogeneic transplantation groups. The allogeneic transplantation group showed particularly significant regeneration of newly formed cementum, which is critical for the periodontal regeneration. Serum levels of inflammatory markers from peripheral blood sera showed little difference between the autologous and allogeneic groups. EGFP amplicons were detectable in the paraffin sections of the allogeneic group. These results suggest

  18. Fibrocyte-like cells recruited to the spleen support innate and adaptive immune responses to acute injury or infection

    PubMed Central

    von Köckritz-Blickwede, Maren; Reichart, Donna; McGillvray, Shauna M.; Wingender, Gerhard; Kronenberg, Mitchell; Glass, Christopher K.; Nizet, Victor; Brenner, David A.

    2011-01-01

    Bone marrow (BM)-derived fibrocytes are a population of CD45+ and collagen Type I-expressing cells that migrate to the spleen and to target injured organs, such as skin, lungs, kidneys, and liver. While CD45+Col+ fibrocytes contribute to collagen deposition at the site of injury, the role of CD45+Col+ cells in spleen has not been elucidated. Here, we demonstrate that hepatotoxic injury (CCl4), TGF-β1, lipopolysaccharide, or infection with Listeria monocytogenes induce rapid recruitment of CD45+Col+ fibrocyte-like cells to the spleen. These cells have a gene expression pattern that includes antimicrobial factors (myleoperoxidase, cathelicidin, and defensins) and MHC II at higher levels than found on quiescent or activated macrophages. The immune functions of these splenic CD45+Col+ fibrocyte-like cells include entrapment of bacteria into extracellular DNA-based structures containing cathelicidin and presentation of antigens to naïve CD8+ T cells to induce their proliferation. Stimulation of these splenic fibrocyte-like cells with granulocyte macrophage-colony stimulating factor or macrophage-colony stimulating factor induces downregulation of collagen expression and terminal differentiation into the dendritic cells or macrophage. Thus, splenic CD45+Col+ cells are a population of rapidly mobilized BM-derived fibrocyte-like cells that respond to inflammation or infection to participate in innate and adaptive immune responses. PMID:21499735

  19. Post-allogeneic Hematopoietic Stem Cell Transplantation (HSCT) changes in inorganic salivary components.

    PubMed

    Boer, C C; Correa, M E P; Tenuta, L M A; Souza, C A; Vigorito, A C

    2015-09-01

    Recent studies have considered the qualitative and quantitative assessment of salivary flow, as well the biochemical components of saliva, as possible biomarkers that might contribute to the pathogenesis of chronic graft-versus-host disease (cGHVD) in hematopoietic stem cell transplantation (HSCT) patients. The aim of this study was to evaluate prospectively the inorganic salivary status at different periods of allogeneic HSCT. Saliva collection and oral examination were performed prior to the HSCT, ​between days 8 and 10, days 80 and 100, and at the cGVHD onset. Concentrations of calcium (Ca), phosphate (Pi), chloride (Cl), magnesium (Mg), potassium (K), and sodium (Na) were performed using colorimetric reactions and atomic absorption. Fifty-five consecutive patients undergoing first allogeneic HSCT were included in this study. Between days 8 and 10, the salivary flow rate was significantly higher (p = 0.05), Pi concentration was decreased (p = 0.007), and Na and Cl were increased (p = 0.001 and p = 0.001, respectively), compared with the baseline. Salivary flow rate during the same period showed a negative correlation with Pi concentration (p = 0.02) and a positive correlation with Na and Cl concentrations (p = 0.003 and p = 0.001, respectively). The salivary flow rate was decreased between days 80 and 100 (p = 0.02) and Na, Cl, and K concentrations were increased (p = 0.03, p = 0.02, and p = 0.003, respectively). Salivary flow rate showed a negative correlation with Na and Cl (p = 0.01 and p = 0.013, respectively). At cGVHD onset, the salivary flow rate showed no statistical difference compared with the other studied periods. A trend was observed in the higher Na concentration compared with the baseline (p = 0.06) and Pi concentration presented a significant decrease (p = 0.004). Ca and Mg concentrations showed no changes during all evaluation periods. The present study showed changes in inorganic

  20. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  1. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).

    PubMed

    Koç, O N; Day, J; Nieder, M; Gerson, S L; Lazarus, H M; Krivit, W

    2002-08-01

    Patients with Hurler syndrome (mucopolysaccharidosis type-IH) and metachromatic leukodystrophy (MLD) develop significant skeletal and neurologic defects that limit their survival. Transplantation of allogeneic hematopoietic stem cells results in partial correction of the clinical manifestations. We postulated that some of these defects may be corrected by infusion of allogeneic, multipotential, bone marrow-derived mesenchymal stem cells (MSC). Patients with Hurler syndrome (n = 5) or MLD (n = 6) who previously underwent successful bone marrow transplantation from an HLA-identical sibling were infused with 2-10 x 10(6)/kg MSCs, isolated and expanded from a bone marrow aspirate of the original donor. There was no infusion-related toxicity. In most recipients culture-purified MSCs at 2 days, 30-60 days and 6-24 months after MSC infusion remained of host type. In two patients the bone marrow-derived MSCs contained 0.4 and 2% donor MSCs by FISH 60 days after MSC infusion. In four patients with MLD there were significant improvements in nerve conduction velocities after MSC infusion. The bone mineral density was either maintained or slightly improved in all patients. There was no clinically apparent change in patients' overall health, mental and physical development after MSC infusion. We conclude that donor allogeneic MSC infusion is safe and may be associated with reversal of disease pathophysiology in some tissues. The role of MSCs in the management of Hurler syndrome and MLD should be further evaluated.

  2. Allogeneic peripheral blood stem cell rescue of late graft failure after bone marrow transplantation in patients with aplastic anemia.

    PubMed Central

    Chung, Ik-Joo; Lee, Je-Jung; Park, Moo-Rim; Kook, Hoon; Cho, Sang-Hee; Hwang, Tai-Ju; Kim, Hyeoung-Joon

    2002-01-01

    We investigated the effect and outcome of allogeneic peripheral blood stem cell (PBSC) rescue for aplastic anemia (AA) patients with graft failure after allogeneic bone marrow transplantation (BMT). Seven (28%) of 25 AA patients who received BMT from HLA-identical sibling donors developed late graft failure at a median of 7 months (range, 2.0-9.3 months) after transplantation. The patients with graft failure were treated with PBSC collected from the original donor after mobilization with granulocyte-colony stimulating factor (G-CSF). The median boost dose of peripheral blood mononuclear cells was 3.1 x 10(8)/kg (range, 1.4-11.9 x 10(8)/kg). Median times to reach an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 50 x 10(9)/L were 7 days (range, 4-14 days) and 9 days (range, 3-41 days), respectively. There was sustained graft function in 6 of 7 patients, with a median follow-up duration of 3.3 yr (range, 1.0-6.2 yr). Grade-I acute graft-versus-host disease (GVHD) occurred in 2 patients, while extensive chronic GVHD developed in 3 patients. This report shows that G-CSF-mobilized allogeneic PBSC rescue is very effective in achieving complete and sustained engraftment in patients with AA after graft failure. However, more efficacious measures to prevent extensive chronic GVHD remain to be developed. PMID:12172040

  3. Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia.

    PubMed

    Lindsay, Julian; Kabir, Masrura; Gilroy, Nicole; Dyer, Gemma; Brice, Lisa; Moore, John; Greenwood, Matthew; Hertzberg, Mark; Gottlieb, David; Larsen, Stephen R; Hogg, Megan; Brown, Louisa; Huang, Gillian; Tan, Jeff; Ward, Christopher; Kerridge, Ian

    2016-12-01

    In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402-item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind-body therapy (17.2%), herbal supplements (13.5%), manipulative and body-based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

  4. Astrovirus Infection in Hospitalized Infants with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Berger, Christoph; Greiner, Oliver; Caduff, Rosmarie; Trkola, Alexandra; Bossart, Walter; Gerlach, Daniel; Schibler, Manuel; Cordey, Samuel; McKee, Thomas Alexander; Van Belle, Sandra; Kaiser, Laurent; Tapparel, Caroline

    2011-01-01

    Infants with severe primary combined immunodeficiency (SCID) and children post-allogeneic hematopoietic stem cell transplantation (HSCT) are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA) techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients. PMID:22096580

  5. Optimizing outcomes following allogeneic hematopoietic progenitor cell transplantation in AML: the role of hypomethylating agents.

    PubMed

    Martino, Massimo; Fedele, Roberta; Moscato, Tiziana; Ronco, Francesca

    2013-07-01

    Aberrant DNA methylation is a key pathological mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and provides rationale for the clinical development of hypomethylating agents (HMAs) for the treatment of these diseases. One HMA, azacitidine (Vidaza®, Celgene Corp.), has demonstrated improved survival versus conventional care regimens in patients with intermediate-2/high-risk MDS and AML (20-30% blasts) and has a favorable tolerability profile. Emerging evidence indicates that azacitidine can have an immunomodulatory effect by, for example, increasing functional regulatory T-cell (Treg) numbers and killer-cell-immunoglobulin-like receptor expression. Allogeneic hematopoietic progenitor cell transplantation (allo HPCT) is the only potentially curative treatment approach in patients with advanced MDS or AML. Unfortunately, allo HPCT in these settings is limited because most patients are ineligible due to age/comorbidities, or are at a high risk of treatment failure due to disease relapse. Recent studies have shown that azacitidine after allo HPCT increases Treg numbers while inducing a cytotoxic CD8+ T-cell response, suggesting a potential mechanism for augmenting the graft-versus-leukemia (GvL) effect without increasing graft-versushost- disease (GVHD). In patients at a high risk of relapse following allo HPCT, pre-emptive azacitidine may help prevent/delay relapse. For patients who have relapsed following allo HPCT, azacitidine may be a salvage therapy option, either as monotherapy or in combination with donor lymphocyte infusions (DLI). In this mini-review, we discuss these emerging clinical data for HMAs in the post-allo HPCT regimens and highlight the possible future role of azacitidine in this setting.

  6. Fetal Liver-Derived Mesenchymal Stem Cell Engraftment After Allogeneic In Utero Transplantation into Rabbits

    PubMed Central

    Moreno, Rafael; Martínez-González, Itziar; Rosal, Marta; Nadal, Marga; Petriz, Jordi; Gratacós, Eduard

    2012-01-01

    Prenatal transplantation of genetically engineered mesenchymal stem cells (MSCs) might benefit prevention or treatment of early-onset genetic disorders due to the cells' intrinsic regenerative potential plus the acquired advantage from therapeutic transgene expression. However, a thorough assessment of the safety, accessibility, and behavior of these MSCs in the fetal environment using appropriate animal models is required before we can advance toward a clinical application. We have recently shown that fetal rabbit liver MSCs (fl-MSCs) have superior growth rate, clonogenic capability, and in vitro adherence and differentiation abilities compared with adult rabbit bone marrow MSCs. In this follow-up study, we report safe and widespread distribution of recombinant pSF-EGFP retrovirus-transduced fl-MSCs (EGFP+-fl-MSCs) in neonatal rabbit tissues at 10 days after fetal allogeneic transplantation through both intrahepatic and intra-amniotic administration. Conversely, a more restricted biodistribution pattern according to the route of administration was apparent in the young rabbits intervened at 16 weeks after fetal EGFP+-fl-MSC transplantation. Furthermore, the presence of these cells in the recipients' tissues, tracked with the reporter provirus, was inversely related to the developmental stage of the fetuses at the time of intervention. Long-term engraftment was confirmed both by fluorescence in situ hybridization analysis on touch tissue imprints using a chromosome Y-specific BAC probe, and by immunohistochemical localization of EGFP expression. Finally, there was no evidence of immune responses against the transplanted EGFP+-fl-MSCs or the EGFP transgenic product in the treated young rabbits. Thus, cell transplantation approaches using genetically engineered fetal MSCs may prove particularly valuable to frontier medical treatments for congenital birth defects in perinatology. PMID:21495909

  7. Adenoviral Infections in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience

    PubMed Central

    Yilmaz, Musa; Chemaly, Roy F.; Han, Xiang Y.; Thall, Peter F.; Fox, Patricia S.; Tarrand, Jeffrey J.; De Lima, Marcos J.; Hosing, Chitra M.; Popat, Uday R.; Shpall, Elizabeth; Champlin, Richard E.; Qazilbash, Muzaffar H.

    2014-01-01

    Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). A better understanding of AI in allo-HCT recipients can serve a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HCT at M.D. Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that, when the joint effects of all covariates were accounted for, a cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm3, and male gender were associated with a higher probability of disseminated AI. The overall survival was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months versus 28 months, respectively, p<0.001) and for patients with ALC ≤ 200/mm3 (p<0.001). Disseminated AI, in patients who received allo-HCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients. PMID:23503529

  8. Serum proteomic profiling and haptoglobin polymorphisms in patients with GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    McGuirk, Joseph; Hao, Gang; Hou, Weijian; Abhyankar, Sunil; Williams, Casey; Yan, Weisi; Yuan, Jianda; Guan, Xiuqin; Belt, Robert; Dejarnette, Shaun; Wieman, Jeffery; Yan, Ying

    2009-01-01

    We studied serum proteomic profiling in patients with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) by two-dimensional gel electrophoresis (2-DE) and mass spectrometry analysis. The expression of a group of proteins, haptoglobin (Hp), alpha-1-antitrypsin, apolipoprotein A-IV, serum paraoxonase and Zn-alpha-glycoprotein were increased and the proteins, clusterin precursor, alpha-2-macroglobulin, serum amyloid protein precursor, sex hormone-binding globulin, serotransferrin and complement C4 were decreased in patients with extensive chronic GVHD (cGVHD). Serum haptoglobin (Hp) levels in patients with cGVHD were demonstrated to be statistically higher than in patients without cGVHD and normal controls (p < 0.01). We used immunoblotting and PCR in combination with 2-DE gel image analysis to determine Hp polymorphisms in 25 allo-HCT patients and 16 normal donors. The results demonstrate that patients with cGVHD had a higher incidence of HP 2-2 phenotype (43.8%), in comparison to the patients without cGVHD (0%) and normal donors (18.7%), suggesting the possibility that specific Hp polymorphism may play a role in the development of cGVHD after allo-HCT. In this study, quantitative serum Hp levels were shown to be related to cGVHD development. Further, the data suggest the possibility that specific Hp polymorphisms may be associated with cGVHD development and warrant further investigation. PMID:19379511

  9. Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Vantyghem, Marie-Christine; Cornillon, Jérôme; Decanter, Christine; Defrance, Frédérique; Karrouz, Wassila; Leroy, Clara; Le Mapihan, Kristell; Couturier, Marie-Anne; De Berranger, Eva; Hermet, Eric; Maillard, Natacha; Marcais, Ambroise; Francois, Sylvie; Tabrizi, Reza; Yakoub-Agha, Ibrahim

    2014-10-29

    Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

  10. Salivary proteomic analysis and acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Chiusolo, Patrizia; Giammarco, Sabrina; Fanali, Chiara; Bellesi, Silvia; Metafuni, Elisabetta; Sica, Simona; Iavarone, Federica; Cabras, Tiziana; Messana, Irene; Leone, Giuseppe; Castagnola, Massimo

    2013-06-01

    Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), developing in 35%-70% of all allo-HSCT recipients despite immunosuppressive prophylaxis. The recent application of proteomic tools that allow screening for differentially expressed or excreted proteins in body fluids could possibly identify specific biomarkers for GVHD. Whole saliva is highly attractive for noninvasive specimen collection. In the present study, we collected saliva specimens from 40 consecutives patients who underwent allo-HSCT between December 2008 and March 2011 at our institution. The specimens were analyzed by HPLC coupled to electrospray-ionization mass spectrometry. Variable expression of S100 protein family members (S100A8, S100A9, and S100A7) was detected. Fourteen of 23 patients with GVHD demonstrated the presence of S100A8, compared with only 2 patients without GVHD and 0 patients in the control group (P = .001). S100A7 was detectable in 11 of the 23 patients with GVHD but was absent in the other 2 groups (P = .0001). S100A9-short was detected in 20 patients with GVHD, in 9 patients without GVHD, and in 8 healthy volunteers (P = .01) Further studies are needed to clarify the role of these proteins as a marker of GVHD or as an index of mucosal inflammation.

  11. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs.

    PubMed

    Griffith, Linda M; Cowan, Morton J; Kohn, Donald B; Notarangelo, Luigi D; Puck, Jennifer M; Schultz, Kirk R; Buckley, Rebecca H; Eapen, Mary; Kamani, Naynesh R; O'Reilly, Richard J; Parkman, Robertson; Roifman, Chaim M; Sullivan, Kathleen E; Filipovich, Alexandra H; Fleisher, Thomas A; Shearer, William T

    2008-12-01

    Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible. A conference of experts in HCT treatment of PID has recommended (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of patients with SCID receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants before compromise by infection; and (4) studies of the natural history of disease in patients who do or do not receive HCT for the non-SCID diseases of Wiskott-Aldrich syndrome and chronic granulomatous disease. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases, and analysis will be required for the success of these studies.

  12. Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Uhlving, Hilde Hylland; Andersen, Claus B; Christensen, Ib Jarle; Gormsen, Magdalena; Pedersen, Karen Damgaard; Buchvald, Frederik; Heilmann, Carsten; Nielsen, Kim Gjerum; Mortensen, Jann; Moser, Claus; Sengeløv, Henrik; Müller, Klaus Gottlob

    2015-03-01

    Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases.

  13. Allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis

    PubMed Central

    Rashidi, Armin; Ebadi, Maryam; Cashen, Amanda F.

    2016-01-01

    Allogeneic stem cell transplantation (allo-SCT) outcomes in patients with Hodgkin lymphoma (HL) remain poorly defined. We performed a meta-analysis of allo-SCT studies in HL patients. The primary endpoints were 6-month, 1-year, 2-year, and 3-year relapse-free survival (RFS) and overall survival (OS). A total of 42 reports (1,850 patients) were included. The pooled estimates (95%CI) for 6-month, 1-year, 2-year, and 3-year RFS were 77 (59–91)%, 50 (42–57)%, 37 (31–43)%, and 31 (25–37)%, respectively. The corresponding numbers for OS were 83 (75–91)%, 68 (62–74)%, 58 (52–64)%, and 50 (41–58)%, respectively. There was statistical heterogeneity among studies in all outcomes. In meta-regression, accrual initiation year in 2000 or later was associated with higher 6-month (P = 0.012) and 1-year OS (P = 0.046), and pre-SCT remission with higher 2-year OS (P = 0.047) and 1-year RFS (P = 0.016). In conclusion, outcomes of allo-SCT in HL have improved over time, with 5–10% lower non-relapse mortality and relapse rates and 15–20% higher RFS and OS in studies that initiated accrual in 2000 or later compared to earlier studies. However, there is no apparent survival plateau, demonstrating the need to improve on current allo-SCT strategies in relapsed/refractory HL. PMID:26726948

  14. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation

    PubMed Central

    Marks, David I; Pagliuca, Antonio; Kibbler, Christopher C; Glasmacher, Axel; Heussel, Claus-Peter; Kantecki, Michal; Miller, Paul JS; Ribaud, Patricia; Schlamm, Haran T; Solano, Carlos; Cook, Gordon

    2011-01-01

    Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P <0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P<0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P<0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals. PMID:21880032

  15. Invasive fungal infection in allogeneic hematopoietic stem cell transplant recipients: single center experiences of 12 years*

    PubMed Central

    Shi, Ji-min; Pei, Xu-ying; Luo, Yi; Tan, Ya-min; Tie, Ru-xiu; He, Jing-song; Zheng, Wei-yan; Zhang, Jie; Cai, Zhen; Lin, Mao-fang; Huang, He

    2015-01-01

    Invasive fungal infection (IFI) is a growing cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively reviewed the records of 408 patients undergoing allo-HSCTs during the period November 1998 to December 2009, analyzed the incidence and risk factors of IFI, and examined the impact of IFI on overall survival. A total of 92 (22.5%) episodes suffered proven or probable IFI (4 patients were proven, 88 patients were probable). Candida was the most common pathogen for early IFI, and mold was the most frequent causative organism for late IFI. A prior history of IFI, human leukocyte antigen (HLA) mismatch, long-time neutropenia, and acute graft-versus-host-disease (GVHD) were risk factors for early IFI. A prior history of IFI, corticosteroid therapy, cytomegalovirus (CMV) disease, and chronic GVHD were risk factors for late IFI. IFI-related mortality was 53.26%. The 12-year overall survival (OS) rate for IFI was significantly lower than that of patients without IFI (41.9% vs. 63.6%, P<0.01). PMID:26365122

  16. Allogeneic stem cell transplant for adults with myelodysplastic syndromes: relevance of pre-transplant disease status.

    PubMed

    Busca, Alessandro; Pecoraro, Clara; Giaccone, Luisa; Bruno, Benedetto; Allione, Bernardino; Corsetti, Maria Teresa; Pini, Massimo; Marmont, Filippo; Audisio, Ernesta; D'Ardia, Stefano; Frairia, Chiara; Castiglione, Anna; Ciccone, Giovannino; Levis, Alessandro; Vitolo, Umberto; Falda, Michele

    2014-04-01

    The aim of the present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplant between January 1995 and September 2010 in two Italian hematology centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 33% (95% confidence interval [CI] 21-45%) and 78% (95% CI 66-90%), respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (95% CI 6-21%). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (95% CI 31-51%) and 49% (95% CI 38-59%), respectively. On multivariate analysis, advanced disease stage at transplant was the major independent variable associated with an inferior 2-year PFS (HR 3.66, 95% CI 1.98-6.76) and OS (HR 3.68, 95% CI 1.95-6.93). Use of an alternative donor was an independent variable associated with TRM (HR 3.18, 95% CI 1.31-7.72). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to an improved outcome.

  17. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J; Long-Boyle, Janel

    2016-05-01

    Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

  18. Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Nomura, Shosaku; Maeda, Yoshinobu; Ishii, Kazuyoshi; Katayama, Yuta; Yagi, Hideo; Fujishima, Naoto; Ota, Shuichi; Moriyama, Masato; Ikezoe, Takayuki; Miyazaki, Yasuhiko; Hayashi, Kunio; Fujita, Shinya; Satake, Atsushi; Ito, Tomoki; Kyo, Taiichi; Tanimoto, Mitsune

    2016-01-01

    Background Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. Materials and methods The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. Conclusion Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity. PMID:26848281

  19. Chest computed tomography of late invasive aspergillosis after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kojima, Rie; Tateishi, Ukihide; Kami, Masahiro; Murashige, Naoko; Nannya, Yasuhito; Kusumi, Eiji; Sakai, Miwa; Tanaka, Yuji; Kanda, Yoshinobu; Mori, Shin-Ichiro; Chiba, Shigeru; Kusumoto, Masahiko; Miyakoshi, Shigesaburo; Hirai, Hisamaru; Taniguchi, Shuichi; Sakamaki, Hisashi; Takaue, Yoichi

    2005-07-01

    Computed tomography (CT) is a powerful diagnostic tool for invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT); however, little information is available concerning CT findings of late IA after allo-SCT. To characterize CT findings of late IA, we retrospectively examined medical records and high-resolution CT findings of 27 allo-SCT recipients with late IA. Either acute or chronic GVHD was diagnosed in 24 patients. All 27 patients were given corticosteroids at IA diagnosis. High-resolution CT findings included halo (n=12), centrilobular nodules (n=12), ill-defined consolidation (n=13), ground-glass attenuation (n=8), pleural effusion (n=7), pleural-based consolidation (n=4), and cavitation (n=4). CT findings showing centrilobular nodules and either halo or cavitation were classified into bronchopneumonia type and angioinvasive type, respectively. Angioinvasive-type, bronchopneumonia-type, and combination-type IA were diagnosed in 11, 8, and 4 patients, respectively. CT findings were nonspecific in the other 4 patients. One bronchopneumonia-type case and 2 angioinvasive-type IA cases were subsequently diagnosed as combination type. Although there were no significant differences in patient characteristics between the 2 types of IA, bronchopneumonia-type IA had a poorer prognosis than angioinvasive IA ( P=.022). Halo is a useful diagnostic marker in late IA as well as early IA, and late IA frequently manifests as bronchopneumonia.

  20. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial.

    PubMed

    Jaspers, Aurélie; Baron, Frédéric; Willems, Evelyne; Seidel, Laurence; Hafraoui, Kaoutar; Vanstraelen, Gaetan; Bonnet, Christophe; Beguin, Yves

    2014-07-03

    We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (N = 131) were randomized (1:1) between no treatment (control arm) or erythropoietin at 500 U/kg per week (EPO arm). Patients were also stratified into 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day (D)28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on D28, and patients also given NMHCT but with rhEPO to start on D0. The proportion of complete correctors (ie, Hb ≥13 g/dL) before D126 posttransplant was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median, 90 days) (P < .001). Hb levels were higher and transfusion requirements decreased (P < .001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on D0. There was no difference in rates of thromboembolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT.

  1. Up-front allogeneic hematopoietic cell transplantation in acute myeloid leukemia arising from the myelodysplastic syndrome.

    PubMed

    Choi, Yunsuk; Kim, Sung-Doo; Park, Young-Hoon; Lee, Jae Seok; Kim, Dae-Young; Lee, Jung-Hee; Lee, Kyoo-Hyung; Seol, Miee; Lee, Young-Shin; Kang, Young-Ah; Jeon, Mijin; Jung, Ah Rang; Lee, Je-Hwan

    2015-01-01

    In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up-front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available.

  2. [Cold autoimmune hemolytic anemia complicated with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation].

    PubMed

    Okamura, Hiroshi; Nakane, Takahiko; Fujino, Keizo; Koh, Shiro; Yoshimura, Takuro; Nishimoto, Mitsutaka; Hayashi, Yoshiki; Koh, Hideo; Nakao, Yoshitaka; Nakamae, Hirohisa; Hino, Masayuki

    2015-04-01

    Myelodysplastic syndrome (MDS) is known to often be complicated by a range of autoimmune diseases. We herein present a case with MDS complicated by cold autoimmune hemolytic anemia (cold AIHA). The patient was a 51-year-old woman. She was diagnosed with MDS (refractory cytopenia with multilineage dysplasia) in May 2009. In January 2010, she underwent unrelated allogeneic bone marrow transplantation but was re-admitted in October 2010 for treatment of relapsed MDS. Despite daily transfusions of red blood cells, her anemia failed to improve. Her laboratory examinations showed a low haptoglobin level and elevation of indirect bilirubin and LDH. The direct Coombs test was positive at a low and at room temperature and cold agglutinin was negative. After confirming the diagnosis of cold AIHA, all transfusion fluids were warmed but her anemia still failed to improve. In addition to the warmed transfusion fluids, we administered corticosteroids, immunosuppressive agents and high-dose intravenous immunoglobulin infusions. This management strategy ameliorated the patient's hemolytic anemia. To our knowledge, MDS cases complicated by cold AIHA are rare. Our patient thus provides a valuable contribution to medical knowledge.

  3. Risk factors for recurrent Clostridium difficile infection in allogeneic hematopoietic cell transplant recipients.

    PubMed

    Mani, S; Rybicki, L; Jagadeesh, D; Mossad, S B

    2016-05-01

    Clostridium difficile infection (CDI) is one of the leading causes of hospital-acquired infections in recent times. Hematopoietic stem cell transplantation (HSCT) confers increased risk for CDI because of prolonged hospital stay, immunosuppression, the need to use broad-spectrum antibiotics and a complex interplay of preparative regimen and GvHD-induced gut mucosal damage. Our study evaluated risk factors (RF) for recurrent CDI in HSCT recipients given the ubiquity of traditional RF for CDI in this population. Of the 499 allogeneic HSCT recipients transplanted between 2005 and 2012, 61 (12%) developed CDI within 6 months before transplant or 2 years after transplant and were included in the analysis. Recurrent CDI occurred in 20 (33%) patients. One year incidence of CDI recurrence was 31%. Multivariable analyses identified the number of antecedent antibiotics other than those used to treat CDI as the only significant RF for recurrence (hazard ratio 1.96, 95% confidence interval 1.09-3.52, P=0.025). Most recurrences occurred within 6 months of the first CDI, and the recurrence of CDI was associated with a trend for increased risk of mortality. This prompts the need for further investigation into secondary prophylaxis to prevent recurrent CDI.

  4. HEMORRHAGIC CYSTITIS AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION: RISK FACTORS, GRAFT SOURCE, AND SURVIVAL

    PubMed Central

    Lunde, Laura E.; Dasaraju, Sandhyarani; Cao, Qing; Cohn, Claudia S.; Reding, Mark; Bejanyan, Nelli; Trottier, Bryan; Rogosheske, John; Brunstein, Claudio; Warlick, Erica; Young, Jo Anne H.; Weisdorf, Daniel J.; Ustun, Celalettin

    2017-01-01

    Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well-known. We evaluated HC in a large cohort (n=1321, 2003 – 2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute graft-versus-host disease (GVHD), fever, severe thrombocytopenia, and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III–IV) was associated with increased treatment-related mortality (TRM) but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis and early interventions to limit its severity are still needed. PMID:26168069

  5. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation.

    PubMed

    Nannya, Yasuhito; Shinohara, Akihito; Ichikawa, Motoshi; Kurokawa, Mineo

    2014-03-01

    Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

  6. Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation

    PubMed Central

    Inaba, Hiroto; Hartford, Christine M.; Pei, Deqing; Posner, Meredith J.; Yang, Jie; Hayden, Randall T.; Srinivasan, Ashok; Triplett, Brandon M.; McCulllers, Jon A.; Pui, Ching-Hon; Leung, Wing

    2011-01-01

    Summary The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to 8 vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children’s Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft-versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations. PMID:22017512

  7. Risk of melanocytic nevi and nonmelanoma skin cancer in children after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Song, J S; London, W B; Hawryluk, E B; Guo, D; Sridharan, M; Fisher, D E; Lehmann, L E; Duncan, C N; Huang, J T

    2017-04-03

    There is a known increased risk of skin cancer in the adult population after hematopoietic stem cell transplantation (HSCT). However, late dermatologic effects that children may experience after HSCT have not been well described. The primary objective of this study was to characterize nevi and skin cancers affecting children after allogeneic HSCT. A cross-sectional cohort study of 85 pediatric HSCT recipients and 85 controls matched for age, sex and skin phototype was performed at a single institution. All participants underwent a full skin examination. Median age at study visit was 13.8 years in HSCT patients with median time post-HSCT of 3.6 years. HSCT patients had significantly more nevi than control patients (median (range): 44 (0-150) vs 11 (0-94), P<0.0001). HSCT patients also had significantly more nevi >5 mm in diameter and atypical nevi than controls. Factors associated with increased nevus count included malignant indication for HSCT, pretransplant chemotherapy, TBI exposure and myeloablative conditioning. A total of 16.5% of HSCT patients developed cancerous, precancerous lesions and/or lentigines. Our study suggests that pediatric HSCT recipients have an increased risk of benign and atypical melanocytic proliferations and nonmelanoma skin cancer that can manifest even during childhood.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.57.

  8. Digital PCR Panel for Sensitive Hematopoietic Chimerism Quantification after Allogeneic Stem Cell Transplantation

    PubMed Central

    Stahl, Tanja; Rothe, Caroline; Böhme, Manja U.; Kohl, Aloisa; Kröger, Nicolaus; Fehse, Boris

    2016-01-01

    Accurate and sensitive determination of hematopoietic chimerism is a crucial diagnostic measure after allogeneic stem cell transplantation to monitor engraftment and potentially residual disease. Short tandem repeat (STR) amplification, the current “gold standard” for chimerism assessment facilitates reliable accuracy, but is hampered by its limited sensitivity (≥1%). Digital PCR (dPCR) has been shown to combine exact quantification and high reproducibility over a very wide measurement range with excellent sensitivity (routinely ≤0.1%) and thus represents a promising alternative to STR analysis. We here aimed at developing a whole panel of digital-PCR based assays for routine diagnostic. To this end, we tested suitability of 52 deletion/insertion polymorphisms (DIPs) for duplex analysis in combination with either a reference gene or a Y-chromosome specific PCR. Twenty-nine DIPs with high power of discrimination and good performance were identified, optimized and technically validated. We tested the newly established assays on retrospective patient samples that were in parallel also measured by STR amplification and found excellent correlation. Finally, a screening plate for initial genotyping with DIP-specific duplex dPCR assays was designed for convenient assay selection. In conclusion, we have established a comprehensive dPCR system for precise and high-sensitivity measurement of hematopoietic chimerism, which should be highly useful for clinical routine diagnostics. PMID:27618030

  9. Selective inhibitory effects of 50-nm gold nanoparticles on mouse macrophage and spleen cells.

    PubMed

    Kingston, Micah; Pfau, Jean C; Gilmer, John; Brey, Richard

    2016-01-01

    Nanoparticles (NP) are significant to multiple industrial processes, consumer products and medical applications today. The health effects of many different types of NP, however, are largely unknown. The purpose of this study was to test the effects of 50-nm gold NP coated with poly-N-vinylpyrrolidone (PVP) on mouse macrophage and spleen cells with and without lipopolysaccharide (LPS), testing the hypothesis that the NP would modulate immune responses without being overtly toxic. Gold NP had no effect on macrophage viability and, in the absence of LPS, they had no effect on tumor necrosis factor (TNF)-α production as measured by ELISA. The presence of LPS significantly increased the release of TNFα from the macrophages above no-treatment controls, but increasing gold NP concentration led to decreasing release of TNFα. The reactive oxygen species (ROS) produced by exposed macrophages were also reduced compared to untreated controls, both with and without LPS, suggesting some kind of oxygen radical scavenging. In splenocyte cultures, gold NP had no effect alone, but significantly reduced the release of interleukin (IL)-17 and TNFα triggered by LPS. These results suggest that the gold NP used here are not cytotoxic to immune cells at these concentrations, but may affect cellular responses to infection or inflammation by altering the balance of cytokines.

  10. Normalization of red cell enolase level following allogeneic bone marrow transplantation in a child with Diamond-Blackfan anemia.

    PubMed

    Park, Jeong A; Lim, Yeon Jung; Park, Hyeon Jin; Kong, Sun Young; Park, Byung Kiu; Ghim, Thad T

    2010-04-01

    We describe a girl with Diamond-Blackfan anemia with accompanying red cell enolase deficiency. At the age of 9 yr old, the patient received allogeneic bone marrow transplantation from her HLA-identical sister who had normal red cell enolase activity. While the post transplant DNA analysis with short tandem repeat has continuously demonstrated a stable mixed chimerism on follow-up, the patient remains transfusion independent and continues to show a steady increase in red cell enolase activity for over two and a half years following bone marrow transplantation.

  11. Role of naive-derived T memory stem cells in T-cell reconstitution following allogeneic transplantation

    PubMed Central

    Roberto, Alessandra; Castagna, Luca; Zanon, Veronica; Bramanti, Stefania; Crocchiolo, Roberto; McLaren, James E.; Gandolfi, Sara; Tentorio, Paolo; Sarina, Barbara; Timofeeva, Inna; Santoro, Armando; Carlo-Stella, Carmelo; Bruno, Benedetto; Carniti, Cristiana; Corradini, Paolo; Gostick, Emma; Ladell, Kristin; Price, David A.; Roederer, Mario; Mavilio, Domenico

    2015-01-01

    Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580. PMID:25742699

  12. Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants.

    PubMed

    Solh, Melhem; Brunstein, Claudio; Morgan, Shanna; Weisdorf, Daniel

    2011-05-01

    Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.

  13. Adoptive transfer of unresponsiveness to allogeneic skin grafts with hepatic gamma delta + T cells.

    PubMed Central

    Gorczynski, R M

    1994-01-01

    C3H/HEJ mice injected with irradiated multiple minor incompatible B10.BR lymphoid cells via the portal vein showed delayed rejection of subsequent B10.BR skin grafts. Similar delayed rejection was produced by lateral tail vein injection of B10.BR hepatic mononuclear cells or H-2k cells pulsed in vivo with B10 minor histocompatibility antigens. Inhibition of C3H anti-B10.BR immunity in vivo (assessed by delayed graft rejection) and in vitro (assessed by B10.BR-induced lymphokine production) can be transferred by radioresistant, plastic-adherent F4/80+33D1-CD4-CD8-alpha beta TcR-gamma delta TcR- mononuclear hepatic cells from (C3H/HEJ x C3H.SW)F1 mice injected 36 hr earlier with 100 x 10(6) irradiated spleen cells. By 10 days post-injection, cells transferring delayed rejection are radiosensitive, plastic non-adherent, F4/80-33D1-CD4-CD8- alpha beta Tc+- gamma delta TcR+ cells. Injection of interleukin-2 (IL-2) in vivo into mice receiving pretreatment with B10.BR cells via the portal vein, or adoptive transfer into such mice of immune anti-B10.BR lymphoid cells, abolished delayed rejection on subsequent skin grafting. Delayed rejection or modulation of lymphokine production was associated in all cases with suppression of IL-2 production and preferential retention of IL-4 production from cells stimulated in vitro. PMID:8132216

  14. Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.

    PubMed

    Iwen, P C; Rupp, M E; Bishop, M R; Rinaldi, M G; Sutton, D A; Tarantolo, S; Hinrichs, S H

    1998-12-01

    The first case of disseminated aspergillosis caused by Aspergillus ustus in an allogeneic peripheral stem cell transplant patient is described. The patient, a 46-year-old female with a history of myelodysplastic syndrome, underwent high-dose chemotherapy and total body irradiation prior to transplantation. She was released from the hospital 49 days posttransplant (p.t.) in a stable condition with an absolute neutrophil count (ANC) of 2,700 cells per microl. Multiple antimicrobial agents, including itraconazole (ITR), were prescribed during hospitalization and at the time of discharge. Three days after discharge, the patient was readmitted with hemorrhagic cystitis, persistent thrombocytopenia, and bilateral pulmonary consolidation, although no fever was present. The ANC at the time of readmission was 3,500. Upon detection of a pulmonary nodule (day 67 p.t.), a bronchoalveolar lavage was performed; the lavage fluid was positive for both cytomegalovirus and parainfluenza virus and negative for fungus. The patient was placed on ganciclovir. A biopsy specimen from a leg lesion also noted on day 67 p.t. revealed septate hyphae consistent with Aspergillus species, and a culture subsequently yielded Aspergillus ustus. Confirmation detection of A. ustus was made by demonstration of characteristic reproductive structures with the presence of Hülle cells. On day 67 p.t., ITR was discontinued and liposomal amphotericin B (AMB) was initiated. The patient's condition worsened, and she died 79 days p.t. At the time of autopsy, septate hyphae were present in heart, thyroid, and lung tissues, with lung tissue culture positive for A. ustus. In vitro susceptibility testing indicated probable resistance to AMB but not to ITR. This case supports the need for the development of rapid methods to determine antifungal susceptibility.

  15. ABO mismatch is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation.

    PubMed

    Logan, Aaron C; Wang, Zhiyu; Alimoghaddam, Kamran; Wong, Ruby M; Lai, Tze; Negrin, Robert S; Grumet, Carl; Logan, Brent R; Zhang, Mei-Jie; Spellman, Stephen R; Lee, Stephanie J; Miklos, David B

    2015-04-01

    We evaluated ABO associated outcomes in 1737 patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, overall survival (OS) was inferior in minor MM hematopoietic cell transplantations (median 2.1 versus 6.3 years; hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.19 to 2.05; P = .001) in comparison with ABO-matched grafts. ABO minor MM was associated with an increase in early nonrelapse mortality (NRM) (18% versus 13%; HR, 1.48; 95% CI, 1.06 to 2.06; P = .02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR, 1.55; 95% CI, 1.07 to 2.25; P = .021) and increased NRM (HR, 1.72; 95% CI, 1.11 to 2.68; P = .03) were observed in recipients of ABO minor-MM grafts. A second independent analysis of a CIBMTR data set including 5179 patients with acute myeloid leukemia and myelodysplastic syndrome identified a nonsignificant trend toward decreased OS in recipients of ABO minor-MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR, 1.19; 95% CI, 1.08 to 1.31; P < .001) and increased NRM (HR, 1.23; 95% CI, 1.08 to 1.4; P = .002). ABO minor and major MM are risk factors for worse transplantation outcomes, although the associated hazards may not be uniform across different transplantation populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B cell therapy or other peri-transplantation treatments.

  16. Allogeneic hematopoietic stem-cell transplantation for adult and adolescent hemophagocytic lymphohistiocytosis: a single center analysis.

    PubMed

    Fu, Li; Wang, Jingshi; Wei, Na; Wu, Lin; Wang, Yini; Huang, Wenqiu; Zhang, Jia; Liu, Jinli; Wang, Zhao

    2016-11-01

    Myeloablative conditioning-based allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of adult and adolescent hemophagocytic lymphohistiocytosis (HLH) is rarely reported. We conducted a retrospective study of 30 adult and adolescent HLH transplanted for primary HLH (n = 4), tumor-HLH (n = 8), EBV-HLH (n = 14), and underlying disease-unknown (UDU)-HLH (n = 4). Peripheral blood stem cells (PBSCs) were the stem-cell source in all patients. Twenty-three patients were transplanted from HLA-haploidentical family donors, six from HLA-identical sibling donors, and one from a matched unrelated donor. Four patients appeared with mixed chimerism (MC), and no patient presented with graft failure. There was a high risk for EBV reactivation with an incidence of 47 %. Two patients developed post-transplant lymphoproliferative disorder (PTLD) and three were considered primary disease recurrent. With a median follow-up of 26 months, 19 patients survived and 11 patients died. The estimated 2-year overall survival (OS) was 63.3 ± 8.8 % in all patients, 100 % in primary HLH, 64.3 ± 12.8 % in EBV-HLH, 50.0 ± 17.7 % in tumor-HLH, and 50.0 ± 25.0 % in UDU-HLH. Myeloablative conditioning-based allo-HSCT is an effective treatment for adult and adolescent HLH to achieve complete remission and long-term survival.

  17. Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment

    PubMed Central

    Thiel, U; Koscielniak, E; Blaeschke, F; Grunewald, T G P; Badoglio, M; Diaz, M A; Paillard, C; Prete, A; Ussowicz, M; Lang, P; Fagioli, F; Lutz, P; Ehninger, G; Schneider, P; Santucci, A; Bader, P; Gruhn, B; Faraci, M; Antunovic, P; Styczynski, J; Krüger, W H; Castagna, L; Rohrlich, P; Ouachée-Chardin, M; Salmon, A; Peters, C; Bregni, M; Burdach, S

    2013-01-01

    Background: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. Methods: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. Results: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. Conclusion: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials. PMID:24149176

  18. Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo.

    PubMed

    Yu, Yu; Yu, Jing; Iclozan, Cristina; Kaosaard, Kane; Anasetti, Claudio; Yu, Xue-Zhong

    2012-01-01

    Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim(-/-) T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation.

  19. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

    PubMed

    Kayser, S; Benner, A; Thiede, C; Martens, U; Huber, J; Stadtherr, P; Janssen, J W G; Röllig, C; Uppenkamp, M J; Bochtler, T; Hegenbart, U; Ehninger, G; Ho, A D; Dreger, P; Krämer, A

    2016-07-29

    The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.

  20. Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with acute myeloid leukemia harboring trisomy 8.

    PubMed

    Konuma, Takaaki; Kondo, Tadakazu; Yamashita, Takuya; Uchida, Naoyuki; Fukuda, Takahiro; Ozawa, Yukiyasu; Ohashi, Kazuteru; Ogawa, Hiroyasu; Kato, Chiaki; Takahashi, Satoshi; Kanamori, Heiwa; Eto, Tetsuya; Nakaseko, Chiaki; Kohno, Akio; Ichinohe, Tatsuo; Atsuta, Yoshiko; Takami, Akiyoshi; Yano, Shingo

    2017-03-01

    Trisomy 8 (+8) is one of the most common cytogenetic abnormalities in adult patients with acute myeloid leukemia (AML). However, the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with AML harboring +8 remains unclear. To evaluate, the outcome and prognostic factors in patients with AML harboring +8 as the only chromosomal abnormality or in association with other abnormalities, we retrospectively analyzed the Japanese registration data of 631 adult patients with AML harboring +8 treated with allogeneic HSCT between 1990 and 2013. In total, 388 (61%) patients were not in remission at the time of HSCT. With a median follow-up of 38.5 months, the probability of overall survival and the cumulative incidence of relapse at 3 years were 40 and 34%, respectively. In the multivariate analysis, two or more additional cytogenetic abnormalities and not being in remission at the time of HSCT were significantly associated with a higher overall mortality and relapse. Nevertheless, no significant impact on the outcome was observed in cases with one cytogenetic abnormality in addition to +8. Although more than 60% of the patients received HSCT when not in remission, allogeneic HSCT offered a curative option for adult patients with AML harboring +8.

  1. Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

    PubMed

    Michelis, F V; Atenafu, E G; Gupta, V; Kim, D D; Kuruvilla, J; Lipton, J H; Loach, D; Seftel, M D; Uhm, J; Alam, N; Lambie, A; McGillis, L; Messner, H A

    2015-07-01

    Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

  2. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen.

    PubMed

    Boztug, Heidrun; Karitnig-Weiß, Cäcilia; Ausserer, Bernd; Renner, Ellen D; Albert, Michael H; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H; Mann, Georg; Horcher, Ernst; Rümmele-Waibel, Alexandra; Geyeregger, Rene; Lakatos, Karoly; Peters, Christina; Lawitschka, Anita; Matthes-Martin, Susanne

    2012-10-01

    Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

  3. [The comparative pathomorphological evaluation of the mice-recipient's brain cell-tissue reactions by the intracerebral imlantation of syngeneic and allogeneic neural cells].

    PubMed

    Liubych, L D; Semenova, V M; Lisianyĭ, M I

    2013-01-01

    The aim of the study was to compare the mice-recipient's brain tissue cell-structural reactions in response to intracerebral implantation of syngeneic and allogeneic cell suspensions of neural progenitor cells (NPC) (E13-15). The NPC suspensions from mice-donors of C57BL/6 and CBA containing 72.7 +/- 9.9% Vimentin+ and 81, 812, 5% GFAP+ cells were inoculated by standard procedure in right temporal segment of cerebral hemisphere of mice-recipients C57BL/6 (1 x 10(6) cells per animal). The certain part of mice-recipients of allogeneic NPC were immunosupressed by Sandimmune (100 mkg per animal) on day 0, 3, 6 after neurotransplantation. The standard histological preparations of mice brains were performed after 24 hours, 6, 12, 18 and 37 days after NPC neurotransplantation, which were investigated by cytoanalyzer "IBAS" (Germany). After intracerebral inoculation of allogeneic foetal NPC the signs of the pericellular edema and lymphocyte infiltration were detected in adjacent brain sections on day 12-18 and decreased on day 37. Allogeneic foetal NPC were reserved till day 18 and revealed the signs of primary differentiation. After immunosupression by "Sandimmune" the foetal NPC underwent the phoenotypic differentiation and infiltration in related brain sections. On the day 37 the implanted NPC were not detected. Focal reaction of the brain glial component to implanted NPC declined faster after syngeneic NPC neuroimplantation (up to day 18) than after allogeneic NPC neuroimplantation (up to day 37). After the syngeneic NPC inoculation on the 37th day at the site of implantation the formation of a small fragment of immature bone was fixed, which may indicate the possibility of NPC transdifferentiation in other cell types.

  4. Partial rescue of mucopolysaccharidosis type VII mice with a lifelong engraftment of allogeneic stem cells in utero

    PubMed Central

    Ihara, Norimasa; Akihiro, Umezawa; Onami, Naoko; Tsumura, Hideki; Inoue, Eisuke; Hayashi, Satoshi; Sago, Haruhiko; Mizutani, Shuki

    2015-01-01

    In utero hematopoietic cell transplantation (IUHCT) has been performed in Mucopolysaccharidosis Type VII (MPSVII) mice, but a lifelong engraftment of allogeneic donor cells has not been achieved. In this study, we sought to confirm a lifelong engraftment of allogeneic donor cells immunologically matched to the mother and to achieve partial rescue of phenotypes in the original MPSVII strain through IUHCT by intravenous injection. We performed in vitro fertilization in a MPSVII murine model and transferred affected embryos to ICR/B6-GFP surrogate mothers in cases where fetuses receiving IUHCT were all homozygous. Lineage-depleted cells from ICR/B6-GFP mice were injected intravenously at E14.5. Chimerism was confirmed by flow cytometry at 4 weeks after birth, and β-glucuronidase activity in serum and several phenotypes were assessed at 8 weeks of age or later. Donor cells in chimeric mice from ICR/B6-GFP mothers were detected at death, and were confirmed in several tissues including the brains of sacrificed chimeric mice. Although the serum enzyme activity of chimeric mice was extremely low, the engraftment rate of donor cells correlated with enzyme activity. Furthermore, improvement of bone structure and rescue of reproductive ability were confirmed in our limited preclinical study. We confirmed the lifelong engraftment of donor cells in an original immunocompetent MPSVII murine model using intravenous IUHCT with cells immunologically matched to the mother without myeloablation, and the improvement of several phenotypes. PMID:25421592

  5. Mouse bone marrow-derived mesenchymal stem cells inhibit leukemia/lymphoma cell proliferation in vitro and in a mouse model of allogeneic bone marrow transplant.

    PubMed

    Song, Ningxia; Gao, Lei; Qiu, Huiying; Huang, Chongmei; Cheng, Hui; Zhou, Hong; Lv, Shuqing; Chen, Li; Wang, Jianmin

    2015-07-01

    The allogeneic hematopoietic stem cell (HSC) transplantation of mesenchymal stem cells (MSCs) contributes to the reconstitution of hematopoiesis by ameliorating acute graft‑versus‑host disease (aGVHD). However, the role of MSCs in graft‑versus‑leukemia remains to be determined. In the present study, we co‑cultured C57BL/6 mouse bone marrow (BM)‑derived MSCs with A20 murine B lymphoma, FBL3 murine erythroleukemia and P388 murine acute lymphocytic leukemia cells. Cell proliferation, apoptosis, cell cycle progression and the amount of cytokine secretion were then measured using a Cell Counting kit‑8, Annexin V/propidium iodide staining, flow cytometry and ELISA, respectively. We also established a model of allogeneic bone marrow transplantation (BMT) using BALB/c mice. Following the administration of A20 cells and MSCs, we recorded the symptoms and the survival of the mice for 4 weeks, assessed the T cell subsets present in peripheral blood, and, after the mice were sacrifice, we determined the infiltration of MSCs into the organs by histological staining. Our results revealed that the MSCs inhibited the proliferation of the mouse lymphoma and leukemia cells in vitro, leading to cell cycle arrest and reducing the secretion of interleukin (IL)‑10. In our model of allogeneic BMT, the intravenous injection of MSCs into the mice injected wth A20 cells decreased the incidence of lymphoma, improved survival, increased the fraction of CD3+CD8+ T cells, decreased the fraction of CD3+CD4+ T cells and CD4+CD25+ T cells in peripheral blood, and ameliorated the manifestation of aGVHD. The results from the present study indicate that MSCs may be safe and effective when used in allogeneic BMT for the treatment of hemotological malignancies.

  6. Human dendritic cell subsets from spleen and blood are similar in phenotype and function but modified by donor health status.

    PubMed

    Mittag, Diana; Proietto, Anna I; Loudovaris, Thomas; Mannering, Stuart I; Vremec, David; Shortman, Ken; Wu, Li; Harrison, Leonard C

    2011-06-01

    Mouse dendritic cells (DC) have been extensively studied in various tissues, especially spleen, and they comprise subsets with distinct developmental origins, surface phenotypes, and functions. Considerably less is known about human DC due to their rarity in blood and inaccessibility of other human tissues. The study of DC in human blood has revealed four subsets distinct in phenotype and function. In this study, we describe four equivalent DC subsets in human spleen obtained from deceased organ donors. We identify three conventional DC subsets characterized by surface expression of CD1b/c, CD141, and CD16, and one plasmacytoid DC subset characterized by CD304 expression. Human DC subsets in spleen were very similar to those in human blood with respect to surface phenotype, TLR and transcription factor expression, capacity to stimulate T cells, cytokine secretion, and cross-presentation of exogenous Ag. However, organ donor health status, in particular treatment with corticosteroid methylprednisolone and brain death, may affect DC phenotype and function. DC T cell stimulatory capacity was reduced but DC were qualitatively unchanged in methylprednisolone-treated deceased organ donor spleen compared with healthy donor blood. Overall, our findings indicate that human blood DC closely resemble human spleen DC. Furthermore, we confirm parallels between human and mouse DC subsets in phenotype and function, but also identify differences in transcription factor and TLR expression as well as functional properties. In particular, the hallmark functions of mouse CD8α(+) DC subsets, that is, IL-12p70 secretion and cross-presentation, are not confined to the equivalent human CD141(+) DC but are shared by CD1b/c(+) and CD16(+) DC subsets.

  7. Platelet and Red Blood Cell Utilization and Transfusion Independence in Umbilical Cord Blood and Allogeneic Peripheral Blood Hematopoietic Cell Transplants

    PubMed Central

    Solh, Melhem; Brunstein, Claudio; Morgan, Shanna; Weisdorf, Daniel

    2010-01-01

    Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range 2–45 days, and PBSC 14, range 3–34 days), only 135 of 229 (59% cumulative incidence, CI) achieved RBC independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 vs. PBSC 14 days) and in patients who had received a prior transplant (median 48 vs. 32 days). Patients who received UCB grafts required more RBC through day 60 post HCT (mean UCB 7.8 (95% CI 6.7–8.9) vs. PBSC 5.2 (3.7–6.7) transfusions, p=0.04), and more platelet transfusions (mean 25.2 (95% CI 22.1–28.2) vs. 12.9 (9.4–16.4), p<0.01) compared to PBSC recipients. Patient receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post HCT compared to reduced intensity conditioning (RIC) (7.4 vs. 6.2, p=0.3 for RBC; 23.2 vs 17.5, p=0.07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation. PMID:20813199

  8. Intramuscular Transplantation of Allogeneic Mesenchymal Stromal Cells Derived from Equine Umbilical Cord

    PubMed Central

    Dias, Marianne Camargos; da Cruz Landim-Alvarenga, Fernanda; de Moraes, Carolina Nogueira; da Costa, Leonardo Dourado; Geraldini, Caroline Medeiros; de Vasconcelos Machado, Vânia Maria; Maia, Leandro

    2016-01-01

    Background and Objectives Mesenchymal stromal cells (MSCs) have great therapeutic potential, particularly in the process of tissue repair and immunomodulation through the secretion of biomolecules. Thus, the aim of this study was to evaluate the hypothesis that intramuscular transplantation of allogeneic MSCs obtained from equine umbilical cord (UC-MSCs) is safe, demonstrating that this is a suitable source of stem cells for therapeutic use. Methods and Results For this, UC-MSCs were cultured, characterized and cryopreserved for future transplantation in six healthy mares. On day 0, transplantation of three million UC-MSCs diluted in Hank’s Balanced Solution (HBSS) was performed on right and left sides of the rump muscle. As a control, HBSS injections were performed caudally in the same muscle. Muscle biopsies were obtained as a control 30 days before transplantation (D-30). The biopsies were collected again on day 2 (left side) and day 7 (right side) post transplantation and examined histologically. All procedures were preceded by ultrasound examination and blood sampling. Hematologic evaluation remained within normal limits and no differences were observed between time points (p>0.05). Ultrasound examination was suggestive of inflammation 48 hours after transplantation in both groups (control and treated). At histological evaluation it was found only discrete inflammation signals between D-30×D2 (p<0.05) in the treated group, without differences (p> 0.05) between the groups at different time points. Conclusions Equine UC-MSCs under the experimental conditions did not promote severe inflammation that causes tissue damage or lead to its rejection by the host organism and therefore has a good potential for clinical use. PMID:27572709

  9. Recombinant Human Factor VIIa for Alveolar Hemorrhage Following Allogeneic Stem Cell Transplantation

    PubMed Central

    Elinoff, Jason M.; Bagci, Ulas; Moriyama, Brad; Dreiling, Jennifer L.; Foster, Brent; Gormley, Nicole J.; Salit, Rachel B.; Cai, Rongman; Sun, Junfeng; Beri, Andrea; Reda, Debra J.; Fakhrejahani, Farhad; Battiwalla, Minoo; Baird, Kristin; Cuellar-Rodriguez, Jennifer M.; Kang, Elizabeth M.; Pavletic, Stephen Z.; Fowler, Dan H.; Barrett, A. John; Lozier, Jay N.; Kleiner, David E.; Mollura, Daniel J.; Childs, Richard W.; Suffredini, Anthony F.

    2014-01-01

    The mortality rate of alveolar hemorrhage following allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high dose steroids. We performed a retrospective cohort analysis to assess the benefits and risks of rFVIIa as a therapeutic adjunct for alveolar hemorrhage. From 2005 to 2012, 57 episodes of alveolar hemorrhage occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median (interquartile range) steroid dose was 1.9 mg/kg/d (0.8 – 3.5; methylprednisolone equivalents) and did not differ statistically between the two groups. The median rFVIIa dose was 41 μg/kg (39-62) and a median of 3 doses (2-17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [141-262]); 72% required mechanical ventilation and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of alveolar hemorrhage (p = 0.50), duration of mechanical ventilation (p = 0.89), duration of oxygen supplementation (p = 0.55), or hospital mortality (p = 0.27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa when used in combination with corticosteroids did not confer clear clinical advantages compared to corticosteroids alone. In patients with AH following hematopoietic stem cell transplant, clinical factors (i.e. worsening infection, multiple organ failure or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa. PMID:24657447

  10. Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities.

    PubMed

    Barker, Juliet N; Byam, Courtney E; Kernan, Nancy A; Lee, Sinda S; Hawke, Rebecca M; Doshi, Kathleen A; Wells, Deborah S; Heller, Glenn; Papadopoulos, Esperanza B; Scaradavou, Andromachi; Young, James W; van den Brink, Marcel R M

    2010-11-01

    Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access because of the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (P < .001). However, the majority of both groups had 5-6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (P < .001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (P < .001). Their median weight was significantly higher than CB transplant recipients (P <.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.

  11. ABO mismatch is associated with increased non-relapse mortality after allogeneic hematopoietic cell transplantation

    PubMed Central

    Logan, Aaron C.; Wang, Zhiyu; Alimoghaddam, Kamran; Wong, Ruby M.; Lai, Tze; Negrin, Robert S.; Grumet, Carl; Logan, Brent R.; Zhang, Mei-Jie; Spellman, Stephen R.; Lee, Stephanie J.; Miklos, David B.

    2015-01-01

    We evaluated ABO associated outcomes in 1,737 patients who underwent allogeneic hematopoietic cell transplant (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, OS was inferior in minor MM HCT (median 2.1 vs 6.3 years; HR 1.56; 95%CI 1.19-2.05; p=0.001) in comparison with ABO matched grafts. ABO minor MM was associated with an increase in early NRM (18% vs 13%; HR 1.48, 95%CI 1.06-2.06; p=0.02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR 1.55; 95%CI 1.07 – 2.25; p=0.021) and increased NRM (HR 1.72; 95%CI 1.11 – 2.68; p=0.03) was observed in recipients of ABO minor MM grafts. A second independent analysis of a CIBMTR dataset including 5,179 patients with AML and MDS identified a non-significant trend toward decreased OS in recipients of ABO minor MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR 1.19, 95% CI 1.08 – 1.31, p<0.001) and increased NRM (HR 1.23, 95%CI 1.08 – 1.4, p=0.002). ABO minor and major MM are risk factors for worse transplant outcomes, although the associated hazards may not be uniform across different transplant populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B-cell therapy or other peri-transplant treatments. PMID:25572032

  12. Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation for Solid Cancer.

    PubMed

    Omazic, Brigitta; Remberger, Mats; Barkholt, Lisbeth; Söderdahl, Gunnar; Potácová, Zuzana; Wersäll, Peter; Ericzon, Bo-Göran; Mattsson, Jonas; Ringdén, Olle

    2016-04-01

    We wanted to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) may result in long-term survival in patients with solid cancer. HSCT was performed in 61 patients with solid cancer: metastatic renal carcinoma (n = 22), cholangiocarcinoma (n = 17), colon carcinoma (n = 15), prostate cancer (n = 3), pancreatic adenocarcinoma (n = 3), or breast cancer (n = 1). Liver transplantation was performed for tumor debulking in 18 patients. Median age was 56 years (range, 28 to 77). Donors were either HLA-identical siblings (n = 29) or unrelated (n = 32). Conditioning was nonmyeloablative (n = 23), reduced (n = 36), or myeloablative (n = 2). Graft failure occurred in 13 patients (21%). The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 47%, and that of chronic GVHD was 32%. Treatment-related mortality was 21%. At 5 years cancer-related mortality was 63%. Currently, 6 patients are alive, 2 with renal cell carcinoma, 1 with cholangiocarcinoma, and 3 with pancreatic carcinoma. Eight-year survival was 12%. Risk factors for mortality were nonmyeloablative conditioning (HR, 2.95; P < .001), absence of chronic GVHD (HR, 3.57; P < .001), acute GVHD of grades II to IV (HR, 2.90; P = .002), and HLA-identical transplant (HR, 5.00; P = .03). With none of these risk factors, survival at 6 years was 50% (n = 6). Long-term survival can be achieved in some patients with solid cancer after HSCT.

  13. Dynamic of bone marrow fibrosis regression predicts survival after allogeneic stem cell transplantation for myelofibrosis.

    PubMed

    Kröger, Nicolaus; Zabelina, Tatjana; Alchalby, Haefaa; Stübig, Thomas; Wolschke, Christine; Ayuk, Francis; von Hünerbein, Natascha; Kvasnicka, Hans-Michael; Thiele, Jürgen; Kreipe, Hans-Heinrich; Büsche, Guntram

    2014-06-01

    We correlate regression of bone marrow fibrosis (BMF) on day 30 and 100 after dose- reduced allogeneic stem cell transplantation (allo-SCT) in 57 patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis with graft function and survival. The distribution of International Prognostic Scoring System (IPSS) risk score categories was 1 patient with low risk, 5 patients with intermediate-1 risk, 18 patients with intermediate-2 risk, and 33 patients with high risk. Before allo-SCT, 41 patients (72%) were classified as XXX [myclofibrosis (MF)]-3 and 16 (28%) were classified as MF-2 according to the World Health Organization criteria. At postengraftment day +30 (±10 days), 21% of the patients had near-complete or complete regression of BMF (MF-0/-1), and on day +100 (±20 days), 54% were MF-0/-1. The 5-year overall survival rate at day +100 was 96% in patients with MF-0/-1 and 57% for those with MF-2/-3 (P = .04). There was no difference in BMF regression at day +100 between IPSS high-risk and low/intermediate-risk patients. Complete donor cell chimerism at day +100 was seen in 81% of patients with MF-0/-1 and in 31% of those with MF-2/-3. Patients with MF-2/-3 at day +100 were more likely to be transfusion-dependent for either RBCs (P = .014) or platelets (P = .018). Rapid BMF regression after reduced-intensity conditioning allo-SCT resulted in a favorable survival independent of IPSS risk score at transplantation.

  14. Persistent poor long-term prognosis of allogeneic hematopoietic stem cell transplant recipients surviving invasive aspergillosis

    PubMed Central

    Salmeron, Géraldine; Porcher, Raphaël; Bergeron, Anne; Robin, Marie; de Latour, Régis Peffault; Ferry, Christèle; Rocha, Vanderson; Petropoulou, Anna; Xhaard, Aliénor; Lacroix, Claire; Sulahian, Annie; Socié, Gérard; Ribaud, Patricia

    2012-01-01

    Background Voriconazole treatment increases early survival of allogeneic hematopoietic stem cell transplant recipients with invasive aspergillosis. We investigated whether this survival advantage translates into an increased long-term survival. Design and Methods This retrospective study involved all patients with an invasive aspergillosis diagnosis transplanted between September 1997 and December 2008, at the Saint-Louis Hospital, Paris, France. The primary end point was survival up to 36 months. Survival analysis before and after 12 weeks, as well as cumulative incidence analysis in a competing risk framework, were used to assess the effect of voriconazole treatment and other factors on mortality. Results Among 87 patients, 42 received first-line voriconazole and 45 received another antifungal agent. Median survival time was 2.6 months and survival rate at 36 months was 18%. Overall, there was a significant difference in the survival rates of the two groups. Specifically, there was a dramatic difference in survival rates up to ten months post-aspergillosis diagnosis but no significant difference after this time. Over the first 36 months as a whole, no significant difference in survival rate was observed between the two groups. First-line voriconazole significantly reduced aspergillosis-attributable mortality. However, first-line voriconazole patients experienced a significantly higher probability of death from a non-aspergillosis-attributable cause. Conclusions Although the prognosis for invasive aspergillosis after stem cell transplantation has dramatically improved with the use of voriconazole, this major advance in care does not translate into increased long-term survival for these severely immunocompromised patients. PMID:22371177

  15. Shift in FTIR spectrum patterns in methomyl-exposed rat spleen cells.

    PubMed

    Suramana, T; Sindhuphak, R; Dusitsin, N; Posayanonda, T; Sinhaseni, P

    2001-04-10

    Methomyl is a highly toxic carbamate insecticide which is widely used in many agricultural countries. We have applied the Fourier-transformed infrared (FTIR) spectroscopic method to study the toxicity of methomyl on cytoskeletal protein and the nucleic acid of rat spleen cells. Rats were given methomyl by gavage at 2, 6 and 8 mg/kg in single doses. Colchicine, a microtubule-disrupting agent, was given to rats at 2, 4, and 6 mg/kg in single doses and mitomycin C, an alkylating agent which acts as a DNA-cross-linking agent, was given by an intraperitoneal route to rats at 1 mg/kg. It was shown that the wavenumber of FTIR spectra at amide I and amide II in both methomyl- and colchicine-exposed rats shifted in dose response manner when compared with the control (P < 0.05). The amide I and II shifts in these regions have been proposed to be the result of an alpha-helix protein conformational change. Toxic doses of mitomycin C, a DNA-cross-linking agent, did not result in this pattern. Moreover, all exposed rats showed an increase in the absorbance ratios that were related to the vibrational mode of the phosphodiester group in nucleic acid (P < 0.05).

  16. Allogeneic CD34+ -selected peripheral stem cell transplantation from parental donors in children with non-malignant diseases.

    PubMed

    Kremens, B; Basu, O; Peceny, R; Grosse-Wilde, H; Schaefer, U W; Havers, W

    2002-01-01

    Allogeneic peripheral stem cell transplantation in six children with non-malignant hematologic or metabolic diseases which are eventually fatal was carried out with parental donors. Given three to five HLA mismatches, all grafts underwent CD34+ cell selection as graft-versus-host prophylaxis. The patients received median doses of 16.7 x 10(6) CD34+ cells/kg and 1.2 x 10(4) CD3+ cells/kg. All transplants engrafted. Neutrophils >0.5/nl were reached on day 11 (9-19) and platelets >50/nl on day 13 (10-25). Acute GVHD responding to steriods occured in three of six patients; it was restricted to the skin and overall did not exceed grade I. Two patients died of viral infections and four are alive with stable blood counts for 13, 15, 25 and 26 months. For children with non-malignant diseases which will eventually be fatal and which can be cured or ameliorated by allogeneic BMT, CD34+-selected stem cell transplants from mismatched or even haploidentical parents can be used if no other suitable donor is available. With high CD34+ cell doses and low CD3+ cell numbers, engraftment and avoidance of acute GVHD can be expected. Infections after transplantation remain the primary threat to survival.

  17. 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.

  18. Graft Immune Cell Composition Associates with Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML.

    PubMed

    Impola, Ulla; Larjo, Antti; Salmenniemi, Urpu; Putkonen, Mervi; Itälä-Remes, Maija; Partanen, Jukka

    2016-01-01

    Complications of allogeneic hematopoietic stem cell transplantation (HSCT) have been attributed to immune cells transferred into the patient with the graft. However, a detailed immune cell composition of the graft is usually not evaluated. In the present study, we determined the level of variation in the composition of immune cells between clinical HSCT grafts and whether this variation is associated with clinical outcome. Sizes of major immune cell populations in 50 clinical grafts from a single HSCT Centre were analyzed using flow cytometry. A statistical comparison between cell levels and clinical outcomes of HSCT was performed. Overall survival, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and relapse were used as the primary endpoints. Individual HSCT grafts showed considerable variation in their numbers of immune cell populations, including CD123(+) dendritic cells and CD34(+) cells, which may play a role in GVHD. Acute myeloid leukemia (AML) patients who developed aGVHD were transplanted with higher levels of effector CD3(+) T, CD19(+) B, and CD123(+) dendritic cells than AML patients without aGVHD, whereas grafts with a high CD34(+) content protected against aGVHD. AML patients with cGVHD had received grafts with a lower level of monocytes and a higher level of CD34(+) cells than those without cGVHD. There is considerable variation in the levels of immune cell populations between HSCT grafts, and this variation is associated with outcomes of HSCT in AML patients. A detailed analysis of the immune cell content of the graft can be used in risk assessment of HSCT.

  19. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency. PMID:27602064

  20. Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells.

    PubMed

    Pène, Frédéric; Courtine, Emilie; Ouaaz, Fatah; Zuber, Benjamin; Sauneuf, Bertrand; Sirgo, Gonzalo; Rousseau, Christophe; Toubiana, Julie; Balloy, Viviane; Chignard, Michel; Mira, Jean-Paul; Chiche, Jean-Daniel

    2009-12-01

    Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. By 24 h, a decrease in the relative percentage of CD11c(high) spleen DC occurred in wild-type mice but was prevented in TLR2(-/-), TLR4(-/-), and TLR2(-/-) TLR4(-/-) mice. In wild-type mice, sepsis dramatically affected both CD11c(+) CD8alpha(+) and CD11c(+) CD8alpha(-) subsets. In all three types of knockout mice studied, the CD11c(+) CD8alpha(+) subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c(+) CD8alpha(-) cells was attenuated in TLR2(-/-) and TLR4(-/-) mice and completely prevented in TLR2(-/-) TLR4(-/-) mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis.

  1. Risk factor analysis of autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation in children

    PubMed Central

    Chang, Tsung-Yen; Jaing, Tang-Her; Wen, Yu-Chuan; Huang, I-Anne; Chen, Shih-Hsiang; Tsay, Pei-Kwei

    2016-01-01

    Abstract Autoimmune hemolytic anemia (AIHA) is a clinically relevant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, there is no established consensus regarding the optimal therapeutic approach. Whether AIHA contributes to increased mortality is still somewhat controversial. We investigated the incidence, risk factors, and outcome of post-transplant AIHA in 265 consecutive pediatric patients undergoing allo-HSCT over a 17-year period. Onset of AIHA was calculated from the first documented detection of AIHA by either clinical symptoms or positive direct agglutinin test. Resolution of AIHA was defined as normalization of hemoglobin and biochemical markers of hemolysis with sustained transfusion independence. We identified 15 cases of AIHA after allo-HSCT (incidence rate, 6%). Ten (67%) of these patients had a positive direct antiglobulin test. Data were obtained for 9 boys and 6 girls after a median follow-up of 53 months (range 4–102). The median age was 5.1 years (range 0.5–15.4) at the time of HSCT and the median time to emergence was 149 days (range 42–273). No significant risk factor for post-transplant AIHA has emerged from our data to date. In the majority (14 of 15; 93%) of AIHA patients, multiple agents for treatment were required, with 12 of 15 (80%) patients achieving complete resolution of AIHA. No splenectomy was performed in any of our patients. For various reasons, post-transplantation AIHA poses an extraordinary challenge to transplant physicians. Despite the advancements in diagnostic tools, therapeutic challenges remain due to the myriad interacting pathways in AIHA. PMID:27861376

  2. Nonmyeloablative Allogeneic Stem Cell Transplantation in Relapsed/Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Khouri, Issa F.; Bassett, Roland; Poindexter, Nancy; O'Brien, Susan; Bueso-Ramos, Carlos E.; Hsu, Yvonne; Ferrajoli, Alessandra; Keating, Michael J.; Champlin, Richard; Fernandez-Vina, Marcelo

    2015-01-01

    BACKGROUND The role of nonmyeloablative allogeneic stem cell transplantation (NST) in the treatment of chronic lymphocytic leukemia (CLL) is not well established. The authors report on long-term experience with NST in relapsed/refractory CLL and define prognostic factors associated with outcome. METHODS The authors reviewed the outcome of 86 patients with relapsed/relapsed CLL enrolled in sequential NST protocols. RESULTS The median patient age was 58 years. Patients were heavily pretreated before transplantation, and 43 required immunomanipulation after NST for persistent or recurrent disease. Immunomanipulation included withdrawal of immunosuppression, rituximab, and step-wise donor lymphocyte infusions. Of 43 patients receiving immunomanipulation, 20 (47%) experienced a complete remission. Patients with human leukocyte antigen (HLA) genotype A1+/A2−/B44− were more likely to experience a complete remission (P ¼ .0009), with rates of 9%, 36%, 50%, and 91%, respectively, for 0, 1, 2, and 3 of these HLA factors. This resulted in significant improvement in progression-free-survival rates of 68.2% at 5 years for patients with all 3 HLA factors. Overall, the estimated 5-year survival rate was 51%. In a multivariate model, a CD4 count of <100/mm3 and a below normal serum immunoglobulin G level at study entry were associated with a short survival duration (P < .0001). CONCLUSIONS These results confirm the potential cure of relapsed/refractory CLL with NST and provide the first evidence that immunoglobulin G and CD4 levels are predictive of overall survival after NST in CLL and that human leukocyte antigen alleles predict response to immunomanipulation. PMID:21455998

  3. Safety of posaconazole and sirolimus coadministration in allogeneic hematopoietic stem cell transplants.

    PubMed

    Kubiak, David W; Koo, Sophia; Hammond, Sarah P; Armand, Philippe; Baden, Lindsey R; Antin, Joseph H; Marty, Francisco M

    2012-09-01

    Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.

  4. Quality of life following allogeneic stem cell transplantation, comparing parents' and children's perspective.

    PubMed

    Forinder, Ulla; Löf, Catharina; Winiarski, Jacek

    2006-06-01

    There is insufficient knowledge about the quality of life (QoL) among children after allogeneic stem cell transplantation (SCT). We recently reported an overall, good self-assessed QoL and health in 52 children who were three yr or more beyond SCT. The focus of this paper is the QoL as assessed by their parents, of whom 42 participated in the study. Using Swedish child health questionnaire (SCHQ)-PF50, parents rated their children's QoL lower on both the psychosocial (p<0.001) and physical summary scales (p<0.001) than the normative group of parents of children without chronic disease. Although essentially following each other, parent scores tended to be lower than children's own SCHQ-CF87 scores, particularly in the domains 'role socially due to physical limitations' (p<0.01) and 'self-esteem' (p<0.05). In the 'bodily pain' domain, patients' and parents' low scores agreed. The child's condition had a greater impact on parents' emotional situation than in the norm population (p<0.001). The severity of the child's physician-rated late effects (p<0.05) or of self-assessed subjective symptoms (p<0.01-0.05) was associated with a lower parental rating of the child's QoL. High Lansky or Karnofsky scores corresponded, respectively, to higher psychosocial (p<0.05) and physical (p<0.05) summary scores. It is concluded that as children, parents, and clinicians do not necessarily adopt similar views of a child's illness and of its impact on the child's life, clarity with regard to who is responsible for assessing the child's QoL is crucial when interpreting pediatric QoL studies.

  5. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes

    PubMed Central

    Rezvani, Andrew R.; McCune, Jeannine S.; Storer, Barry E.; Batchelder, Ami; Kida, Aiko; Deeg, H. Joachim; McDonald, George B.

    2013-01-01

    Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis. PMID:23583825

  6. An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation outcomes.

    PubMed

    Ross, Julie A; Tolar, Jakub; Spector, Logan G; DeFor, Todd; Lund, Troy C; Weisdorf, Daniel J; Langer, Erica; Hooten, Anthony J; Thyagarajan, Bharat; Gleason, Michelle K; Wagner, John E; Robien, Kimberly; Verneris, Michael R

    2015-01-01

    Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.

  7. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation

    PubMed Central

    Lee, Stephanie J.; Ahn, Kwang Woo; Spellman, Stephen; Wang, Hai-Lin; Aljurf, Mahmoud; Askar, Medhat; Dehn, Jason; Fernandez Viña, Marcelo; Gratwohl, Alois; Gupta, Vikas; Hanna, Rabi; Horowitz, Mary M.; Hurley, Carolyn K.; Inamoto, Yoshihiro; Kassim, Adetola A.; Nishihori, Taiga; Mueller, Carlheinz; Oudshoorn, Machteld; Petersdorf, Effie W.; Prasad, Vinod; Robinson, James; Saber, Wael; Schultz, Kirk R.; Shaw, Bronwen; Storek, Jan; Wood, William A.; Woolfrey, Ann E.; Anasetti, Claudio

    2014-01-01

    We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated. PMID:25161269

  8. Immunomodulatory and neuroprotective effect of cryopreserved allogeneic mesenchymal stem cells on spinal cord injury in rats.

    PubMed

    Rosado, I R; Carvalho, P H; Alves, E G L; Tagushi, T M; Carvalho, J L; Silva, J F; Lavor, M S L; Oliveira, K M; Serakides, R; Goes, A M; Melo, E G

    2017-03-22

    This study aimed to evaluate the immunomodulatory and neuroprotective effects of allogeneic and cryopreserved mesenchymal stem cells (MSCs) on spinal cord injury. A total of 120 rats were distributed into the following groups: negative control (NC) - without injury, positive control (PC) - with injury without treatment, and group treated with MSC (GMSC) - with injury and treated. Motor function was evaluated by the BBB test at 24, 48, and 72 h and at 8 and 21 postoperative days. Spinal cords were evaluated by histopathology and immunohistochemistry to determine the expression of CD68, NeuN, and GFAP. IL-10, TNF-α, IL-1β, TGF-β, BDNF, GDNF, and VEGF expression was quantified by RT-PCR. The GMSC presented higher scores for motor function at 72 h and 8 and 21 days after injury, lower expression of CD68 at 8 days, and lower expression of GFAP at 21 days compared to the PC. In addition, higher expression of NeuN and lower degeneration of the white matter occurred at 21 days. The GMSC also showed higher expression of IL-10 24 h after injury, GDNF at 48 h and 8 days, and VEGF at 21 days. Moreover, lower expression of TNF-α was observed at 8 and 21 days and TGF-β at 24 h and 21 days. There were no differences in the expression of IL-1β and BDNF between the GMSC and PC. Thus, cryopreserved MSCs promote immunomodulatory and neuroprotective effects in rats with spinal cord injury by increasing IL-10, GDNF, and VEGF expression and reducing TNF-α and TGF-β expression.

  9. Risk factor analysis of autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation in children.

    PubMed

    Chang, Tsung-Yen; Jaing, Tang-Her; Wen, Yu-Chuan; Huang, I-Anne; Chen, Shih-Hsiang; Tsay, Pei-Kwei

    2016-11-01

    Autoimmune hemolytic anemia (AIHA) is a clinically relevant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Currently, there is no established consensus regarding the optimal therapeutic approach. Whether AIHA contributes to increased mortality is still somewhat controversial.We investigated the incidence, risk factors, and outcome of post-transplant AIHA in 265 consecutive pediatric patients undergoing allo-HSCT over a 17-year period. Onset of AIHA was calculated from the first documented detection of AIHA by either clinical symptoms or positive direct agglutinin test. Resolution of AIHA was defined as normalization of hemoglobin and biochemical markers of hemolysis with sustained transfusion independence.We identified 15 cases of AIHA after allo-HSCT (incidence rate, 6%). Ten (67%) of these patients had a positive direct antiglobulin test. Data were obtained for 9 boys and 6 girls after a median follow-up of 53 months (range 4-102). The median age was 5.1 years (range 0.5-15.4) at the time of HSCT and the median time to emergence was 149 days (range 42-273). No significant risk factor for post-transplant AIHA has emerged from our data to date. In the majority (14 of 15; 93%) of AIHA patients, multiple agents for treatment were required, with 12 of 15 (80%) patients achieving complete resolution of AIHA. No splenectomy was performed in any of our patients.For various reasons, post-transplantation AIHA poses an extraordinary challenge to transplant physicians. Despite the advancements in diagnostic tools, therapeutic challenges remain due to the myriad interacting pathways in AIHA.

  10. BK virus disease after allogeneic stem cell transplantation: a cohort analysis.

    PubMed

    Rorije, Nienke M G; Shea, Margaret M; Satyanarayana, Gowri; Hammond, Sarah P; Ho, Vincent T; Baden, Lindsey R; Antin, Joseph H; Soiffer, Robert J; Marty, Francisco M

    2014-04-01

    The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.

  11. Comorbidity-Age Index: A Clinical Measure of Biologic Age Before Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Sorror, Mohamed L.; Storb, Rainer F.; Sandmaier, Brenda M.; Maziarz, Richard T.; Pulsipher, Michael A.; Maris, Michael B.; Bhatia, Smita; Ostronoff, Fabiana; Deeg, H. Joachim; Syrjala, Karen L.; Estey, Elihu; Maloney, David G.; Appelbaum, Frederick R.; Martin, Paul J.; Storer, Barry E.

    2014-01-01

    Purpose Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown. Patients and Methods Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models. Results In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens. Conclusion Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT. PMID:25154831

  12. A Trial of Alemtuzumab Adjunctive Therapy in Allogeneic Hematopoietic Cell Transplantation with Minimal Conditioning for Severe Combined Immunodeficiency

    PubMed Central

    Dvorak, Christopher C.; Horn, Biljana N.; Puck, Jennifer M.; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J.

    2014-01-01

    For infants with severe combined immunodeficiency (SCID) the ideal conditioning regimen before allogeneic hematopoietic cell transplantation (HCT) would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled 4 patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The 2 patients who engrafted had delayed T cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T cell development in patients with SCID in the setting of a T-cell depleted graft. PMID:24977928

  13. NCI first International Workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: report from the committee on the biological considerations of hematological relapse following allogeneic stem cell transplantation unrelated to graft-versus-tumor effects: state of the science.

    PubMed

    Cairo, Mitchell S; Jordan, Craig T; Maley, Carlo C; Chao, Clifford; Melnick, Ari; Armstrong, Scott A; Shlomchik, Warren; Molldrem, Jeff; Ferrone, Soldano; Mackall, Crystal; Zitvogel, Laurence; Bishop, Michael R; Giralt, Sergio A; June, Carl H

    2010-06-01

    Hematopoietic malignant relapse still remains the major cause of death following allogeneic hematopoietic stem cell transplantation (HSCT). Although there has been a large focus on the immunologic mechanisms responsible for the graft-versus-tumor (GVT) effect or lack thereof, there has been little attention paid to investigating the biologic basis of hematologic malignant disease relapse following allogeneic HSCT. There are a large number of factors that are responsible for the biologic resistance of hematopoietic tumors following allogeneic HSCT. We have focused on 5 major areas including clonal evolution of cancer drug resistance, cancer radiation resistance, genomic basis of leukemia resistance, cancer epigenetics, and resistant leukemia stem cells. We recommend increased funding to pursue 3 broad areas that will significantly enhance our understanding of the biologic basis of malignant relapse after allogeneic HSCT, including: (1) genomic and epigenetic alterations, (2) cancer stem cell biology, and (3) clonal cancer drug and radiation resistance.

  14. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biological Considerations of Hematological Relapse following Allogeneic Stem Cell Transplantation Unrelated to Graft-versus-Tumor Effects: State of the Science

    PubMed Central

    Cairo, Mitchell S.; Jordan, Craig T.; Maley, Carlo C.; Chao, Clifford; Melnick, Ari; Armstrong, Scott A.; Shlomchik, Warren; Molldrem, Jeff; Ferrone, Soldano; Mackall, Crystal; Zitvogel, Laurence; Bishop, Michael R.; Giralt, Sergio A.; June, Carl H.

    2012-01-01

    Hematopoietic malignant relapse still remains the major cause of death following allogeneic hematopoietic stem cell transplantation (HSCT). Although there has been a large focus on the immunologic mechanisms responsible for the graft-versus-tumor (GVT) effect or lack thereof, there has been little attention paid to investigating the biologic basis of hematologic malignant disease relapse following allogeneic HSCT. There are a large number of factors that are responsible for the biologic resistance of hematopoietic tumors following allogeneic HSCT. We have focused on 5 major areas including clonal evolution of cancer drug resistance, cancer radiation resistance, genomic basis of leukemia resistance, cancer epigenetics, and resistant leukemia stem cells. We recommend increased funding to pursue 3 broad areas that will significantly enhance our understanding of the biologic basis of malignant relapse after allogeneic HSCT, including: (1) genomic and epigenetic alterations, (2) cancer stem cell biology, and (3) clonal cancer drug and radiation resistance. PMID:20227509

  15. Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors

    PubMed Central

    Miklos, David B.; Kim, Haesook T.; Zorn, Emmanuel; Hochberg, Ephraim P.; Guo, Luxuan; Mattes-Ritz, Alex; Viatte, Sebastien; Soiffer, Robert J.; Antin, Joseph H.

    2005-01-01

    Minor histocompatibility antigens (mHAs) recognized by donor T cells play a central role as immunologic targets of graft-versus-host disease (GVHD) and graft versus leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Men who have undergone sex-mismatched allogeneic HSCT are at high risk for GVHD because of immune responses directed against mHAs encoded by genes on the Y chromosome (termed H-Y antigens). We hypothesized that the immunogenicity of mHAs results in a coordinated response involving B cells as well as T cells. To test this, we measured antibody responses to a well-characterized H-Y antigen, dead box RNA helicase Y (DBY), and its homolog, DBX, in 150 HSCT patients. Using Western blot and enzyme-linked immunosorbent assay (ELISA), we found that 50% of male patients who received stem cell grafts from female donors developed antibody responses to recombinant DBY protein. Antibodies to DBY were also detected in 17% of healthy women, but not in healthy men. Antibody responses were directed primarily against areas of amino acid disparity between DBY and DBX. These studies demonstrate that the immune response to mHA includes the generation of specific antibodies and suggests that the serologic response to these antigens may also be useful in the identification of new mHAs. PMID:14512314

  16. Evaluation of spleen lymphocyte responsiveness to a T-cell mitogen during early infection with larval Taenia taeniaeformis.

    PubMed

    Letonja, T; Hammerberg, C; Schurig, G

    1987-01-01

    The effect of taeniid infection on the in vitro cellular response of the host was investigated. Infections of Taenia taeniaeformis decreased the ability of spleen cells from susceptible C3H/He mice to respond to the T-cell mitogen concanavalin A (Con A) as early as 2 days postinfection (pi) reaching a suppression peak at day 12 pi. Similar experiments performed with spleen cells from infected BALB/c mice, resistant to the infection, revealed little or no suppression of Con A stimulation. The results suggested that susceptibility to the parasite may be due to its ability to induce a partial suppression of the host's immune system. The role of adherent splenocytes from infected C3H/He mice in the production of a deficient response to Con A during early infection was studied by coculturing experiments. These experiments demonstrated that adherent populations from infected mice did not play a direct role in the Con A-suppressor mechanisms. Concomitant with the suppressor activity an increased background proliferation was observed with nonstimulated splenocytes from C3H/He mice infected with T. taeniaeformis. Plasma from infected mice was able to suppress the response of normal spleen cells to Con A and to stimulate a proliferative response in cultured splenocytes from noninfected animals. The results suggest the presence of factors in the plasma of infected mice which may be modulating the immune response to the parasite.

  17. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone

    PubMed Central

    Horwitz, Edwin M.; Gordon, Patricia L.; Koo, Winston K. K.; Marx, Jeffrey C.; Neel, Michael D.; McNall, Rene Y.; Muul, Linda; Hofmann, Ted

    2002-01-01

    Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors. PMID:12084934

  18. The immune reconstitution after an allogeneic stem cell transplant correlates with the risk of graft-versus-host disease and cytomegalovirus infection.

    PubMed

    Torelli, Giovanni F; Lucarelli, Barbarella; Iori, Anna P; De Propris, Maria S; Capobianchi, Angela; Barberi, Walter; Valle, Veronica; Iannella, Emilia; Natalino, Fiammetta; Mercanti, Caterina; Perrone, Salvatore; Gentile, Giuseppe; Guarini, Anna; Foà, Robin

    2011-08-01

    Aim of the study was to correlate the clinical outcome of eighteen patients who have undergone an allogeneic stem cell transplant (SCT) with the concentration in the peripheral blood (PB) of lymphocyte subpopulations evaluated at 1 year from transplant. The occurrence of acute GVHD and CMV infection correlated with the concentration of Tregs in the PB; CMV infection also correlated with the content of NK cells. The obtained results document that the concentration of Tregs in the PB after an allogeneic SCT may protect from GVHD and from CMV infection; the potential anti-viral role of NK cells is confirmed.

  19. Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab.

    PubMed

    Kako, Shinichi; Kanda, Yoshinobu; Oshima, Kumi; Nishimoto, Nahoko; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Motokura, Toru; Miyakoshi, Shigesaburo; Taniguchi, Shuichi; Kamijo, Aki; Takahashi, Koki; Chiba, Shigeru; Kurokawa, Mineo

    2008-03-01

    Hemolytic anemia and pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported to be mainly related to ABO-incompatibility between donor and recipient. Autoimmune hemolytic anemia (AIHA) without ABO-incompatibility has been also reported after allogeneic HSCT, especially with T-cell depletion. However, optimal management of AIHA or PRCA remains unclear. A 54-year-old male with myelodysplastic syndrome (MDS) underwent haploidentical human leukocyte antigen-mismatched HSCT using in vivo alemtuzumab and developed AIHA and PRCA simultaneously 15 months after transplantation, following the administration of cidofovir and probenecid for persistent cytomegalovirus (CMV) antigenemia and retinitis. AIHA was successfully treated with rituximab, and subsequently PRCA with cyclosporine without relapse of MDS or recurrence of CMV infection. The clinical course suggested that AIHA was mainly caused by humoral immune response, while PRCA was mainly caused by cell-mediated immune response in this patient, although these immune responses might be related to each other.

  20. A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    PubMed

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J

    2014-09-01

    For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

  1. Expression of Immunoglobulin Receptors with Distinctive Features Indicating Antigen Selection by Marginal Zone B Cells from Human Spleen

    PubMed Central

    Colombo, Monica; Cutrona, Giovanna; Reverberi, Daniele; Bruno, Silvia; Ghiotto, Fabio; Tenca, Claudya; Stamatopoulos, Kostas; Hadzidimitriou, Anastasia; Ceccarelli, Jenny; Salvi, Sandra; Boccardo, Simona; Calevo, Maria Grazia; De Santanna, Amleto; Truini, Mauro; Fais, Franco; Ferrarini, Manlio

    2013-01-01

    Marginal zone (MZ) B cells, identified as surface (s)IgMhighsIgDlowCD23low/−CD21+CD38− B cells, were purified from human spleens, and the features of their V(D)J gene rearrangements were investigated and compared with those of germinal center (GC), follicular mantle (FM) and switched memory (SM) B cells. Most MZ B cells were CD27+ and exhibited somatic hypermutations (SHM), although to a lower extent than SM B cells. Moreover, among MZ B-cell rearrangements, recurrent sequences were observed, some of which displayed intraclonal diversification. The same diversifying sequences were detected in very low numbers in GC and FM B cells and only when a highly sensitive, gene-specific polymerase chain reaction was used. This result indicates that MZ B cells could expand and diversify in situ and also suggested the presence of a number of activation-induced cytidine deaminase (AID)-expressing B cells in the MZ. The notion of antigen-driven expansion/selection in situ is further supported by the VH CDR3 features of MZ B cells with highly conserved amino acids at specific positions and by the finding of shared (“stereotyped”) sequences in two different spleens. Collectively, the data are consistent with the notion that MZ B cells are a special subset selected by in situ antigenic stimuli. PMID:23877718

  2. Enhancement of terminal B lymphocyte differentiation in vitro by fibroblast-like stromal cells from human spleen.

    PubMed

    Skibinski, G; Skibinska, A; Stewart, G D; James, K

    1998-12-01

    Stromal elements are major components of lymphoid tissues contributing to both tissue architecture and function. In this study we report on the phenotype and function of fibroblast-like stromal cells obtained from human spleen. These cells express high levels of CD44 and ICAM-1 and moderate levels of VLA-4, VCAM, CD40 and CD21. They fail to express endothelial, epithelial, lymphocyte and monocyte/macrophage markers. We show that these cells interact with B cell blasts induced in vitro by anti-CD40 and anti-mu stimulation. As a result of these interactions both IL-6 and IgG secretion into culture medium is increased. The enhanced secretion of IgG is partly inhibited by abolishing B cell blaststromal cell contact or by anti-IL-6, anti-VCAM or anti-CD49d antibodies. Our studies also suggest that the ability of stromal cells to promote B cell survival is most likely the underlying mechanism of the enhanced immunoglobulin secretion. Comparison of stromal cells from different lymphoid and non-lymphoid organs revealed that bone marrow- and spleen-derived stromal cells are the most effective in promoting B cell blast differentiation.

  3. Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.

    PubMed

    Unal, Sule; Sag, Erdal; Kuskonmaz, Baris; Kesici, Selman; Bayrakci, Benan; Ayvaz, Deniz C; Tezcan, Ilhan; Yalnızoglu, Dilek; Uckan, Duygu

    2014-05-01

    Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up.

  4. [Allogenic hematopoietic stem cell transplantation with unrelated cord blood: report of three cases from the Chilean cord blood bank].

    PubMed

    Barriga, Francisco; Wietstruck, Angélica; Rojas, Nicolás; Bertin, Pablo; Pizarro, Isabel; Carmona, Amanda; Guilof, Alejandro; Rojas, Iván; Oyarzún, Enrique

    2013-08-01

    Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

  5. Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

    PubMed

    Lucas, Matthew C; Bhagirath, Niala; Chiao, Eric; Goldstein, David M; Hermann, Johannes C; Hsu, Pei-Yuan; Kirchner, Stephan; Kennedy-Smith, Joshua J; Kuglstatter, Andreas; Lukacs, Christine; Menke, John; Niu, Linghao; Padilla, Fernando; Peng, Ying; Polonchuk, Liudmila; Railkar, Aruna; Slade, Michelle; Soth, Michael; Xu, Daigen; Yadava, Preeti; Yee, Calvin; Zhou, Mingyan; Liao, Cheng

    2014-03-27

    Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.

  6. A biomimetic microfluidic chip to study the circulation and mechanical retention of red blood cells in the spleen.

    PubMed

    Picot, Julien; Ndour, Papa Alioune; Lefevre, Sophie D; El Nemer, Wassim; Tawfik, Harvey; Galimand, Julie; Da Costa, Lydie; Ribeil, Jean-Antoine; de Montalembert, Mariane; Brousse, Valentine; Le Pioufle, Bruno; Buffet, Pierre; Le Van Kim, Caroline; Français, Olivier

    2015-04-01

    Red blood cells (RBCs) are deformable and flow through vessels narrower than their own size. Their deformability is most stringently challenged when they cross micrometer-wide slits in the spleen. In several inherited or acquired RBC disorders, blockade of small vessels by stiff RBCs can trigger organ damage, but a functional spleen is expected to clear these abnormal RBCs from the circulation before they induce such complications. We analyzed flow behavior of RBCs in a microfluidic chip that replicates the mechanical constraints imposed on RBCs as they cross the human spleen. Polymer microchannels obtained by soft lithography with a hydraulic diameter of 25 μm drove flow into mechanical filtering units where RBCs flew either slowly through 5- to 2-μm-wide slits or rapidly along 10-μm-wide channels, these parallel paths mimicking the splenic microcirculation. Stiff heated RBCs accumulated in narrow slits seven times more frequently than normal RBCs infused simultaneously. Stage-dependent retention of Plasmodium falciparum-infected RBCs was also observed in these slits. We also analyzed RBCs from patients with hereditary spherocytosis and observed retention for those having the most altered mechanical properties as determined by ektacytometry. Thus, in keeping with previous observations in vivo and ex vivo, the chip successfully discriminated poorly deformable RBCs based on their distinct mechanical properties and on the intensity of the cell alteration. Applications to the exploration of the pathogenesis of malaria, hereditary spherocytosis, sickle cell disease and other RBC disorders are envisioned.

  7. Longitudinal analyses of leukemia-associated antigen-specific CD8(+) T cells in patients after allogeneic stem cell transplantation.

    PubMed

    Rücker-Braun, Elke; Link, Cornelia S; Schmiedgen, Maria; Tunger, Antje; Vizjak, Petra; Teipel, Raphael; Wehner, Rebekka; Kühn, Denise; Fuchs, Yannik F; Oelschlägel, Uta; Germeroth, Lothar; Schmitz, Marc; Bornhäuser, Martin; Schetelig, Johannes; Heidenreich, Falk

    2016-11-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GVL) effects, which are exerted by donor T cells directed against leukemic-associated antigens (LAAs), are considered to play a crucial role in disease eradication. Although the expansion of cytotoxic T lymphocytes (CTLs) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data on CTLs mediating GVL effects are limited. To evaluate a potential increase or decrease of T lymphocytes specific for LAAs in the setting of allogeneic HSCT, we monitored leukemia-specific CD8(+) T cells throughout the first year after HSCT in 18 patients using streptamer technology. A broad panel of promising LAAs was selected: Wilms tumor protein, proteinase 3, receptor for hyaluronan acid-mediated motility, apoptosis regulator Bcl-2, survivin, nucleophosmin, and fibromodulin. T cells specifically directed against AML- or CLL-associated antigens were found at very low frequencies in peripheral blood. Substantial frequencies of LAA-specific T cells could not be measured at any time point by flow cytometry. In contrast, abundant CMV-pp65-specific T cells were detected in CMV-seropositive patient-recipient pairs and an increase prompted by CMV infection could be demonstrated. In conclusion, T lymphocytes with specificities for the aforementioned LAAs can only be detected in minimal quantities in the early phase after allogeneic HSCT.

  8. Preclinical Study of Cell Therapy for Osteonecrosis of the Femoral Head with Allogenic Peripheral Blood-Derived Mesenchymal Stem Cells

    PubMed Central

    Fu, Qiang; Tang, Ning-Ning; Zhang, Qian; Liu, Yi; Peng, Jia-Chen; Fang, Ning; Yu, Li-Mei; Liu, Jin-Wei

    2016-01-01

    Purpose To explore the value of transplanting peripheral blood-derived mesenchymal stem cells from allogenic rabbits (rPBMSCs) to treat osteonecrosis of the femoral head (ONFH). Materials and Methods rPBMSCs were separated/cultured from peripheral blood after granulocyte colony-stimulating factor mobilization. Afterwards, mobilized rPBMSCs from a second passage labeled with PKH26 were transplanted into rabbit ONFH models, which were established by liquid nitrogen freezing, to observe the effect of rPBMSCs on ONFH repair. Then, the mRNA expressions of BMP-2 and PPAR-γ in the femoral head were assessed by RT-PCR. Results After mobilization, the cultured rPBMSCs expressed mesenchymal markers of CD90, CD44, CD29, and CD105, but failed to express CD45, CD14, and CD34. The colony forming efficiency of mobilized rPBMSCs ranged from 2.8 to 10.8 per million peripheral mononuclear cells. After local transplantation, survival of the engrafted cells reached at least 8 weeks. Therein, BMP-2 was up-regulated, while PPAR-γ mRNA was down-regulated. Additionally, bone density and bone trabeculae tended to increase gradually. Conclusion We confirmed that local transplantation of rPBMSCs benefits ONFH treatment and that the beneficial effects are related to the up-regulation of BMP-2 expression and the down-regulation of PPAR-γ expression. PMID:27189298

  9. L-asparaginase-based regimens followed by allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive natural killer cell leukemia.

    PubMed

    Jung, Ki Sun; Cho, Su-Hee; Kim, Seok Jin; Ko, Young Hyeh; Kang, Eun-Suk; Kim, Won Seog

    2016-04-18

    Aggressive nature killer cell leukemia (ANKL) is a mature NK-T cell lymphoma with worse prognosis, but optimal treatment is unclear. Therefore, we analyzed the efficacy of L-asparaginase-based regimens for ANKL patients. Twenty-one patients who received dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) or etoposide, ifosfamide, dexamethasone, and L-asparaginase (VIDL) chemotherapy at Samsung Medical Center were selected. The overall response rate for all patients was 33% (7/21); 38% (5/13) in SMILE and 40% (2/5) in VIDL, respectively. The median progression-free survival was 3.9 months (95% CI 0.0-8.1 months) and median overall survival was 7.0 months (95% CI 2.3-11.7 months). Treatment response (P = 0.001), hematopoietic stem cell transplantation (HSCT) (P = 0.007) and negative conversion of Epstein-Barr virus (EBV) DNA titer after treatment (P = 0.004) were significantly associated with survival. Thus, L-asparaginase-based regimens followed by allogeneic HSCT seem to improve the outcome for ANKL patients.

  10. Pure Red Cell Aplasia in Major ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Severe Pancytopenia.

    PubMed

    Aung, Fleur M; Lichtiger, Benjamin; Rondon, Gabriela; Yin, C Cameron; Alousi, Amin; Ahmed, Sairah; Andersson, Borje S; Bashir, Qaiser; Ciurea, Stefan O; Hosing, Chitra; Jones, Roy; Kebriaei, Partow; Khouri, Issa; Nieto, Yago; Oran, Betul; Parmar, Simrit; Qazilbash, Muzaffar; Shah, Nina; Shpall, Elizabeth J; Champlin, Richard E; Popat, Uday

    2016-05-01

    In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/μL or requiring granulocyte colony-stimulating factor, platelets < 50 K/μL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients.

  11. Natural Killer Cells in Allogeneic Transplantation: Effect on Engraftment, Graft- versus-Tumor, and Graft-versus-Host Responses

    PubMed Central

    Gill, Saar; Olson, Janelle A.; Negrin, Robert S.

    2010-01-01

    Natural killer (NK) cells are effectors of the innate immune system and recognize cells transformed by viruses or neoplasia. Their response to “missing self” signals was described 3 decades ago, but the recent discovery of a panoply of activating receptors has made it clear that NK cell reactivity arises from a combination of inhibitory and activating signals. Successful clinical exploitation of NK cell reactivity was demonstrated in allogeneic transplantation for acute myelogenous leukemia from HLA-haploidentical donors when matched donors were not available. Multiple clinical studies have since attempted to use NK reactivity in the setting of both HLA-matched and -mismatched transplantation, with varying results. This review summarizes the heterogeneous clinical results and explains them based on a succinct description of NK cell biology. PMID:19539207

  12. Interactions of allogeneic human mononuclear cells in the two-way mixed leucocyte culture (MLC): influence of cell numbers, subpopulations and cyclosporin

    PubMed Central

    Sato, T; Deiwick, A; Raddatz, G; Koyama, K; Schlitt, H J

    1999-01-01

    With organ allografts considerable numbers of donor-type mononuclear cells are transferred to the recipient, leading to bilateral immunological interactions between donor and recipient lymphocytes. To study such bilateral immune reactions in detail, human two-way MLC were performed. In this model proliferation kinetics, patterns of activation, and survival of the two populations were analysed, and the relevance of initial cell subset composition, relative cell numbers, and the effect of immunosuppression on this co-culture were evaluated. It could be demonstrated that with an initial 50:50 ratio of two populations of allogeneic cells one population dominated after 21 days of co-culture in 78 out of 80 combinations (97%) tested; the other population decreased markedly after an initially stable phase of 6–7 days. With unequal starting conditions the larger population dominated when resting cells were used, but small populations of preactivated cells or separated CD8+ cells could also dominate. Depletion of CD16+ natural killer (NK) cells and of CD2− cells (B cell and monocytes) had no effect on domination. Addition of cyclosporin delayed or blocked the domination process while addition of IL-2 accelerated it. Disappearance of one population was associated with detection of apoptotic cells. The findings indicate that co-cultures of allogeneic mononuclear cells are generally not stable for more than 1 week, but lead to active elimination of one population. CD8+ cells and particularly preactivated cells seem to play the most important role in that process, while NK cells are of less importance. Cyclosporin can prolong survival of allogeneic cells in co-culture. These observations suggest that under the conditions of clinical organ transplantation even small amounts of immunocompetent donor cells transferred by the graft may persist for some time and may, thereby, have the chance to exert immunomodulatory functions. PMID:9933457

  13. Adherent-phagocytic cells influence suppressed concanavalin-A induced proliferation of spleen lymphoid cells in copper deficient rats

    SciTech Connect

    Kramer, T.R.; Briske-Anderson, M.; Johnson, W.T.

    1986-03-01

    Weanling male Lewis rats (N = 10/group) were fed ad-libitum for 42 days diets based on AIN standards containing 21% casein, 5% safflower oil, and deficient (0.6 ..mu..g/g) or adequate (5.6 ..mu..g/g) levels of cu. Cu-deficient rats showed typical biochemical and hematological changes. Immunological changes exhibited by Cu-deficient rats were influenced by the presence of splenic adherent-phagocytic cells (macrophage-like), but not by cytochrome-c oxidase activity of spleen lymphoid cells (SLC). Decreased proliferation was exhibited by concanavalin-A (Con-A) stimulated SLC of Cu-deficient rats. Following removal of plastic-adherent phagocytic cells from the SLC suspensions, equivalent proliferation was exhibited by Con-A stimulated nonadherent-SLC of Cu-deficient and Cu-adequate rats. Decreased cytochrome-c oxidase activity was exhibited by both unstimulated SLC and nonadherent-SLC of Cu-deficient rats, but decreased proliferation was exhibited only in Con-A stimulated SLC of Cu-deficient rats. These findings indicate that nonadherent splenic T-lymphocytes of Cu-deficient rats are not impaired in their ability to proliferate, and that cytochrome-c oxidase activity in unstimulated lymphoid cells of Cu-deficient rats is apparently not related to levels of proliferation by the Con-A stimulated cells.

  14. IL28B genetic variation and cytomegalovirus-specific T-cell immunity in allogeneic stem cell transplant recipients.

    PubMed

    Corrales, Isabel; Solano, Carlos; Amat, Paula; Giménez, Estela; de la Cámara, Rafael; Nieto, José; López, Javier; García-Noblejas, Ana; Piñana, José Luis; Navarro, David

    2017-04-01

    A single nucleotide polymorphism (SNP), 3 kbp upstream of the IL28B gene (rs12979860; C/T), has been shown to influence the dynamics of cytomegalovirus (CMV) replication in allogeneic stem cell transplant recipients (Allo-SCT). We investigated whether this SNP had any effect on the dynamics of CMV-specific T-cell immunity in these patients. CMV pp65/IE-1 IFN-γ CD8(+) and CD4(+) T cells were enumerated by flow cytometry in 85 patients with no prior CMV DNAemia (group A) and in 57 after the onset of CMV DNAemia (group B). Donor IL28B genotype was determined by real-time PCR and plasma levels of IL-28B were quantitated by ELISA. CMV-specific T-cell counts and plasma IL-28B levels in patients in group A were not significantly different among the IL28B genotype groups. Patients harboring the donor IL28B T/T genotype appeared to expand CMV-specific IFN-γ CD8(+) cells to a higher level in response to viral replication than their C/T and C/C counterparts. Fewer patients in the T/T group received pre-emptive antiviral therapy (P = 0.05). Overall, a significant inverse correlation was observed between median IL-28B levels measured prior to the CMV DNAemia onset and the level of CMV-specific CD8(+) T cells enumerated after detection of CMV DNAemia (σ = -0.471; P = 0.013). In summary, the data suggested that the protective effect attributed to the rs12979860 SNP minor T allele could be mediated, at least in part, by eliciting robust CMV-specific T-cell responses. J. Med. Virol. 89:685-695, 2017. © 2016 Wiley Periodicals, Inc.

  15. The Isolation and Enrichment of Large Numbers of Highly Purified Mouse Spleen Dendritic Cell Populations and Their In Vitro Equivalents.

    PubMed

    Vremec, David

    2016-01-01

    Dendritic cells (DCs) form a complex network of cells that initiate and orchestrate immune responses against a vast array of pathogenic challenges. Developmentally and functionally distinct DC subtypes differentially regulate T-cell function. Importantly it is the ability of DC to capture and process antigen, whether from pathogens, vaccines, or self-components, and present it to naive T cells that is the key to their ability to initiate an immune response. Our typical isolation procedure for DC from murine spleen was designed to efficiently extract all DC subtypes, without bias and without alteration to their in vivo phenotype, and involves a short collagenase digestion of the tissue, followed by selection for cells of light density and finally negative selection for DC. The isolation procedure can accommodate DC numbers that have been artificially increased via administration of fms-like tyrosine kinase 3 ligand (Flt3L), either directly through a series of subcutaneous injections or by seeding with an Flt3L secreting murine melanoma. Flt3L may also be added to bone marrow cultures to produce large numbers of in vitro equivalents of the spleen DC subsets. Total DC, or their subsets, may be further purified using immunofluorescent labeling and flow cytometric cell sorting. Cell sorting may be completely bypassed by separating DC subsets using a combination of fluorescent antibody labeling and anti-fluorochrome magnetic beads. Our procedure enables efficient separation of the distinct DC subsets, even in cases where mouse numbers or flow cytometric cell sorting time is limiting.

  16. Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kheav, Vissal David; Busson, Marc; Scieux, Catherine; Peffault de Latour, Régis; Maki, Guitta; Haas, Philippe; Mazeron, Marie-Christine; Carmagnat, Maryvonnick; Masson, Emeline; Xhaard, Aliénor; Robin, Marie; Ribaud, Patricia; Dulphy, Nicolas; Loiseau, Pascale; Charron, Dominique; Socié, Gérard; Toubert, Antoine; Moins-Teisserenc, Hélène

    2014-12-01

    Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56(bright) natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56(dim) natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C(+)CD56(dim) and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.

  17. A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    PubMed

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Czechowicz, Agnieszka; Shizuru, Judy A; Ko, Rose M; Cowan, Morton J

    2014-09-01

    For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with G-CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34-selected haploidentical cells and one who received T-replete matched unrelated BM. All patients receiving G-CSF and plerixafor had generally poor CD34(+) cell and Lin(-) CD34(+) CD38(-) CD90(+) CD45RA(-) HSC mobilization, and developed donor T cells, but no donor myeloid or B-cell engraftment. Although well tolerated, G-CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.

  18. Ceruloplasmin Is a Potential Biomarker for aGvHD following Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Zhao, Xiao-su; Zhao, Xiang-yu; Chang, Ying-jun; Liu, Dai-hong; Xu, Lan-ping; Huang, Xiao-jun

    2013-01-01

    Acute graft-versus-host-disease (aGvHD) is the major cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, diagnostic biomarkers for aGvHD have been shown to play important roles in evaluating disease status and mortality risk after allo-HSCT. To identify plasma biomarkers for aGvHD with high sensitivity and specificity, a quantitative proteomic approach using 8-plex isobaric tags for relative and absolute quantitation (8-plex iTRAQ) was employed to screen differentially expressed proteins in peripheral blood before and after the onset of aGvHD. Four target proteins, ceruloplasmin (CP), myeloperoxidase (MPO), complement factor H (CFH), and alpha-1-acid glycoprotein (AGP), were chosen for preliminary validation with enzyme linked immunosorbent assay (ELISA) in 20 paired samples at both the time of diagnosis of aGvHD and the time of complete response. The most promising candidate, ceruloplasmin, was further validated at fixed time points after allo-HSCT and during aGvHD. The plasma ceruloplasmin levels were significantly increased during the period of aGvHD onset and were markedly decreased as aGvHD resolved. The plasma ceruloplasmin levels at different time points post-transplant in the aGvHD (+) group were significantly higher than those in the aGvHD (−) group (p<0.001). The elevation of ceruloplasmin level in patients with active aGvHD was independent of infection status. Patients whose ceruloplasmin levels were elevated above 670 μg/ml at 7, 14 and 21 days after allo-HSCT had a remarkably increased probability of subsequently developing aGvHD. In conclusion, our results suggest that plasma ceruloplasmin is a potential plasma biomarker of aGvHD, and it also has prognostic value for risk-adapted prophylaxis during the consecutive time points monitored in the first month after allo-HSCT. PMID:23505556

  19. Allogeneic Hematopoietic Stem Cell Transplantation is Underutilized in Older Patients with Myelodysplastic Syndromes.

    PubMed

    Getta, Bartlomiej M; Kishtagari, Ashwin; Hilden, Patrick; Tallman, Martin S; Maloy, Molly; Gonzales, Patrick; Castro-Malaspina, Hugo; Perales, Miguel-Angel; Giralt, Sergio; Tamari, Roni; Klimek, Virginia

    2017-03-20

    Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplant evaluation, those undergoing transplantation and the reasons for not undergoing transplant are unknown. In this retrospective analysis, pre-defined HCT eligibility and indications criteria were applied to 362 unselected patients with newly diagnosed MDS seen by Leukemia faculty between 2008 and 2015 at Memorial Sloan Kettering Cancer Center. Two hundred ninety four patients (81%) were deemed eligible for transplant and among these, transplant was considered indicated in 244 (83%). Of these, 158/244 (65%) were referred for transplant evaluation at a median of 3.9 months from diagnosis. Overall 120/362 (33%) underwent transplant at a median of 7.7 months from diagnosis. Metastatic solid organ malignancy was the major reason for transplant ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who were not transplanted, was the major reason for not undergoing transplant. Factors associated with a lower likelihood of referral for transplant evaluation included age ≥65 (p<0.001), ≥2 co-morbidities (p=0.008), intermediate-1/low risk MDS (p<0.001), <5% blasts at diagnosis (overall p<0.001), having medicare/medicaid health insurance (p<0.001), not being married (p=0.017) and diagnosis between 2008-2011 (p=0.035). On multivariate analysis adjusting for all of the previous, diagnosis between 2008-2011 (p<0.001), age ≥65 (p=0.001) and <5% blasts at diagnosis (overall p=0.031) were associated with a lower likelihood of referral for transplant evaluation. Factors associated with a lower likelihood of undergoing transplant included age ≥65 (p<0.001), ≥2 co-morbidities (p=0.003), intermediate-1/low risk MDS (p<0.001), <5% blasts (overall p<0.001), very low/low/intermediate risk IPSS-R karyotype (p=0.018) and having medicare/medicaid health insurance (p<0.001). In

  20. 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

  1. Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients.

    PubMed

    Würthwein, Gudrun; Young, Charlotte; Lanvers-Kaminsky, Claudia; Hempel, Georg; Trame, Mirjam N; Schwerdtfeger, Rainer; Ostermann, Helmut; Heinz, Werner J; Cornely, Oliver A; Kolve, Hedwig; Boos, Joachim; Silling, Gerda; Groll, Andreas H

    2012-01-01

    Liposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n = 17; 3 mg/kg once a day [QD]), CAS (n = 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB; n = 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V(1)) (CL, 0.462 liter/h ± 25%; V(1), 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V(2)], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%; V(1), 19.2 liters ± 38%; Q, 2.18 liters/h ± 47%; V(2), 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK

  2. 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

  3. Allogeneic Hematopoietic Cell Transplantation for Aggressive NK Cell Leukemia. A Center for International Blood and Marrow Transplant Research Analysis.

    PubMed

    Hamadani, Mehdi; Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang Woo; Smith, Sonali M; Lee, Jong Wook; Ayala, Ernesto; Chao, Nelson; Hari, Parameswaran; Bolaños-Meade, Javier; Gress, Ronald; Smedegaard Anderson, Niels; Chen, Yi-Bin; Farooq, Umar; Schiller, Gary; Yared, Jean; Sureda, Anna; Fenske, Timothy S; Olteanu, Horatiu

    2017-02-01

    Aggressive NK cell leukemia (ANKL) is an exceedingly rare form of leukemia and carries a poor prognosis, with a median survival of only 2 months. Using the Center for International Blood and Marrow Transplant Research database, we evaluated outcomes of allogeneic hematopoietic cell transplantation (alloHCT) in patients with ANKL. Twenty-one patients with a centrally confirmed diagnosis of ANKL were included. Median patient age was 42 years and 15 patients (71%) were Caucasian. Fourteen patients (67%) were in complete remission (CR) at the time of alloHCT, and 5 patients had active disease. Median follow-up of survivors was 25 months (range, 12 to 116). The 2-year estimates of nonrelapse mortality, relapse/progression, progression-free (PFS), and overall survival (OS) were 21%, 59%, 20%, and 24%, respectively. The 2-year PFS of patients in CR at the time of alloHCT was significantly better than that of patients with active disease at transplantation (30% versus 0%; P = .001). The 2-year OS in similar order was 38% versus 0% (P < .001). In conclusion, this registry analysis that included majority non-Asian patient population shows that alloHCT can provide durable disease control in a subset of ANKL patients. Achieving CR before transplantation appears to be a prerequisite for successful transplantation outcomes.

  4. 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.

  5. Different effects of lansoprazole and rabeprazole on the plasma voriconazole trough levels in allogeneic hematopoietic cell transplant recipients.

    PubMed

    Yasu, Takeo; Konuma, Takaaki; Kato, Seiko; Kurokawa, Yosuke; Takahashi, Satoshi; Tojo, Arinobu

    2016-10-01

    Voriconazole (VRC) is widely used as prophylaxis and in the treatment of invasive fungal disease (IFD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively examined the results of VRC therapeutic drug monitoring (TDM) in allogeneic HCT recipients. A total of 474 samples were obtained from 59 adult patients who received VRC during the first 100 days following HCT between 2009 and 2014 in our institute. Seventeen patients received VRC for prophylaxis of IFD, and 42 received VRC for the empirical or preemptive therapy for IFD. A total of 299 samples (63 %) were obtained during the administration of the intravenous form of VRC. The median VRC daily dose based on the actual body weight was 6.68 mg/kg/day (range, 1.92-10.41 mg/kg/day). The median VRC trough level was 0.99 mg/l (range, <0.09-5.45 mg/l). The multivariate analysis using a logistic regression model demonstrated significantly higher VRC trough levels (≥1.0 mg/l) in males (P < 0.001), empirical or preemptive therapy (P = 0.002), VRC daily dose based on the actual body weight ≥7 mg/kg/day (P < 0.001), and concomitant use of lansoprazole as compared to rabeprazole (P < 0.001). The concomitant use of calcineurin inhibitors and corticosteroids had no effects on VRC trough levels in multivariate analysis. These data suggest that lansoprazole and rabeprazole have different effects on the plasma VRC trough levels in the allogeneic HCT recipients.

  6. Identification of anti-thrombopoietin receptor antibody in prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation treated successfully with eltrombopag.

    PubMed

    Fujimi, Akihito; Kamihara, Yusuke; Hashimoto, Akari; Kanisawa, Yuji; Nakajima, Chisa; Hayasaka, Naotaka; Yamada, Shota; Okuda, Toshinori; Minami, Shinya; Ono, Kaoru; Iyama, Satoshi; Kato, Junji

    2015-10-01

    A 55-year-old female with stage IVA follicular lymphoma in third complete remission underwent allogeneic peripheral blood stem cell transplantation. Neutrophil engraftment was achieved on day +18; however, platelet counts remained below 10 × 10(3)/µL, necessitating transfusions twice a week for more than 3 months. Bone marrow showed a decreased number of megakaryocytes with hypolobulated nuclei. No graft versus host disease, viral infection, or disease relapse was observed. Furthermore, severe thrombocytopenia below 5.0 × 10(3)/µL refractory to transfusion appeared on day +240 after influenza virus infection. Treatments with intravenous immunoglobulin, romiplostim, and rituximab were administered without any recovery. Subsequently, eltrombopag was initiated on day +443, after which platelet counts rose gradually and continued to rise above 20 × 10(3)/µL after 10 weeks of administration. The serum thrombopoietin (TPO) level was markedly elevated, and anti-TPO receptor (TPOR) antibody was detected in the patient's serum. Anti-TPOR antibody may play an important role in some cases of prolonged thrombocytopenia after allogeneic hematopoietic stem cell transplantation with unknown etiology, and eltrombopag could be a novel therapeutic option for such cases.

  7. Dynamic imaging of allogeneic adipose-derived regenerative cells transplanted in ischemic hind limb of apolipoprotein E mouse model

    PubMed Central

    Zheng, Yi; Qin, Jinbao; Wang, Xin; Peng, Zhiyou; Hou, Peiyong; Lu, Xinwu

    2017-01-01

    Background Transplantation of allogeneic adipose-derived regenerative cells (ADRCs) is a promising treatment modality for severe ischemic diseases. However, minimal information is available on the in vivo effects, fate, and migration of ADRCs, as well as the mechanisms of their therapeutic angiogenesis. Materials and methods In this study, green fluorescent protein-expressing ADRCs (GFP-ADRCs) were obtained, labeled with acetylated 3-aminopropyltrimethoxysilane (APTS)-coated iron oxide nanoparticles (APTS NPs), and injected into an old apolipoprotein E knockout (ApoE-KO) mouse model with hind limb ischemia. Then, 3.0 T magnetic resonance imaging (MRI) was performed to dynamically trace the role of ADRCs targeting hind limb ischemia in the ApoE-KO mice model. Results Labeled cells were visualized as large hypointense spots in ischemic muscles by serial 3.0 T MRI scans during a 4-week follow-up. The presence of labeled GFP-ADRCs was confirmed by Prussian blue staining and fluorescence microscopy on postmortem specimens. Conclusion This study showed that allogeneic ADRCs offer great potential application for therapeutic angiogenesis in severe ischemic disease based on the efficacy and feasibility of ADRC transplantation and on the available amounts of tissue. PMID:28053524

  8. Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression Free Survival for Patients with Chronic Myelomonocytic Leukemia

    PubMed Central

    Kongtim, Piyanuch; Popat, Uday; Jimenez, Antonio; Gaballa, Sameh; Fakih, Riad El; Rondon, Gabriela; Chen, Julianne; Bueso-Ramos, Carlos; Borthakur, Gautam; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Kantarjian, Hagop; Alousi, Amin; Hosing, Chitra; Anderlini, Paolo; Khouri, Issa F.; Kebriaei, Partow; Andersson, Borje S.; Oran, Betul; Rezvani, Katayoun; Marin, David; Shpall, Elizabeth J.; Champlin, Richard E.; Ciurea, Stefan O.

    2016-01-01

    The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival. The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; p=0.84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; p=0.04). Our data support the use of hypomethylating agents before allogeneic stem cell transplantation for patients with CMML to achieve morphologic remission and improve progression-free survival of these patients. Future studies are needed to confirm these findings. PMID:26343946

  9. Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer

    PubMed Central

    Karadurmus, Nuri; Sahin, Ugur; Basgoz, Bilgin Bahadir; Arpaci, Fikret; Demirer, Taner

    2016-01-01

    Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced intensity conditioning (RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor (GvT) effect may also be observed in the treatment of some solid tumors (e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors. PMID:28058217

  10. Activation of the mitochondrial ATP-sensitive K+ channel reduces apoptosis of spleen mononuclear cells induced by hyperlipidemia

    PubMed Central

    2013-01-01

    Background We have previously demonstrated that increased rates of superoxide generation by extra-mitochondrial enzymes induce the activation of the mitochondrial ATP-sensitive potassium channel (mitoKATP) in the livers of hypertriglyceridemic (HTG) mice. The resulting mild uncoupling mediated by mitoKATP protects mitochondria against oxidative damage. In this study, we investigate whether immune cells from HTG mice also present increased mitoKATP activity and evaluate the influence of this trait on cell redox state and viability. Methods Oxygen consumption (Clark-type electrode), reactive oxygen species production (dihydroethidium and H2-DCF-DA probes) and cell death (annexin V, cytocrome c release and Trypan blue exclusion) were determined in spleen mononuclear cells. Results HTG mice mononuclear cells displayed increased mitoKATP activity, as evidenced by higher resting respiration rates that were sensitive to mitoKATP antagonists. Whole cell superoxide production and apoptosis rates were increased in HTG cells. Inhibition of mitoKATP further increased the production of reactive oxygen species and apoptosis in these cells. Incubation with HTG serum induced apoptosis more strongly in WT cells than in HTG mononuclear cells. Cytochrome c release into the cytosol and caspase 8 activity were both increased in HTG cells, indicating that cell death signaling starts upstream of the mitochondria but does involve this organelle. Accordingly, a reduced number of blood circulating lymphocytes was found in HTG mice. Conclusions These results demonstrate that spleen mononuclear cells from hyperlipidemic mice have more active mitoKATP channels, which downregulate mitochondrial superoxide generation. The increased apoptosis rate observed in these cells is exacerbated by closing the mitoKATP channels. Thus, mitoKATP opening acts as a protective mechanism that reduces cell death induced by hyperlipidemia. PMID:23764148

  11. DISTRIBUTION OF ANTIBODY-FORMING CELLS OF DIFFERENT SPECIFICITIES IN THE LYMPH NODES AND SPLEENS OF GUINEA PIGS

    PubMed Central

    Green, Ira

    1968-01-01

    The distribution of antibody-forming cells of different specificities in the lymph nodes and spleens of guinea pigs immunized with two separate antigens or with antigens bearing two determinants was studied. When animals were immunized with two soluble protein antigens or antigens in which the two antigenic determinants were on the same molecule, antibody-forming cells of different specificities were always randomly intermixed. However, when animals were immunized with two heat-aggregated particulate protein antigens and then boosted with soluble protein antigens, cells of different specificities were often seen to occur in groups. These results suggest that antibody-forming cells may not arise by the antigen-stimulated proliferation of precommitted antibody-forming cells, but rather antibody-forming cells arise by a transformation of uncommitted precursor cells as the result of their interactions with a locally produced material derived from the processing of antigen. PMID:4877427

  12. Successful hematopoietic reconstitution with transplantation of erythrocyte-depleted allogeneic human umbilical cord blood cells in a child with leukemia.

    PubMed Central

    Pahwa, R N; Fleischer, A; Than, S; Good, R A

    1994-01-01

    Cord blood, a potent source of hematopoietic stem cells, has been shown to successfully reconstitute hematopoiesis following allogeneic transplantation in a variety of disorders. A major drawback of cord blood has been the risk of transfusion reactions in ABO blood group incompatibility and drastic reduction in the stem cell pool if the cord blood is manipulated to remove red cells prior to cryopreservation or after thawing. This report describes an erythrocyte depletion method employing 3% gelatin-induced erythrocyte sedimentation for the selective removal of red cells from cord blood. The red cell-depleted fraction was shown to be enriched in progenitor cells and in cells secreting hematopoietic cytokines interleukin 3, granulocyte/macrophage colony-stimulating factor, and interleukin 6; a major source for cytokines was from cord T cells. This preparative technique was employed to separate out red cells from cord blood of an infant delivered by cesarean section who had an 8-year-old sibling with leukemia. Histocompatibility testing of cord cells revealed complete matching with the patient. A cord cell transplant of cryopreserved and thawed cells consisting of 4 x 10(7) nucleated cells per kg was administered to the patient following myeloablative chemotherapy. The patient's quick hematologic recovery and 9-month disease-free period to date suggest that 3% gelatin separation of erythrocytes is a simple method that can be successfully used for transplanting cord cells for malignant/nonmalignant diseases. PMID:8183934

  13. Development of a walleye spleen stromal cell line sensitive to viral hemorrhagic septicemia virus (VHSV IVb) and to protection by synthetic dsRNA.

    PubMed

    Vo, Nguyen T K; Bender, Aaron W; Ammendolia, Dustin A; Lumsden, John S; Dixon, Brian; Bols, Niels C

    2015-07-01

    A cell line, WE-spleen6, has been developed from the stromal layer of primary spleen cell cultures. On conventional plastic, WE-spleen6 cells had a spindle-shaped morphology at low cell density but grew to become epithelial-like at confluency. On the commercial extracellular matrix (ECM), Matrigel, the cells remained spindle-shaped and formed lumen-like structures. WE-spleen6 cells had intermediate filament protein, vimentin and the ECM protein, collagen I, but not smooth muscle α-actin (SMA) and von Willebrand factor (vWF) and lacked alkaline phosphatase and phagocytic activities. WE-spleen6 was more susceptible to infection with VHSV IVb than a fibroblast and epithelial cell lines from the walleye caudal fin, WE-cfin11f and WE-cfin11e, respectively. Viral transcripts and proteins appeared earlier in WE-spleen6 cultures as did cytopathic effect (CPE) and significant virus production. The synthetic double-stranded RNA (dsRNA), polyinosinic: polycytidylic acid (pIC), induced the antiviral protein Mx in both cell lines. Treating WE-spleen6 cultures with pIC prior to infection with VHSV IVb inhibited the early accumulation of viral transcripts and proteins and delayed the appearance of CPE and significant viral production. Of particular note, pIC caused the disappearance of viral P protein 2 days post infection. WE-spleen6 should be useful for investigating the impact of VHSV IVb on hematopoietic organs and the actions of pIC on the rhabdovirus life cycle.

  14. High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Luznik, Leo

    2010-01-01

    Graft-versus-host disease, or GVHD, is a major complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) for the treatment of hematologic malignancies. Here, we describe a novel method for preventing GVHD after alloHSCT using high-dose, post-transplantation cyclophosphamide (Cy). Post-transplantation Cy promotes tolerance in alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloHSCT. High-dose, post-transplantation Cy facilitates partially HLA-mismatched HSCT without severe GVHD and is effective as sole prophylaxis of GVHD after HLA-matched alloHSCT. By reducing the morbidity and mortality of alloHSCT, post-transplantation Cy may expand the applications of this therapy to the treatment of autoimmune diseases and non-malignant hematologic disorders such as sickle cell disease. PMID:20066512

  15. Induction of Cytomegalovirus-Specific T Cell Responses in Healthy Volunteers and Allogeneic Stem Cell Recipients Using Vaccination With Messenger RNA–Transfected Dendritic Cells

    PubMed Central

    Van Craenenbroeck, Amaryllis H.; Smits, Evelien L.J.; Anguille, Sébastien; Van de Velde, Ann; Stein, Barbara; Braeckman, Tessa; Van Camp, Kirsten; Nijs, Griet; Ieven, Margareta; Goossens, Herman; Berneman, Zwi N.; Van Tendeloo, Viggo F.I.; Verpooten, Gert A.; Van Damme, Pierre; Cools, Nathalie

    2015-01-01

    Background Infection with human cytomegalovirus (CMV) is a significant cause of morbidity and mortality in solid organ and hematopoietic stem cell transplant (HSCT) recipients. Methods The present study explored the safety, feasibility, and immunogenicity of CMV pp65 messenger RNA–loaded autologous monocyte-derived dendritic cells (DC) as a cellular vaccine for active immunization in healthy volunteers and allogeneic HSCT recipients. Four CMV-seronegative healthy volunteers and three allogeneic HSCT recipients were included in the study. Four clinical-grade autologous monocyte-derived DC vaccines were prepared after a single leukapheresis procedure and administered intradermally at a weekly interval. Results De novo induction of CMV-specific T-cell responses was detected in three of four healthy volunteers without serious adverse events. Of the HSCT recipients, none developed CMV disease and one of two patients displayed a remarkable threefold increase in CMV pp65-specific T cells on completion of the DC vaccination trial. Conclusion In conclusion, our DC vaccination strategy induced or expanded a CMV-specific cellular response in four of six efficacy-evaluable study subjects, providing a base for its further exploration in larger cohorts. PMID:25050468

  16. Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Kim, Ji Hyun; Stein, Anthony; Schultheiss, Timothy E.; Palmer, Joycelynne; Liu, An; Rosenthal, Joseph; Forman, Stephen J.

    2014-05-01

    Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

  17. B-1a B Cells that Link the Innate and Adaptive Immune Responses Are Lacking in the Absence of the Spleen

    PubMed Central

    Wardemann, Hedda; Boehm, Thomas; Dear, Neil; Carsetti, Rita

    2002-01-01

    Splenectomized individuals are prone to overwhelming infections with encapsulated bacteria and splenectomy of mice increases susceptibility to streptococcal infections, yet the exact mechanism by which the spleen protects against such infections is unknown. Using congenitally asplenic mice as a model, we show that the spleen is essential for the generation of B-1a cells, a B cell population that cooperates with the innate immune system to control early bacterial and viral growth. Splenectomy of wild-type mice further demonstrated that the spleen is also important for the survival of B-1a cells. Transfer experiments demonstrate that lack of these cells, as opposed to the absence of the spleen per se, is associated with an inability to mount a rapid immune response against streptococcal polysaccharides. Thus, absence of the spleen and the associated increased susceptibility to streptococcal infections is correlated with lack of B-1a B cells. These findings reveal a hitherto unknown role of the spleen in generating and maintaining the B-1a B cell pool. PMID:11901202

  18. Long-Term Reduction in Peripheral Blood HIV Type 1 Reservoirs Following Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation

    PubMed Central

    Henrich, Timothy J.; Hu, Zixin; Li, Jonathan Z.; Sciaranghella, Gaia; Busch, Michael P.; Keating, Sheila M.; Gallien, Sebastien; Lin, Nina H.; Giguel, Francoise F.; Lavoie, Laura; Ho, Vincent T.; Armand, Philippe; Soiffer, Robert J.; Sagar, Manish; LaCasce, Ann S.; Kuritzkes, Daniel R.

    2013-01-01

    Background. The long-term impact of allogeneic hematopoietic stem cell transplantation (HSCT) on human immunodeficiency virus type 1 (HIV-1) reservoirs in patients receiving combination antiretroviral therapy (cART) is largely unknown. Methods. We studied the effects of a reduced-intensity conditioning allogeneic HSCT from donors with wild-type–CCR5+ cells on HIV-1 peripheral blood reservoirs in 2 patients heterozygous for the ccr5Δ32 mutation. In-depth analyses of the HIV-1 reservoir size in peripheral blood, coreceptor use, and specific antibody responses were performed on samples obtained before and up to 3.5 years after HSCT receipt. Results. Although HIV-1 DNA was readily detected in peripheral blood mononuclear cells (PBMCs) before and 2–3 months after HSCT receipt, HIV-1 DNA and RNA were undetectable in PBMCs, CD4+ T cells, or plasma up to 21 and 42 months after HSCT. The loss of detectable HIV-1 correlated temporally with full donor chimerism, development of graft-versus-host disease, and decreases in HIV-specific antibody levels. Conclusions. The ability of donor cells to engraft without evidence of ongoing HIV-1 infection suggests that HIV-1 replication may be fully suppressed during cART and does not contribute to maintenance of viral reservoirs in peripheral blood in our patients. HSCTs with wild-type–CCR5+ donor cells can lead to a sustained reduction in the size of the peripheral reservoir of HIV-1. PMID:23460751

  19. Comparison of characteristics of bacterial bloodstream infection between adult patients with allogeneic and autologous hematopoietic stem cell transplantation.

    PubMed

    Hong, Junshik; Moon, Song Mi; Ahn, Hee Kyung; Sym, Sun Jin; Park, Yoon Soo; Park, Jinny; Cho, Yong Kyun; Cho, Eun Kyung; Shin, Dong Bok; Lee, Jae Hoon

    2013-06-01

    Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥ 2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered.

  20. Financial impact of allogeneic hematopoietic cell transplantation on patients and families over 2 years: results from a multicenter pilot study.

    PubMed

    Denzen, E M; Thao, V; Hahn, T; Lee, S J; McCarthy, P L; Rizzo, J D; Ammi, M; Drexler, R; Flesch, S; James, H; Omondi, N; Murphy, E; Pederson, K; Majhail, N S

    2016-09-01

    Hematopoietic cell transplantation (HCT) is a procedure that can significantly influence the socioeconomic wellbeing of patients, caregivers and their families. Among 30 allogeneic HCT recipients and their caregivers enrolled on a pilot study evaluating the feasibility of studying financial impact of HCT, 16 agreed to participate in the long-term phase, completed a baseline questionnaire and received phone interviews at 6, 12, 18 and 24 months post HCT. Analyses showed that by 2 years post HCT, 54% of patients who previously contributed to household earnings had not returned to work and 80% of patients/caregivers reported transplant as having moderate to great impact on household income. However, patients' levels of confidence in their abilities to meet household financial obligations increased from baseline to 2 years. A relatively large proportion of patients reported inability to pay for medical care through this time period. Case studies demonstrated that patients' individual perceptions of the financial impact of HCT varies considerably, regardless of actual income. We demonstrate the feasibility of conducting a study to evaluate the financial impact of allogeneic HCT through 2 years post transplantation. Some patients/caregivers continue to experience a significant long-term financial burden after this procedure. Our study lays the foundation for a larger evaluation of patient/caregiver financial burden associated with HCT.

  1. Similar and Promising Outcomes in Lymphoma Patients Treated with Myeloablative or Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Tomblyn, Marcie; Brunstein, Claudio; Burns, Linda J.; Miller, Jeffrey S.; MacMillan, Margaret; DeFor, Todd E.; Weisdorf, Daniel J.

    2008-01-01

    We compared the outcomes of 141 consecutive patients who received allogeneic transplantation with either myeloablative (MA) or nonmyeloablative/reduced intensity (NMA) conditioning for non-Hodgkin and Hodgkin lymphoma at the University of Minnesota. All patients were transplanted between 1997 and 2004. NMA transplant recipients were older and received umbilical cord blood grafts more frequently (MA: 6 [9%]; NMA: 33 [43%], P < .001). NMA patients had more advanced disease and 30 (39%) patients had undergone prior autologous transplantation. The 4-year overall survival (OS) (MA: 46% versus NMA: 49%; p = .34) and the 3-year progression-free survival (PFS) (MA: 44% versus NMA: 31%; P = 0.82) were similar after MA or NMA conditioning. However, MA conditioning resulted in significantly higher 1-year treatment-related mortality (TRM) (MA: 43% versus NMA: 17%; P < .01) but a lower risk of relapse at 3 years (MA: 11% versus NMA: 36%; P < .01). We conclude that similar transplant outcomes are achieved after allogeneic hematopoietic stem cell transplantation using MA conditioning in younger patients and NMA conditioning in older patients or those with prior autologous transplantation not eligible for MA conditioning. Modifications to refine patient assignment to the preferred conditioning intensity and reduce relapse risks with NMA approaches are needed. PMID:18410896

  2. Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

    PubMed

    Mayo, S; Messner, H A; Rourke, S B; Howell, D; Victor, J C; Kuruvilla, J; Lipton, J H; Gupta, V; Kim, D D; Piescic, C; Breen, D; Lambie, A; Loach, D; Michelis, F V; Alam, N; Uhm, J; McGillis, L; Metcalfe, K

    2016-06-01

    Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

  3. Financial Impact of Allogeneic Hematopoietic Cell Transplantation on Patients and Families over 2-years: Results from a Multicenter Pilot Study

    PubMed Central

    Denzen, Ellen M.; Thao, Viengneesee; Hahn, Theresa; Lee, Stephanie J.; McCarthy, Philip L.; Rizzo, J. Douglas; Ammi, Monique; Drexler, Rebecca; Flesch, Susan; James, Heather; Omondi, Nancy; Murphy, Elizabeth; Pederson, Kate; Majhail, Navneet S.

    2016-01-01

    Hematopoietic cell transplantation (HCT) is a procedure that can significantly influence the socioeconomic wellbeing of patients, caregivers and their families. Among 30 allogeneic HCT recipients and their caregivers enrolled on a pilot study evaluating the feasibility of studying financial impact of HCT, 16 agreed to participate in the long-term phase, completed a baseline questionnaire and received phone interviews at 6, 12, 18 and 24 months post-HCT. Analyses showed that by 2-years post-HCT, 54% of patients who previously contributed to household earnings had not returned to work and 80% of patients/caregivers reported transplant as having moderate to great impact on household income. However, patients’ level of confidence in their ability to meet household financial obligations increased from baseline to 2-years. A relatively large proportion of patients reported inability to pay for medical care through this time period. Case studies demonstrated patient individual perception of financial impact of HCT varies considerably, regardless of actual income. We demonstrate the feasibility of conducting a study to evaluate financial impact of allogeneic HCT through 2-years post-transplantation. Some patients/caregivers continue to experience significant long-term financial burden after this procedure. Our study lays the foundation for a larger evaluation of patient/caregiver financial burden associated with HCT. PMID:27088381

  4. [18F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

    PubMed Central

    Eissenberg, Linda G; Rettig, Michael P; Ritchey, Julie K; Prior, Julie L; Schwarz, Sally W; Frye, Jennifer; White, Brian S; Fulton, Robert S; Ghobadi, Armin; Cooper, Matthew L; Couriel, Daniel R; Seegulam, Muhammad Esa; Piwnica-Worms, David; Dehdashti, Farrokh; Cornetta, Kenneth; DiPersio, John F

    2015-01-01

    Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75+-selected donor T cells (1.0–13 × 105)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18F)fluoro-3-hydroxymethyl-butyl]guanine ([18F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [18F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [18F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID:25807290

  5. Bone marrow mesenchymal stem cells suppressing activation of allogeneic cytokine-induced killer/natural killer cells either by direct or indirect interaction.

    PubMed

    Li, Yang; Qu, Yu H; Wu, Yan F; Liu, Ling; Lin, Xiang H; Huang, Ke; Wei, Jing

    2015-04-01

    Bone marrow mesenchymal stem cells (MSC) were recently found to be associated with some special immunological characteristics, the immunoregulatory effect of MSC was dose-dependent. Low amount of MSC was associated with mild immunosuppression or even immune activation, while the high amount of that was associated with significant immunosuppressive effect. In this study, by using a transwell system, we explored the effect of MSC on the cell cycle, apoptosis rate and the expression of CD69, an activation marker, on the allogeneic cord blood derived cytokine-induced killer(CIK)/natural killer(NK) cells. The results showed that either by transwell or mixed cell-cell co-culture, the MSC can effect CIK/NK cells on the cell cycle, such as arrested in the G0/G1 phase, diminished the ratio of cells in S, G2/M phase, and increased the apoptosis of them. MSC can also depress the expression of CD69 on these killer cells, as well as increased the ratio of CD4(+) CD25(+) CD127(low) T regulatory (Treg) cells in the CIK/NK cell culture system. We draw conclusions that either by transwell or mixed co-culture, the MSC can suppress activation of allogeneic CB-CIK/NK cells in a dose-dependent manner.

  6. CD19 CAR T Cells for B Cell Malignancies After Allogeneic Transplant

    ClinicalTrials.gov

    2017-02-14

    Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia

  7. Systemic and Local Administration of Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells Promotes Fracture Healing in Rats.

    PubMed

    Huang, Shuo; Xu, Liangliang; Zhang, Yifeng; Sun, Yuxin; Li, Gang

    2015-01-01

    Mesenchymal stem cells (MSCs) are immune privileged and a cell source for tissue repair. Previous studies showed that there is systemic mobilization of osteoblastic precursors to the fracture site. We hypothesized that both systemic and local administration of allogeneic MSCs may promote fracture healing. Bone marrow-derived MSCs and skin fibroblasts were isolated from GFP Sprague-Dawley rats, cultured, and characterized. Closed transverse femoral fracture with internal fixation was established in 48 adult male Sprague-Dawley rats, which were randomly assigned into four groups receiving PBS injection, MSC systemic injection, fibroblast systemic injection, and MSC fracture site injection; 2 × 10(6) cells were injected at 4 days after fracture. All animals were sacrificed at 5 weeks after fracture; examinations included weekly radiograph, micro-CT, mechanical testing, histology, immunohistochemistry, and double immunofluorescence. The callus size of MSC injection groups was significantly larger among all the groups. Radiographs and 3D reconstruction images showed that the fracture gaps united in the MSC injected groups, while gaps were still seen in the fibroblast and PBS injection groups. The mechanical properties were significantly higher in the MSC injection groups than those in the fibroblast and PBS groups, but no difference was found between the MSC local and systemic injection groups. Immunohistochemistry and double immunofluorescence demonstrated that GFP-positive MSCs were present in the callus in the MSC injection groups at 5 weeks after fracture, and some differentiated into osteoblasts. Quantitative analysis revealed the number of GFP-positive cells in the callus in the MSC systemic injection group was significantly lower than that of the MSC local injection group. The proportion of GFP osteoblasts in GFP-positive cells in the MSC systemic injection group was significantly lower than that of the MSC local injection group. These findings provide critical

  8. Recombinant IL-7/HGFβ hybrid cytokine enhances T cell recovery in mice following allogeneic bone marrow transplantation.

    PubMed

    Lai, Laijun; Zhang, Mingfeng; Song, Yinhong; Rood, Debra

    2013-01-01

    T cell immunodeficiency is a major complication of bone marrow (BM) transplantation (BMT). Therefore, approaches to enhance T cell reconstitution after BMT are required. We have purified a hybrid cytokine, consisting of IL-7 and the β-chain of hepatocyte growth factor (HGFβ) (IL-7/HGFβ), from a unique long-term BM culture system. We have cloned and expressed the IL-7/HGFβ gene in which the IL-7 and HGFβ genes are connected by a flexible linker to generate rIL-7/HGFβ protein. Here, we show that rIL-7/HGFβ treatment enhances thymopoiesis after allogeneic BMT. Although rIL-7 treatment also enhances the number of thymocytes, rIL-7/HGFβ hybrid cytokine was more effective than was rIL-7 and the mechanisms by which rIL-7 and rIL-7/HGFβ increase the numbers of thymocytes are different. rIL-7 enhances the survival of double negative (DN), CD4 and CD8 single positive (SP) thymocytes. In contrast, rIL-7/HGFβ enhances the proliferation of the DN, SP thymocytes, as well as the survival of CD4 and CD8 double positive (DP) thymocytes. rIL-7/HGFβ treatment also increases the numbers of early thymocyte progenitors (ETPs) and thymic epithelial cells (TECs). The enhanced thymic reconstitution in the rIL-7/HGFβ-treated allogeneic BMT recipients results in increased number and functional activities of peripheral T cells. Graft-versus-host-disease (GVHD) is not induced in the rIL-7/HGFβ-treated BMT mice. Therefore, rIL-7/HGFβ may offer a new tool for the prevention and/or treatment of T cell immunodeficiency following BMT.

  9. Prognostic Limitations of Donor T Cell Chimerism after Myeloablative Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    PubMed

    Wong, Eric; Mason, Kate; Collins, Jenny; Hockridge, Barbara; Boyd, Janis; Gorelik, Alexandra; Szer, Jeffrey; Ritchie, David S

    2017-02-06

    Donor T cell chimerism is associated with relapse outcomes after allogeneic stem cell transplantation (alloSCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, measures of statistical association do not adequately assess the performance of a prognostic biomarker, which is best characterized by its sensitivity and specificity for the chosen outcome. We analyzed donor T cell chimerism results at day 100 (D100chim) after myeloablative alloSCT for AML or MDS in 103 patients and determined its sensitivity and specificity for relapse-free survival at 6 months (RFS6) and 12 months (RFS12) post-alloSCT. The area under the receiver operating characteristic curve for RFS6 was .68, demonstrating only modest utility as a predictive biomarker, although this was greater than RFS12 at .62. Using a D100chim threshold of 65%, the specificity for RFS6 was 96.6%; however, sensitivity was poor at 26.7%. This equated to a negative predictive value of 88.5% and positive predictive value of 57.1%. Changing the threshold for D100chim to 75% or 85% modestly improved the sensitivity of D100chim for RFS6; however, this was at the expense of specificity. D100chim is specific but lacks sensitivity as a prognostic biomarker of early RFS after myeloablative alloSCT for AML or MDS. Caution is required when using D100chim to guide treatment decisions including immunologic manipulation, which may expose patients to unwarranted graft-versus-host disease.

  10. Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion.

    PubMed

    Zeng, Weihong; Liu, Zhicui; Zhang, Siming; Ren, Jiabin; Ma, Xiaoling; Qin, Chuanmei; Tian, Fuju; Zhang, Yan; Lin, Yi

    2016-11-07

    A deeper understanding of the immunological events during pregnancy will provide novel insights into the pathogenesis of pregnancy complications. The fundamental function of T follicular helper (Tfh) cells is to provide cognate help to B cells. Dysregulations of Tfh-cell function and/or development can result in various immunological diseases. However, the role and characteristics of Tfh cells during pregnancy remain unknown. Herein, an allogeneic-normal-pregnant mouse model was used, and we found that the CD4(+) T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype; and the UP-derived CD4(+)CXCR5(hi)PD-1(hi) and CD4(+)CXCR5(hi)ICOS(hi) Tfh cells, which showed a memory/activation phenotype, reached their peak at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Furthermore, increased foetal resorption by PDL1 blockade correlated with enhanced accumulation of Tfh cells and upregulated expressions of ICOS and PD-1 on these cells. Collectively, our findings are the first to indicate that an adequate and balanced accumulation of Tfh cells during gestation is likely to help maintaining a successful pregnancy, whereas an excessively high level of these cells could lead to abortion.

  11. Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion

    PubMed Central

    Zeng, Weihong; Liu, Zhicui; Zhang, Siming; Ren, Jiabin; Ma, Xiaoling; Qin, Chuanmei; Tian, Fuju; Zhang, Yan; Lin, Yi

    2016-01-01

    A deeper understanding of the immunological events during pregnancy will provide novel insights into the pathogenesis of pregnancy complications. The fundamental function of T follicular helper (Tfh) cells is to provide cognate help to B cells. Dysregulations of Tfh-cell function and/or development can result in various immunological diseases. However, the role and characteristics of Tfh cells during pregnancy remain unknown. Herein, an allogeneic-normal-pregnant mouse model was used, and we found that the CD4+ T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype; and the UP-derived CD4+CXCR5hiPD-1hi and CD4+CXCR5hiICOShi Tfh cells, which showed a memory/activation phenotype, reached their peak at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Furthermore, increased foetal resorption by PDL1 blockade correlated with enhanced accumulation of Tfh cells and upregulated expressions of ICOS and PD-1 on these cells. Collectively, our findings are the first to indicate that an adequate and balanced accumulation of Tfh cells during gestation is likely to help maintaining a successful pregnancy, whereas an excessively high level of these cells could lead to abortion. PMID:27819282

  12. The effect of synthetic homopolymer poly I:C on the synthesis of nucleic acids, protein and interferon in spleen cells normally and with radiation

    NASA Technical Reports Server (NTRS)

    Antropova, Y. N.; Konstantinova, I. V.; Fuks, B. B.; Talosh, M. Y.; Veysfeyler, Y. K.

    1974-01-01

    A comparative study is reported of the effect of the synthetic homopolymer poly I:C and Newcastle Disease virus on the synthesis of RNA, DNA, total protein and interferon in the spleen of nonradiated and radiated mice. In radiated animals, poly I:C and NDV had no stimulating effect on the synthesis of RNA; administration of both inducers to radiated mice did not significantly affect the content of lymphoid cellular elements in the spleen. However, while reduction of RNA synthesis, caused by radiation, also increases slightly under the effect of poly I:C and the virus, the synthesis of interferon in spleen cells and in the entire body is activated.

  13. Immunomodulation with dendritic cells and donor lymphocyte infusion converge to induce graft vs neuroblastoma reactions without GVHD after allogeneic bone marrow transplantation

    PubMed Central

    Ash, S; Stein, J; Askenasy, N; Yaniv, I

    2010-01-01

    Background: Mounting evidence points to the efficacy of donor lymphocyte infusion (DLI) and immunisation with tumour-pulsed dendritic cells (DC) in generating graft vs leukaemia reactions after allogeneic bone marrow transplantation (BMT). We assessed the efficacy of DLI and DC in generating potent graft vs neuroblastoma tumour (GVT) reactions following allogeneic BMT. Methods: Mice bearing congenic (H2Ka) Neuro-2a tumours were grafted with allogeneic (H2Kb) T-cell-depleted bone marrow cells. Tumour-pulsed donor DC (DCNeuro2a) were inoculated (on day +7) in conjunction with donor (H2Kb) and haploidentical (H2Ka/b) lymphocytes. Results: Murine Neuro-2a cells elicit immune reactions as efficient as B lymphoma in major histocompatibility complex antigen-disparate mice. Lymphopenia induced by conditioning facilitates GVT, and transition to adaptive immunity is enhanced by simultaneous infusion of and DCNeuro2a and lymphocytes devoid of graft vs host (GVH) activity (H2Ka/b). In variance, the efficacy of DC-mediated immunomodulation was diminished by severe graft vs host disease (GVHD), showing mechanistic dissociation and antagonising potential to GVT. Conclsions: The GVHD is not a prerequisite to induce GVT reactivity after allogeneic BMT, but is rather detrimental to induction of anti-tumour immunity by DC-mediated immunomodulation. Simultaneous inoculation of tumour-pulsed donor DC and DLI synergise in stimulation of potent GVT reactions to the extent of eradication of established NB tumours. PMID:20978501

  14. A Nerve Conduit Containing a Vascular Bundle and Implanted With Bone Marrow Stromal Cells and Decellularized Allogenic Nerve Matrix.

    PubMed

    Kaizawa, Yukitoshi; Kakinoki, Ryosuke; Ikeguchi, Ryosuke; Ohta, Soichi; Noguchi, Takashi; Takeuchi, Hisataka; Oda, Hiroki; Yurie, Hirofumi; Matsuda, Shuichi

    2017-02-16

    Cells, scaffolds, growth factors, and vascularity are essential for nerve regeneration. Previously, we reported that the insertion of a vascular bundle and the implantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) into a nerve conduit promoted peripheral nerve regeneration. In this study, the efficacy of nerve conduits containing a vascular bundle, BM-MSCs, and thermally decellularized allogenic nerve matrix (DANM) was investigated using a rat sciatic nerve model with a 20-mm defect. Lewis rats were used as the sciatic nerve model and for the preparation of BM-MSCs, and Dark Agouti rats were used for the preparation of the DANM. The revascularization and the immunogenicity of the DANM were investigated histologically. The regeneration of nerves through nerve conduits containing vessels, BM-MSCs, and DANM (VBD group) was evaluated based on electrophysiological, morphometric, and reinnervated muscle weight measurements and compared with that of vessel-containing conduits that were implanted with BM-MSCs (VB group). The DANM that was implanted into vessel-containing tubes (VCTs) was revascularized by neovascular vessels that originated from the inserted vascular bundle 5-7 days after surgery. The number of CD8+ cells found in the DANM in the VCT was significantly smaller than that detected in the untreated allogenic nerve segment. The regenerated nerve in the VBD group was significantly superior to that in the VB group with regard to the amplitude of the compound muscle action potential detected in the pedal adductor muscle; the number, diameter, and myelin thickness of the myelinated axons; and the tibialis anterior muscle weight at 12 and 24 weeks. The additional implantation of the DANM into the BM-MSC-implanted VCT optimized the axonal regeneration through the conduit. Nerve conduits constructed with vascularity, cells, and scaffolds could be an effective strategy for the treatment of peripheral nerve injuries with significant segmental defects.

  15. The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study

    PubMed Central

    Klusmann, Jan-Henning; Reinhardt, Dirk; Zimmermann, Martin; Kremens, Bernhard; Vormoor, Josef; Dworzak, Michael; Creutzig, Ursula; Klingebiel, Thomas

    2012-01-01

    Background The role of allogeneic stem cell transplantation in post-remission management of children with high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission. Design and Methods HLA-typed patients with high-risk acute myeloid leukemia, who achieved first complete remission (n=247), were included in this analysis. All patients received double induction and consolidation. Based on the availability of a matched-sibling donor, patients were allocated by genetic chance to allogeneic stem cell transplantation (n=61) or chemotherapy-only (i.e. intensification and maintenance therapy; n=186). The main analysis was done on an intention-to-treat basis according to this allocation. Results Intention-to-treat analysis did not show a significantly different 5-year disease-free survival (49±6% versus 45±4%, Plog rank=0.44) or overall survival (68±6% versus 57±4%, Plog rank=0.17) between the matched-sibling donor and no-matched-sibling donor groups, whereas late adverse effects occurred more frequently after allogeneic stem cell transplantation (72.5% versus 31.8%, PFischer<0.01). These results were confirmed by as-treated analysis corrected for the time until transplantation (5-year overall survival: 72±8% versus 60±4%, PMantel-Byar 0.21). Subgroup analysis demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic stem cell transplantation (5-year overall survival: 94±6% versus 52±7%, Plog-rank=0.01; n=18 versus 49) in contrast to patients without 11q23 aberrations (5-year overall survival: 58±8% versus 55±5%, Plog-rank=0.66). Conclusions Our analyses defined a genetic subgroup of children with high-risk acute myeloid leukemia who benefited from allogeneic stem cell transplantation in the prospective multi-center AML-BFM 98 study. For

  16. A Taenia crassiceps factor induces apoptosis of spleen CD4+T cells and TFG-β and Foxp3 gene expression in mice.

    PubMed

    Zepeda, N; Tirado, R; Copitin, N; Solano, S; Fernández, A M; Tato, P; Molinari, J L

    2016-03-01

    This study was undertaken to determine whether a parasite substance produces structural pathology in the mouse spleen. A low-molecular-weight Taenia crassiceps metacestode factor (MF) isolated from the peritoneal fluid of female mice infected with T. crassiceps metacestodes induced pathological and immunological changes in mouse spleen cells in vivo. Electron microscopy and confocal microscopy revealed severe changes in the spleen histoarchitecture of T. crassiceps-infected and MF-treated mice. Apoptotic degenerated spleen cells were observed in the white and red pulps and were more conspicuous in the white pulp of the spleen from the T. crassiceps-infected mice than in that of the MF-treated mice. Flow cytometry analysis revealed that the numbers of spleen CD4+T cells were significantly lower in both experimental groups than in control mice. The ex vivo expression of transforming growth factor (TGF)-β and factor Foxp3 were significantly higher in splenocytes of the experimental mice than the basal expression observed in the control cells. These findings may have potential applications for a better understanding of the host-parasite relationship in human neurocysticercosis.

  17. Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas.

    PubMed

    de Masson, Adèle; Beylot-Barry, Marie; Bouaziz, Jean-David; Peffault de Latour, Régis; Aubin, François; Garciaz, Sylvain; d'Incan, Michel; Dereure, Olivier; Dalle, Stéphane; Dompmartin, Anne; Suarez, Felipe; Battistella, Maxime; Vignon-Pennamen, Marie-Dominique; Rivet, Jacqueline; Adamski, Henri; Brice, Pauline; François, Sylvie; Lissandre, Séverine; Turlure, Pascal; Wierzbicka-Hainaut, Ewa; Brissot, Eolia; Dulery, Rémy; Servais, Sophie; Ravinet, Aurélie; Tabrizi, Reza; Ingen-Housz-Oro, Saskia; Joly, Pascal; Socié, Gérard; Bagot, Martine

    2014-03-01

    The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.

  18. Dualism of mixed chimerism between hematopoiesis and stroma in chronic idiopathic myelofibrosis after allogeneic stem cell transplantation.

    PubMed

    Thiele, J; Varus, E; Siebolts, U; Kvasnicka, H M; Wickenhauser, C; Metz, K A; Beelen, D W; Ditschkowski, M; Zander, A; Kröger, N

    2007-04-01

    Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).

  19. Fetal allogeneic dopaminergic cell suspension grafts in the ventricular system of the rat: characterization of transplant morphology and graft-host interactions.

    PubMed

    Oertel, J; Samii, M; Walter, G F

    2004-05-01

    Experimental transplantation trials of fetal cells in Parkinson's and Huntington's disease or multiple sclerosis still require allogeneic graft material and raise questions of graft rejection and immunosuppression. Alternatively to the striatum, the lateral ventricles have been discussed as grafting site in Parkinson's and Huntington's disease although little is known of the specific immunology of the ventricular system. To address this question, 28 adult female LEW1.W rats received intraventricular allogeneic dopaminergic cell suspension grafts from E14 DA rat fetuses. Twelve animals with syngeneic grafts served as control. Immunohistochemical examination was performed with staining for MHC expression, microglia-macrophages, various lymphocyte subsets, dopaminergic neurons and astrocytes at 4 days, and 1, 3, 6, and 12 weeks after transplantation. In all animals, intraventricular transplants were found, which showed maturation and integration in the host parenchyma at the later time points. Animals with allogeneic grafts developed a vivid immune response with strong MHC class I expression and dense lymphocyte infiltrates. Surprisingly, this immune response subsided at 12 weeks and healthy grafts remained. These results indicate (1) that, in contrast to intraparenchymal grafts, a strong immune response to allogeneic fetal cell suspension grafts can be elicited by intraventricular grafting, (2) that a peculiar immunological role of the ventricular system has to be considered in further studies, and (3) that a vivid immune response to allografts in the brain may subside without graft destruction.

  20. T cell receptor repertoires after adoptive transfer of expanded allogeneic regulatory T cells.

    PubMed

    Theil, A; Wilhelm, C; Kuhn, M; Petzold, A; Tuve, S; Oelschlägel, U; Dahl, A; Bornhäuser, M; Bonifacio, E; Eugster, A

    2017-02-01

    Regulatory T cell (Treg ) therapy has been exploited in autoimmune disease, solid organ transplantation and in efforts to prevent or treat graft-versus-host disease (GVHD). However, our knowledge on the in-vivo persistence of transfused Treg is limited. Whether Treg transfusion leads to notable changes in the overall Treg repertoire or whether longevity of Treg in the periphery is restricted to certain clones is unknown. Here we use T cell receptor alpha chain sequencing (TCR-α-NGS) to monitor changes in the repertoire of Treg upon polyclonal expansion and after subsequent adoptive transfer. We applied TCR-α-NGS to samples from two patients with chronic GVHD who received comparable doses of stem cell donor derived expanded Treg . We found that in-vitro polyclonal expansion led to notable repertoire changes in vitro and that Treg cell therapy altered the peripheral Treg repertoire considerably towards that of the infused cell product, to different degrees, in each patient. Clonal changes in the peripheral blood were transient and correlated well with the clinical parameters. We suggest that T cell clonotype analyses using TCR sequencing should be considered as a means to monitor longevity and fate of adoptively transferred T cells.

  1. 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

  2. Allogeneic Hematopoietic Stem Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Results from a Single Center, 1993-2011

    PubMed Central

    Yonal-Hindilerden, Ipek; Kalayoglu-Besisik, Sevgi; Gurses-Koc, Nuray; Hindilerden, Fehmi; Sargin, Deniz

    2017-01-01

    Background: For adult ALL patients, the indications and appropriate timing of allogeneic hematopoietic stem cell transplantation (AHSCT) continue to be debated. The primary aim of this single-institution study was to compare the results of our adult ALL patients that had been allografted with those reported in the current literature. Subjects and Methods: This study included 53 consecutive adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic stem cell transplantation (AHSCT) with myeloablative (92%) and reduced-intensity (8%) conditioning between 1993 and 2011. Results: Mean patient age was 27 years (SD:8.62) and donor age was 33.7 years (SD:9.47). Fourteen patients were in first remission; 21 in ≥2nd remission, 15 in relapse and 3 had primary refractory leukemia. Thirty-four, 15 and 4 patients received busulfan plus cyclophosphamide, cyclophosphamide/total body irradiation and fludarabine-based regimens, respectively. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine plus methotrexate were used. Forty-six donors were related and 7 were unrelated. Thirty patients received granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood and 23 received bone marrow as stem cell source. Twenty-six patients relapsed at a mean duration of 11.3 months (SD:19.1). Forty-four patients succumbed to their disease after a mean follow-up of 13.6 months (SD:19.5). The cause of mortality was relapse (n=24; 54.5%) and transplant-related etiologies (n=20; 45.5%). The estimated five year probabilities of overall survival (OS) and progression-free survival (PFS) were 37% and 12%, respectively. Conclusion: By multivariate analyses, transplantation in first remission was the most important predictor of transplant success. PMID:28286617

  3. Treosulfan, Fludarabine and 2 Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with MDS and AML

    PubMed Central

    Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R.; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M.; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T.; Sandmaier, Brenda M.; Estey, Elihu H.; Appelbaum, Frederick R.; Storer, Barry E.; Deeg, H. Joachim

    2014-01-01

    Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogen