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Sample records for induce donor-specific transplantation

  1. In utero hematopoietic cell transplantation: induction of donor specific immune tolerance and postnatal transplants

    PubMed Central

    Peranteau, William H.

    2014-01-01

    In utero hematopoietic cell transplantation (IUHCT) is a non-myeloablative non-immunosuppressive transplant approach that allows for donor cell engraftment across immunologic barriers. Successful engraftment is associated with donor-specific tolerance. IUHCT has the potential to treat a large number of congenital hematologic, immunologic, and genetic diseases either by achieving high enough engraftment levels following a single IUHCT or by inducing donor specific tolerance to allow for non-toxic same-donor postnatal transplants. This review evaluates donor specific tolerance induction achieved by IUHCT. Specifically it addresses the need to achieve threshold levels of donor cell engraftment following IUHCT to consistently obtain immunologic tolerance. The mechanisms of tolerance induction including partial deletion of donor reactive host T cells by direct and indirect antigen presentation and the role of regulatory T cells in maintaining tolerance are reviewed. Finally, this review highlights the promising clinical potential of in utero tolerance induction to provide a platform on which postnatal cellular and organ transplants can be performed without myeloablative or immunosuppressive conditioning. PMID:25429269

  2. Donor-specific antibodies accelerate arteriosclerosis after kidney transplantation.

    PubMed

    Hill, Gary S; Nochy, Dominique; Bruneval, Patrick; Duong van Huyen, J P; Glotz, Denis; Suberbielle, Caroline; Zuber, Julien; Anglicheau, Dany; Empana, Jean-Philippe; Legendre, Christophe; Loupy, Alexandre

    2011-05-01

    In biopsies of renal allografts, arteriosclerosis is often more severe than expected based on the age of the donor, even without a history of rejection vasculitis. To determine whether preformed donor-specific antibodies (DSAs) may contribute to the severity of arteriosclerosis, we examined protocol biopsies from patients with (n=40) or without (n=59) DSA after excluding those with any evidence of vasculitis. Among DSA-positive patients, arteriosclerosis significantly progressed between month 3 and month 12 after transplant (mean Banff cv score 0.65 ± 0.11 to 1.12 ± 0.10, P=0.014); in contrast, among DSA-negative patients, we did not detect a statistically significant progression during the same timeframe (mean Banff cv score 0.65 ± 0.11 to 0.81 ± 0.10, P=not significant). Available biopsies at later time points supported a rate of progression of arteriosclerosis in DSA-negative patients that was approximately one third that in DSA-positive patients. Accelerated arteriosclerosis was significantly associated with peritubular capillary leukocytic infiltration, glomerulitis, subclinical antibody-mediated rejection, and interstitial inflammation. In conclusion, these data support the hypothesis that donor-specific antibodies dramatically accelerate post-transplant progression of arteriosclerosis.

  3. Validation of Donor-Specific Tolerance of Intestinal Transplant by a Secondary Heart Transplantation Model.

    PubMed

    Pengcheng, Wang; Xiaosong, Li; Xiaofeng, Li; Zhongzhi, Li

    2017-02-01

    It is well accepted that survival after a second organ transplant without immunosuppressive agents indicates tolerance for the first transplant. To validate donor-specific tolerance, we established a rat model with a secondary heart transplant after intestinal transplant, which has so far not been described in the literature. We transplanted intestine from Fischer F344 rats to Lewis rats orthotopically. Lewis rats received tacrolimus pretreatment before transplant and a 14-day course of rapamycin 1 month after transplant. At 120 days after primary intestinal transplant, hearts from 6 F344 rats (group A) or 6 Brown Norway rats (group B) were transplanted to Lewis rats that had survived intestinal transplant and without additional immunosuppressive agents. We analyzed survival data, histologic changes, cells positive for the ED1 macrophage marker in transplanted hearts, and 3 lymphocyte levels in both groups. Thirty days after secondary heart transplant, group A hearts were continuously beating; however, group B hearts stopped beating at around 10 days after transplant (8.5 ± 1.5 d; P < .05). Our histologic study showed that both groups had muscle damage and cellular infiltration in hearts that were distinctly different from normal hearts, with ED1-positive cells counted in both groups (85 ± 16 in group A, 116 ± 28 in group B; P > .05). Fluorescence-activated cell sorting showed that CD4/CD25-positive regulatory T cell, CTLA4/CD4/CD25-positive regulatory T cell, and Natural killer T-cell levels were significantly higher level in group A versus B (P < .05). The donor-specific tolerance that we observed was possibly a state of "clinical tolerance" rather than "immunologic tolerance." Our rat model is a feasible and reliable model to study donor-specific tolerance. The higher levels of lymphocytic T cells shown in intestinal transplant recipients were associated with longer allograft survival, possibly contributing to donor-specific tolerance.

  4. The effect of donor-specific transfusion upon rejection in a rat model of laryngeal transplantation.

    PubMed

    Akst, Lee M; Dan, Olivia; Strome, Marshall

    2006-01-01

    Lifelong immunosuppression carries significant morbidity, and techniques to reduce or eliminate such immunosuppression might expand laryngeal transplantation. This study investigates the ability of donor-specific transfusion to establish tolerance in a rat model of laryngeal transplantation. A total of 289 transplants were performed from Lewis-Brown-Norway donors to Lewis recipients. Donor-specific transfusion was provided as single intravenous injections of donor splenocytes 1 hour before transplantation. Different combinations of in vitro irradiation of donor larynges and postoperative cyclosporine doses provided additional immunomodulation. Allograft rejection was scored histologically at sacrifice 15 or 30 days posttransplant. Multivariate analysis was performed across all groups, and paired analyses compared groups with and without donor-specific transfusion. Donor-specific transfusion did not improve rejection score, although increased cyclosporine dose did (P < .001). Donor splenocyte injection on the day of transplantation does not establish tolerance to laryngeal allografts or permit reduction of other immunosuppression. Other immunomodulatory strategies to establish tolerance in rat laryngeal transplantation require further investigation.

  5. Modulation of Donor-Specific Antibody Production After Organ Transplantation by Valproic Acid: A Histone Deacetylase Inhibitor.

    PubMed

    Ye, Junsheng; Li, Juan; Zhou, Minjie; Xia, Renfei; Liu, Rumin; Yu, Lixin

    2016-11-01

    Antibody-mediated rejection, mediated by donor-specific antibodies, is emerging as a leading cause for allograft dysfunction in organ transplantation. Histone deacetylase inhibitors (HDACi) have potential immunosuppressive action, but their effects on antibody-mediated rejection and B cell function in organ transplantation have not been fully explored. The impacts of valproic acid (VPA), an HDACi, on isolated murine B cell proliferation, apoptosis, class switch recombination (CSR), differentiation, and secretion of immunoglobulin were investigated in vitro and in vivo. Molecular mechanisms were also explored by analyzing the expression of the activation-induced cytidinedeaminase, B lymphocyte-induced maturation protein-1 (Blimp-1/Pridm1), X-box-binding protein 1 and interferon-regulatory factor 4. Mouse cardiac transplant model was used to evaluate the regulatory effects of VPA on B cell response in vivo. Valproic acid significantly inhibited B cell CSR, plasma cell differentiation, thereby reduced antibody generation in a dose-dependent manner without altering B cell proliferation and apoptosis in vitro and in vivo. Activation-induced cytidinedeaminase, Blimp-1/Pridm1 and X-box-binding protein 1 expression were repressed by VPA treatment in a dose-dependent manner, whereas no obvious changes were observed on interferon-regulatory factor 4 expression. Although VPA alone did not prolong the graft medium survival time after murine heart transplantation, the low levels of donor-specific antibody, especially IgG in serum and the less numbers of plasma cells in the spleen were observed in VPA-treated mice. Valproic acid inhibited B cell CSR and plasma cell differentiation in vitro and in nitrophenyl-chicken gamma globulin-immunized and heart transplant recipient mice. HDACi might be a therapeutic agent targeting B cell response after organ transplantation.

  6. Behaviour of Non-Donor Specific Antibodies during Rapid Re-Synthesis of Donor Specific HLA Antibodies after Antibody Incompatible Renal Transplantation

    PubMed Central

    Krishnan, Nithya S.; Zehnder, Daniel; Daga, Sunil; Lowe, Dave; Lam, F. T.; Kashi, Habib; Tan, Lam Chin; Imray, Christopher; Hamer, Rizwan; Briggs, David; Raymond, Neil; Higgins, Robert M.

    2013-01-01

    Background HLA directed antibodies play an important role in acute and chronic allograft rejection. During viral infection of a patient with HLA antibodies, the HLA antibody levels may rise even though there is no new immunization with antigen. However it is not known whether the converse occurs, and whether changes on non-donor specific antibodies are associated with any outcomes following HLA antibody incompatible renal transplantation. Methods 55 patients, 31 women and 24 men, who underwent HLAi renal transplant in our center from September 2005 to September 2010 were included in the studies. We analysed the data using two different approaches, based on; i) DSA levels and ii) rejection episode post transplant. HLA antibody levels were measured during the early post transplant period and corresponding CMV, VZV and Anti-HBs IgG antibody levels and blood group IgG, IgM and IgA antibodies were quantified. Results Despite a significant DSA antibody rise no significant non-donor specific HLA antibody, viral or blood group antibody rise was found. In rejection episode analyses, multiple logistic regression modelling showed that change in the DSA was significantly associated with rejection (p = 0.002), even when adjusted for other antibody levels. No other antibody levels were predictive of rejection. Increase in DSA from pre treatment to a post transplant peak of 1000 was equivalent to an increased chance of rejection with an odds ratio of 1.47 (1.08, 2.00). Conclusion In spite of increases or decreases in the DSA levels, there were no changes in the viral or the blood group antibodies in these patients. Thus the DSA rise is specific in contrast to the viral, blood group or third party antibodies post transplantation. Increases in the DSA post transplant in comparison to pre-treatment are strongly associated with occurrence of rejection. PMID:23922659

  7. Behaviour of non-donor specific antibodies during rapid re-synthesis of donor specific HLA antibodies after antibody incompatible renal transplantation.

    PubMed

    Krishnan, Nithya S; Zehnder, Daniel; Daga, Sunil; Lowe, Dave; Lam, F T; Kashi, Habib; Tan, Lam Chin; Imray, Christopher; Hamer, Rizwan; Briggs, David; Raymond, Neil; Higgins, Robert M

    2013-01-01

    HLA directed antibodies play an important role in acute and chronic allograft rejection. During viral infection of a patient with HLA antibodies, the HLA antibody levels may rise even though there is no new immunization with antigen. However it is not known whether the converse occurs, and whether changes on non-donor specific antibodies are associated with any outcomes following HLA antibody incompatible renal transplantation. 55 patients, 31 women and 24 men, who underwent HLAi renal transplant in our center from September 2005 to September 2010 were included in the studies. We analysed the data using two different approaches, based on; i) DSA levels and ii) rejection episode post transplant. HLA antibody levels were measured during the early post transplant period and corresponding CMV, VZV and Anti-HBs IgG antibody levels and blood group IgG, IgM and IgA antibodies were quantified. Despite a significant DSA antibody rise no significant non-donor specific HLA antibody, viral or blood group antibody rise was found. In rejection episode analyses, multiple logistic regression modelling showed that change in the DSA was significantly associated with rejection (p = 0.002), even when adjusted for other antibody levels. No other antibody levels were predictive of rejection. Increase in DSA from pre treatment to a post transplant peak of 1000 was equivalent to an increased chance of rejection with an odds ratio of 1.47 (1.08, 2.00). In spite of increases or decreases in the DSA levels, there were no changes in the viral or the blood group antibodies in these patients. Thus the DSA rise is specific in contrast to the viral, blood group or third party antibodies post transplantation. Increases in the DSA post transplant in comparison to pre-treatment are strongly associated with occurrence of rejection.

  8. Isolation of precursor endothelial cells from peripheral blood for donor-specific crossmatching before organ transplantation.

    PubMed

    Vermehren, Dilki; Sumitran-Holgersson, Suchitra

    2002-12-15

    The clinical importance of endothelial-cell (EC) antibodies (Abs) in allo-transplantation (Tx) has been reported. However, lack of a suitable method for isolation of donor-specific ECs has prevented routine detection of these Abs before Tx. We describe a quick and simple method for the direct isolation of ECs from whole blood, for routine crossmatching (XM) to detect anti-EC Abs. ECs were isolated using magnetic beads coated with Abs against the angiopoietin receptor Tie-2 that is expressed on EC precursors. A retrospective analysis of 50 previously well-characterized XM sera taken immediately before transplantation from patients with end-stage kidney disease were tested. Tie-2+ cells expressed human leukocyte antigen (HLA) class I, class II, and other EC markers. Sera known to contain only EC-specific or EC- and monocyte (EM)-reactive Abs reacted positively with Tie-2+ cells but not with Tie-2- cells from the same individual. In addition, the Tie-2+ cells reacted with sera containing only HLA class I or class II Abs. In all, 3 of 25 sera from patients with stable graft outcome and no rejections reacted with Tie-2+ cells. For the first time, with use of a single-target cell population, the detection of clinically relevant donor-specific HLA class I, class II, EM, and EC-specific Abs can be performed routinely before Tx. This method is promising because it is quick, specific, and easy to perform on whole blood samples and can therefore be used to perform routine donor-specific EC crossmatching (ECXM) in the future. Routine use of ECXM will aid in identifying better donor-recipient combinations and thus have a greater impact on transplant survival as compared with lymphocyte crossmatch (LXM).

  9. Mechanisms of Donor-Specific Tolerance in Recipients of Haploidentical Combined Bone Marrow/Kidney Transplantation

    PubMed Central

    Andreola, G.; Chittenden, M.; Shaffer, J.; Cosimi, A.B.; Kawai, T.; Cotter, P.; LoCascio, S.A.; Morokata, T.; Dey, B.R.; Tolkoff-Rubin, N.T.; Preffer, F.; Bonnefoix, T.; Kattleman, K.; Spitzer, T.R.; Sachs, D.H.; Sykes, M.

    2011-01-01

    We recently reported long-term organ allograft survival without ongoing immunosuppression in 4 of 5 patients receiving combined kidney and bone marrow transplantation from haploidentical donors following non-myeloablative conditioning. In vitro assays up to 18 months revealed donor-specific unresponsiveness. We now demonstrate that T cell recovery is gradual and is characterized by memory-type cell predominance and an increased proportion of CD4+CD25+CD127−FOXP3+ Treg during the lymphopenic period. Complete donor-specific unresponsiveness in proliferative and cytotoxic assays, and in limiting dilution analyses of IL-2-producing and cytotoxic cells, developed and persisted for the 3-year follow-up in all patients, and extended to donor renal tubular epithelial cells. Assays in 2 of 4 patients were consistent with a role for a suppressive tolerance mechanism at 6 months to 1 year, but later (≥18 months) studies on all 4 patients provided no evidence for a suppressive mechanism. Our studies demonstrate, for the first time, long-term, systemic donor-specific unresponsiveness in patients with HLA-mismatched allograft tolerance. While regulatory cells may play an early role, long-term tolerance appears to be maintained by a deletion or anergy mechanism. PMID:21645255

  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. Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation

    PubMed Central

    Sagoo, Pervinder; Lombardi, Giovanna; Lechler, Robert I.

    2012-01-01

    Current clinical strategies to control the alloimmune response after transplantation do not fully prevent induction of the immunological processes which lead to acute and chronic immune-mediated graft rejection, and as such the survival of a solid organ allograft is limited. Experimental research on naturally occurring CD4+CD25highFoxP3+ Regulatory T cells (Tregs) has indicated their potential to establish stable long-term graft acceptance, with the promise of providing a more effective therapy for transplant recipients. Current approaches for clinical use are based on the infusion of freshly isolated or ex vivo polyclonally expanded Tregs into graft recipients with an aim to redress the in vivo balance of T effector cells to Tregs. However mounting evidence suggests that regulation of donor-specific immunity may be central to achieving immunological tolerance. Therefore, the next stages in optimizing translation of Tregs to organ transplantation will be through the refinement and development of donor alloantigen-specific Treg therapy. The altering kinetics and intensity of alloantigen presentation pathways and alloimmune priming following transplantation may indeed influence the specificity of the Treg required and the timing or frequency at which it needs to be administered. Here we review and discuss the relevance of antigen-specific regulation of alloreactivity by Tregs in experimental and clinical studies of tolerance and explore the concept of delivering an optimal Treg for the induction and maintenance phases of achieving transplantation tolerance. PMID:22811678

  12. Donor-specific HLA antibodies: risk factors and outcomes after kidney transplantation.

    PubMed

    Kanter Berga, J; Pallardo Mateu, L M; Beltran Catalan, S; Puig Alcaraz, N; Sancho Calabuig, A; Gavela Martinez, E; Avila Bernabeu, A; Crespo Albiach, J

    2011-01-01

    Anti-human leukocyte antigen antibodies (HLA Abs) have been associated with reduced kidney allograft survival. Our aim was to analyze the prevalence and impact on allograft function of donor-specific HLA antibodies (DSA) among a cohort of kidney transplant recipients. The 321 recipients had received deceased-donor kidneys followed for a median of 70 ± 43 months. We performed a cross-sectional analysis of the presence of HLA Abs with the use of Luminex technology. Fifty patients (15.6%) displayed HLA Abs after transplantation including 21 (6.7%) as de novo HLA Abs. Eight patients (2.5%) developed DSA, and 42 (13%) showed no DSA. We compared 3 groups of patients: with DSA, without DSA, and without HLA sensitization. The DSA patients were younger (P = .03) with a higher percentage of men (P = .00), and having received less frequent induction treatment with basiliximab or thymoglobulin (P = .02). Patients without DSA revealed a higher percentage of pretransplantation HLA sensitization (P = .00), more pretransplantation transfusions (P = .08), and more frequent retransplantations (P = .00). The incidence of acute rejections was higher for DSA patients (P = .02) than for the other 2 groups, behaving as an independent risk factor (relative risk, 4.7; 95% confidence interval, 1.1-18.8; P = .03). Graft survival at 5 years was lower among patients with compared to those without HLA Abs (P = .00). HLA donor-specific sensitization, an uncommon situation in our study, was associated with younger male recipients and less induction treatment. An acute rejection episode was an independent risk factor for the development of DSA; therefore, we think that monitoring of HLA Abs should be included in evaluation of the early postransplantation period. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Long-term Clinical Relevance of De Novo Donor-Specific Antibodies After Pediatric Liver Transplantation.

    PubMed

    Grabhorn, Enke; Binder, Thomas M C; Obrecht, Denise; Brinkert, Florian; Lehnhardt, Anja; Herden, Uta; Peine, Sven; Nashan, Björn; Ganschow, Rainer; Briem-Richter, Andrea

    2015-09-01

    Anti-HLA antibodies and especially donor-specific antibodies (DSA) play a significant role in graft survival after solid organ transplantation. Their impact on long-term survival in adult liver transplantation (LT) is controversial, but they may be a risk factor. The effects of DSA after pediatric LT are still unclear. We performed a retrospective evaluation of DSA in sera from 43 children who had received transplants at our tertiary center. Twenty-four patients had good long-term clinical and laboratory graft function (group 1), whereas 19 LT recipients suffered from histologically confirmed and clinically relevant chronic allograft rejection (group 2); 16 of these have already undergone retransplantation due to graft dysfunction. Inclusion criteria were availability of sera before the first LT to identify preformed antibodies in case of DSA positivity after LT and long-term follow-up at our institution. Sera were analyzed for anti-HLA antibodies using Luminex single antigen beads, where a mean fluorescence intensity value of more than 1500 was considered positive. The prevalence of DSA was 33% for group 1 and 68% for group 2. Antibodies were predominantly HLA class II. Values of mean fluorescence intensity were comparable in both groups. Only one of the DSA+ ve patients from group 1 exhibited preformed antibodies. In conclusion, pediatric patients with chronic rejection revealed a higher rate of de novo DSA, especially of HLA-class II DSA. Further studies are necessary to confirm these data with a larger pediatric cohort.

  14. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.

    PubMed

    Lefaucheur, Carmen; Loupy, Alexandre; Hill, Gary S; Andrade, Joao; Nochy, Dominique; Antoine, Corinne; Gautreau, Chantal; Charron, Dominique; Glotz, Denis; Suberbielle-Boissel, Caroline

    2010-08-01

    The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

  15. Preexisting Donor-Specific HLA Antibodies Predict Outcome in Kidney Transplantation

    PubMed Central

    Loupy, Alexandre; Hill, Gary S.; Andrade, Joao; Nochy, Dominique; Antoine, Corinne; Gautreau, Chantal; Charron, Dominique; Glotz, Denis; Suberbielle-Boissel, Caroline

    2010-01-01

    The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceased-donor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P = 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI >6000 had >100-fold higher risk for AMR than patients with MFI <465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients. PMID:20634297

  16. Development and maintenance of donor-specific chimerism in semi-allogenic and fully major histocompatibility complex mismatched facial allograft transplants.

    PubMed

    Siemionow, Maria; Demir, Yavuz; Mukherjee, Abir; Klimczak, Aleksandra

    2005-03-15

    The clinical application of composite tissue allograft transplants opened the discussion on the restoration of facial deformities by allotransplantation. We introduce a hemifacial allograft transplant model to investigate the rationale for the development of operational tolerance across a major histocompatibility complex (MHC) barrier. Thirty rats were studied in five groups of six animals each. The composite hemiface isograft transplantations were performed in group 1. Allograft rejection controls included semi-allogenic transplantations from LBN (RT1(1+n) donors (group 2) and fully allogenic transplantations from ACI (RT1a) donors (group 3) to LEW (RT1(1)) recipients. In the allograft treatment groups, recipients of LBN (group 4) and ACI donors (group 5) were treated with cyclosporine A monotherapy (16 mg/kg/day, tapered to 2 mg/kg/day). Face allografts were evaluated clinically and histologically. Donor-specific chimerism for MHC class I RT1n and RT1a antigens was assessed by flow cytometry. Mixed lymphocyte reaction for donor-specific tolerance in vitro was tested at day 160 posttransplant. Isograft controls survived indefinitely. All nontreated allografts rejected within 5 to 8 days posttransplant. Long-term survival was achieved in 100% of LBN (up to 400 days) and ACI (up to 330 days) recipients. At day 160, posttransplant donor-specific chimerism was present in recipients of LBN (10.14% CD4/RT1n, 6.38% CD8/RT1n, 10.02% CD45RA/RT1n) and ACI (17.54% CD4/RT1a, 9.28% CD8/RT1a) transplants, and mixed lymphocyte reaction confirmed tolerance in recipients of LBN transplants and moderate reactivity in recipients of ACI allografts. Operational tolerance was induced in hemiface allograft transplants across an MHC barrier under cyclosporine A monotherapy protocol. It was associated directly with the presence of multilineage donor-specific chimerism.

  17. Clinical relevance of HLA donor-specific antibodies detected by single antigen assay in kidney transplantation.

    PubMed

    Caro-Oleas, José Luis; González-Escribano, María Francisca; González-Roncero, Francisco Manuel; Acevedo-Calado, María José; Cabello-Chaves, Virginia; Gentil-Govantes, Miguel Ángel; Núñez-Roldán, Antonio

    2012-03-01

    Clinical relevance of donor-specific antibodies (DSAs) detected by a single antigen Luminex virtual crossmatch in pre-transplant serum samples from patients with a negative cytotoxicity-dependent complement crossmatch is controversial. The aim of this study was to analyse the influence of a pre-transplant positive virtual crossmatch in the outcome of kidney transplantation. A total of 892 patients who received a graft from deceased donors after a negative cytotoxicity crossmatch were included. Presence of anti-human leucocyte antigen (HLA) antibodies was investigated using a Luminex screening assay and anti-HLA specificities were assigned performing a Luminex single antigen assay. Graft survival was significantly worse among patients with anti-HLA DSA compared to both patients with anti-HLA with no DSA (P = 0.001) and patients without HLA antibodies (P < 0.001) using a log-rank test. No graft survival differences between anti-HLA with no DSA and no HLA antibodies patient groups were observed (P = 0.595). Influence of both anti-Class I and anti-Class II DSA was detected (P < 0.0001 in both cases). When the fluorescence values were stratified in four groups, no significant differences in graft survival were observed among the groups with fluorescence levels >1500 (global P > 0.05). The presence of preformed HLA DSA in transplanted patients with a negative cytotoxicity crossmatch is associated with a lower allograft survival. The detection of anti-HLA with no DSA has no influence in the graft outcome. Finally, there were no demonstrable effects of mean fluorescence intensity (MFI) values >1500 on graft survival.

  18. Donor-specific HLA antibodies and graft function in children after renal transplantation.

    PubMed

    Miettinen, Jenni; Peräsaari, Juha; Lauronen, Jouni; Qvist, Erik; Valta, Helena; Pakarinen, Mikko; Merenmies, Jussi; Jalanko, Hannu

    2012-06-01

    The presence of circulating donor-specific human leukocyte antigen antibodies (HLA-DSA) has been associated with chronic antibody-mediated rejection, leading to progressive graft dysfunction and poor graft survival.The aim of this study was to investigate the incidence and significance of HLA-DSA in paediatric renal transplantation(RTx) patients. A total of 294 post-transplant serum samples from 123 RTx patients were retrospectively analysed for HLA antibodies. Positive samples were further tested for HLADSA by a Luminex Single Antigen bead assay. The antibody findings were correlated to measured glomerular filtration rate(GFR) and clinical outcome. HLA antibodies were detected in half of the routine samples (140/294) taken 1 month to 10 years after RTx, and 40% (62/140) of these were HLA-DSA. Overall, one-third(42/123) of the patients had HLA-DSA, which mostly(65%) reacted against class II antigens. Detection of HLADSA was not associated with poor GFR at the time of sampling, and no exceptional deterioration of GFR after the HLA-DSA detection was noted in individual patients regardless of the antibody level. The presence of HLA-DSA in the first 2 years posttransplantation was not associated with poorer graft function later on. Detection of HLA antibodies is common in children after RTx, and this finding, as such, does not predict any deterioration of graft function.

  19. Predicted indirectly recognizable HLA epitopes presented by HLA-DR correlate with the de novo development of donor-specific HLA IgG antibodies after kidney transplantation.

    PubMed

    Otten, Henny G; Calis, Jorg J A; Keşmir, Can; van Zuilen, Arjan D; Spierings, Eric

    2013-03-01

    HLA class-I mismatches selectively induce antibody formation after kidney transplantation. The de novo development of donor-specific IgG HLA class-I antibodies may be dependent on the HLA class-II background of the patient by presenting T-helper epitopes within the recognized HLA class-I antigens. The correlation between antibody production against mismatched donor human leukocyte antigens (HLA) class I and the number of HLA class II-restricted predicted indirectly recognizable HLA epitopes (PIRCHE-II) in the respective HLA class-I mismatches was investigated. To this end, we analyzed sera taken after nephrectomy from a cohort of 21 non-immunized individuals that received a renal transplant. Fourty-nine HLA class-I mismatches were found which all contained immunogenic eplets according to HLAMatchmaker. Donor specific HLA antibody responses were detected against 38 HLA class-I mismatches after nephrectomy. These mismatches were found to contain a larger number of PIRCHE-II when compared to mismatches which did not induce donor specific HLA antibodies. Most PIRCHE-II (68%) were not part of an eplet as defined by HLAMatchmaker. Our data suggest that presentation of donor-derived HLA class-I peptides by recipient HLA class-II molecules plays a significant role in de novo development of donor-specific IgG HLA antibodies. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  20. Donor-specific alloreactive T cells can be quantified from whole blood, and may predict cellular rejection after renal transplantation.

    PubMed

    Fischer, Michaela; Leyking, Sarah; Schäfer, Marco; Elsäßer, Julia; Janssen, Martin; Mihm, Janine; van Bentum, Kai; Fliser, Danilo; Sester, Martina; Sester, Urban

    2017-07-01

    Preformed cellular alloreactivity can exist prior to transplantation and may contribute to rejection. Here, we used a rapid flow-cytometric whole-blood assay to characterize the extent of alloreactive T cells among 1491 stimulatory reactions from 61 renal transplant candidates and 75 controls. The role of preformed donor-specific alloreactive T cells in cellular rejection was prospectively analyzed in 21 renal transplant recipients. Alloreactive CD8(+) T cells were more frequent than respective CD4(+) T cells, and these levels were stable over time. CD8(+) T cells were effector-memory T cells largely negative for expression of CD27, CD62L, and CCR7, and were susceptible to steroid and calcineurin inhibitor inhibition. Alloreactivity was more frequent in samples with higher number of HLA mismatches. Moreover, the percentage of individuals with alloreactive T cells was higher in transplant candidates than in controls. Among transplant candidates, 5/61 exhibited alloreactive CD8(+) T cells against most stimulators, 23/61 toward a limited number of stimulators, and 33/61 did not show any alloreactivity. Among 21 renal transplant recipients followed prospectively, one had donor-specific preformed T-cell alloreactivity. She was the only patient who developed cellular rejection posttransplantation. In conclusion, donor-specific alloreactive T cells may be rapidly quantified from whole blood, and may predict cellular rejection after transplantation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Donor-specific antibodies after pediatric liver transplantation: a cross-sectional study of 50 patients.

    PubMed

    Kivelä, Jesper M; Kosola, Silja; Peräsaari, Juha; Mäkisalo, Heikki; Jalanko, Hannu; Holmberg, Christer; Pakarinen, Mikko P; Lauronen, Jouni

    2016-04-01

    The role of donor-specific HLA antibodies (DSAs) after pediatric liver transplantation (LT) is inadequately established. We conducted a cross-sectional study on the prevalence of DSAs and their association with liver histology and biochemical variables after pediatric LT. Serum samples were drawn for HLA antibody analyses from 50 patients (76% of 66 eligible patients) operated on at age <18 years between 1987 and 2007 with a median of 10.0 (interquartile range 4.0-16.4) years after deceased donor LT. Mixed and single-antigen beads with Luminex were used for HLA antibody screening and detection. A mean fluorescence intensity (MFI) value of 1000 was used for positive cutoff. Twenty-six patients (52%; 95% confidence interval (CI) 39% to 65%) had DSAs. In 22 (85%) patients, DSAs were against class II HLA antigens with a mean (standard deviation) MFI of 13,481 (4727). The unadjusted prevalence ratio for portal inflammation in DSA-positive compared to DSA-negative patients (n = 47; 9/24 vs. 1/23) was 8.6 (95% CI 1.6 to 50.9). Laboratory values at the time of study were comparable between DSA-positive and DSA-negative patients. In conclusion, approximately half of patients studied had DSAs after pediatric LT. Portal inflammation was associated with DSA positivity although the wide confidence interval around the ratio estimate warrants cautious interpretation. © 2016 Steunstichting ESOT.

  2. Clinical impact of preformed donor-specific denatured class I HLA antibodies after kidney transplantation.

    PubMed

    Visentin, Jonathan; Marroc, Mélanie; Guidicelli, Gwendaline; Bachelet, Thomas; Nong, Thoa; Moreau, Jean-François; Lee, Jar-How; Merville, Pierre; Couzi, Lionel; Taupin, Jean-Luc

    2015-05-01

    Class I single-antigen flow beads (SAFB) carry native and denatured human leukocyte antigen (HLA) molecules. Using a cohort of 179 class I HLA-sensitized kidney recipients, we described incidence and clinical relevance of preformed denatured HLA donor-specific antibodies (DSA) using two different assays: an acid-treated SAFB assay (anti-dHLA DSA) and the iBeads assays (SAFB+/iBeads- DSA). Eighty-five class I DSA were found in 67 patients (median mean fluorescence intensity [MFI] of 1729 [range 520-13 882]). Anti-dHLA and SAFB+/iBeads- DSA represented 11% and 18% of class I DSA and were mainly low MFI DSA (500-1000 MFI). Concordance between these two assays was good (90%). None of the patients with only class I anti-dHLA DSA or only SAFB+/iBeads- DSA developed acute clinical antibody-mediated rejection in the first-year post-transplantation, and their five-yr death-censored graft survival was similar to that of patients without DSA. Moreover, all these patients displayed a negative current T-cell flow cytometry cross-match. Therefore, both anti-dHLA DSA and SAFB+/iBeads- DSA appear irrelevant, which could explain the good outcome observed in some patients with preformed class I DSA. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Graft immunologic events in deceased donor kidney transplant recipients with preformed HLA-donor specific antibodies.

    PubMed

    Ixtlapale-Carmona, Xicohténcatl; Arvizu, Adriana; De-Santiago, Adrian; González-Tableros, Norma; López, Mayra; Castelán, Natalia; Marino, Lluvia A; Uribe-Uribe, Norma O; Contreras, Alan G; Vilatobá, Mario; Morales-Buenrostro, Luis E; Alberú, Josefina

    2017-09-30

    Pretransplant donor-specific HLA alloantibodies detected with the Single Antigen Bead (SAB) assay reflect an increased risk for acute antibody-mediated rejection (AMR). We herein report the incidence of both acute AMR and acute cellular rejection (ACR) during the first year posttransplantation, in a cohort of kidney transplant recipients (KTR) of deceased donor (DD) grafts, according to their DSA status. Pretransplant DSA do not preclude DD-KT in negative CDC-XM recipients at our center. 246 KT were performed at our center between 01/2012 and 12/2015 and 100 KTR obtained from a DD were analyzed; 24% harbored DSA by SAB assay, MFI values >500 were considered positive. All recipients received thymoglobulin induction and generic tacrolimus-based maintenance therapy. Graft biopsies were performed by protocol on months 3 and 12 as well as per indication. The incidence of AMR and ACR was correlated with the existence of pretransplant DSA. Overall, 34% of patients developed an acute rejection episode, 54.2% in the DSA group versus 27.6% in the non-DSA group (p=0.032), and most of these events were detected as subclinical conditions in protocol biopsies. AMR events developed in 33.3% and 19.7% (p=0.176) in the DSA and the non-DSA groups, respectively. ACR events were found in 16.6% and 6.6% (p=0.127) in the DSA and non-DSA groups, respectively. Graft function was similar between groups at the end of the 1st year posttransplant and no immunological graft loss occurred. Despite the use of depleting induction therapy and adequate tacrolimus trough levels along with MMF and steroids, a high rate of rejection events was observed during the first year post-transplantation. Copyright © 2017. Published by Elsevier B.V.

  4. De novo DQ donor-specific antibodies are associated with worse outcomes compared to non-DQ de novo donor-specific antibodies following heart transplantation.

    PubMed

    Cole, Robert Townsend; Gandhi, Jonathan; Bray, Robert A; Gebel, Howard M; Morris, Alanna; McCue, Andrew; Yin, Michael; Laskar, S Raja; Book, Wendy; Jokhadar, Maan; Smith, Andrew; Nguyen, Duc; Vega, J David; Gupta, Divya

    2017-04-01

    Antibody-mediated rejection (AMR) resulting from de novo donor-specific antibodies (dnDSA) leads to adverse outcomes following heart transplantation (HTx). It remains unclear what role dnDSA to specific HLA antigens play in adverse outcomes. This study compares outcomes in patients developing dnDSA to DQ antigens with those developing non-DQ dnDSA and those free from dnDSA. The present study was a single-center, retrospective analysis of 122 consecutive HTx recipients. The primary outcome was a composite of death or graft dysfunction. After 3.3 years of follow-up, 31 (28%) patients developed dnDSA. Mean time to dnDSA was 539 days. Of 31 patients, 19 developed DQ antibodies and 12 developed non-DQ antibodies. Compared to non-DQ dnDSA, DQ antibodies presented with higher MFI values (P=.001) were more likely persistent (P=.001) and appeared later post-HTx (654 vs 359 days, P=.035). In a multivariable analysis, DQ dnDSA was associated with increased risk of the primary endpoint (HR 6.15, 95% CI 2.57-14.75, P=.001), whereas no increased risk was seen with non-DQ dnDSA (P=.749). dnDSA to DQ antigens following HTx are associated with increased risk of death and graft dysfunction. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Clinically-relevant threshold of preformed donor-specific anti-HLA antibodies in kidney transplantation.

    PubMed

    Salvadé, Igor; Aubert, Vincent; Venetz, Jean-Pierre; Golshayan, Dela; Saouli, Anne-Catherine; Matter, Maurice; Rotman, Samuel; Pantaleo, Giuseppe; Pascual, Manuel

    2016-06-01

    Pretransplant anti-HLA donor-specific antibodies (DSA) are recognized as a risk factor for acute antibody-mediated rejection (AMR) in kidney transplantation. The predictive value of C4d-fixing capability by DSA or of IgG DSA subclasses for acute AMR in the pretransplant setting has been recently studied. In addition DSA strength assessed by mean fluorescence intensity (MFI) may improve risk stratification. We aimed to analyze the relevance of preformed DSA and of DSA MFI values. 280 consecutive patients with negative complement-dependent cytotoxicity crossmatches received a kidney transplant between 01/2008 and 03/2014. Sera were screened for the presence of DSA with a solid-phase assays on a Luminex flow analyzer, and the results were correlated with biopsy-proven acute AMR in the first year and survival. Pretransplant anti-HLA antibodies were present in 72 patients (25.7%) and 24 (8.6%) had DSA. There were 46 (16.4%) acute rejection episodes, 32 (11.4%) being cellular and 14 (5.0%) AMR. The incidence of acute AMR was higher in patients with pretransplant DSA (41.7%) than in those without (1.6%) (p<0.001). The median cumulative MFI (cMFI) of the group DSA+/AMR+ was 5680 vs 2208 in DSA+/AMR- (p=0.058). With univariate logistic regression a threshold value of 5280 cMFI was predictive for acute AMR. DSA cMFI's ability to predict AMR was also explored by ROC analysis. AUC was 0.728 and the best threshold was a cMFI of 4340. Importantly pretransplant DSA>5280 cMFI had a detrimental effect on 5-year graft survival. Preformed DSA cMFI values were clinically-relevant for the prediction of acute AMR and graft survival in kidney transplantation. A threshold of 4300-5300 cMFI was a significant outcome predictor. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  6. Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation.

    PubMed

    Wozniak, Laura J; Hickey, Michelle J; Venick, Robert S; Vargas, Jorge H; Farmer, Douglas G; Busuttil, Ronald W; McDiarmid, Sue V; Reed, Elaine F

    2015-07-01

    The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

  7. De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

    PubMed

    Tikkanen, Jussi M; Singer, Lianne G; Kim, S Joseph; Li, Yanhong; Binnie, Matthew; Chaparro, Cecilia; Chow, Chung-Wai; Martinu, Tereza; Azad, Sassan; Keshavjee, Shaf; Tinckam, Kathryn

    2016-09-01

    Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

  8. Renal transplantation across the donor-specific antibody barrier: Graft outcome and cancer risk after desensitization therapy.

    PubMed

    Yang, Ching-Yao; Lee, Chih-Yuan; Yeh, Chi-Chuan; Tsai, Meng-Kun

    2016-06-01

    Desensitization regimens including use of intravenous immune globulin and rituximab have been reported to overcome renal transplant hyperacute rejection. A retrospective case-control study was performed to assess the results and complications of renal transplantation with desensitization therapy for donor-specific antibody (DSA) in a transplant center in Asia, where donor exchange was usually not allowed. Between January 2007 and December 2013, 22 patients with DSA received live-donor renal transplantation after desensitization (DSA group). During the same period, the DSA group was compared to the NSA group (152 renal transplants) who had no specific antibody to the donors (66 from deceased donors and 86 from living relatives). Rejection, renal function, graft and patient survival rates, infection, and cancer incidence were reviewed and analyzed from medical records. The DSA group (46.8%) had significantly higher acute rejection rates than the NSA group (13.7%) at the 1-year follow-up. The estimated renal function, 5-year graft, and patient survival rates were comparable between the groups. The DSA group (19.6%) had significantly higher 5-year de novo cancer incidence than the NSA group (8.5%; p = 0.028); three patients of the DSA group developed urothelial carcinoma 17.0 ± 3.0 months after transplantation. By using stepwise Cox regression analysis, desensitization therapy was identified as the sole independent risk factor for post-transplant urothelial carcinoma. When compared to renal transplantation without DSA, desensitization therapy for DSA resulted in equivalent renal transplant outcome but potentially increased risk of urothelial carcinoma after transplantation. Copyright © 2015. Published by Elsevier B.V.

  9. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation

    PubMed Central

    Ciurea, Stefan O.; Thall, Peter F.; Wang, Xuemei; Wang, Sa A.; Hu, Ying; Cano, Pedro; Aung, Fleur; Rondon, Gabriela; Molldrem, Jeffrey J.; Korbling, Martin; Shpall, Elizabeth J.; de Lima, Marcos; Champlin, Richard E.

    2011-01-01

    Anti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation. PMID:21967975

  10. Trends in immune cell function assay and donor-specific HLA antibodies in kidney transplantation: A 3-year prospective study.

    PubMed

    Libri, I; Gnappi, E; Zanelli, P; Reina, M; Giuliodori, S; Vaglio, A; Palmisano, A; Buzio, C; Riva, G; Barozzi, P; Luppi, M; Cravedi, P; Maggiore, U

    2013-12-01

    The immune cell function assay (ICFA) and de novo anti-donor-specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3-year follow-up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy-proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1-2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted-odds ratio of de novo DSA associated with prior infections: 6.03 [95% CI, 1.64-22.06; p = 0.007]). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

  11. Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation.

    PubMed

    Ciurea, Stefan O; Thall, Peter F; Wang, Xuemei; Wang, Sa A; Hu, Ying; Cano, Pedro; Aung, Fleur; Rondon, Gabriela; Molldrem, Jeffrey J; Korbling, Martin; Shpall, Elizabeth J; de Lima, Marcos; Champlin, Richard E; Fernandez-Vina, Marcelo

    2011-11-24

    Anti-HLA donor-specific Abs (DSAs) have been reported to be associated with graft failure in mismatched hematopoietic stem cell transplantation; however, their role in the development of graft failure in matched unrelated donor (MUD) transplantation remains unclear. We hypothesize that DSAs against a mismatched HLA-DPB1 locus is associated with graft failure in this setting. The presence of anti-HLA Abs before transplantation was determined prospectively in 592 MUD transplantation recipients using mixed-screen beads in a solid-phase fluorescent assay. DSA identification was performed using single-Ag beads containing the corresponding donor's HLA-mismatched Ags. Anti-HLA Abs were detected in 116 patients (19.6%), including 20 patients (3.4%) with anti-DPB1 Abs. Overall, graft failure occurred in 19 of 592 patients (3.2%), including 16 of 584 (2.7%) patients without anti-HLA Abs compared with 3 of 8 (37.5%) patients with DSA (P = .0014). In multivariate analysis, DSAs were the only factor highly associated with graft failure (P = .0001; odds ratio = 21.3). Anti-HLA allosensitization was higher overall in women than in men (30.8% vs 12.1%; P < .0001) and higher in women with 1 (P = .008) and 2 or more pregnancies (P = .0003) than in men. We conclude that the presence of anti-DPB1 DSAs is associated with graft failure in MUD hematopoietic stem cell transplantation.

  12. Immunogenicity of Class I HLA but not preformed low MFI donor specific antibodies correlates with outcomes after first renal transplantation.

    PubMed

    Lobashevsky, A; Goggins, W; Rosner, K; Taber, T

    2017-06-17

    The role of low levels of circulating donor specific antibodies (DSA) producing negative flow cytometry cross match is not completely defined. The purpose of this study was to examine the clinical significance of preexisting low levels of class I DSAs in flow cytometry cross match (FC CM) negative first kidney transplant recipients (KTRs). All of the KTRs (n=41) had low levels of anti-class I antibodies only. The kidney transplant outcome was evaluated by the development of a deleterious effect (DE) in recipients in the study cohort (Group 1: DE+, Group 2: DE-). Positivity for DE was determined based on the following criteria: biopsy proven transplant glomerulopathy (TG), de novo development of DSAs, increasing MFI values for preexisting DSAs, and the development of biopsy proven AMR. Anti-HLA antibodies were tested using single antigen Luminex technology. The HLAMatchmaker computer algorithm was used for the immunogenicity analysis of antibody verified (AbVer) mismatched eplets (MME) at the HLA-A and B loci. The results of this study showed that the number of AbVer MME is larger (P=0.03) in the group of KTR who developed DE. We also demonstrated that the number of AbVer MME is a strong predictor of post-transplant DE. These results indicate that persistent weakly reactive DSA is not a significant risk factor for the development of post-transplant DE and that recipients with such antibodies can be successfully transplanted. Immunogenicity of AbVer MME at HLA-A and B loci is strong predictor of post-transplant increases of the MFI values of preexisting or de novo developed DSA in the FC CM negative first KTR. Avoiding of transplants with more than eleven Class I AbVer MMEs may be the optimal approach to reduce the risk of kidney graft failure. Copyright © 2017. Published by Elsevier B.V.

  13. The role of complement-fixing donor specific antibodies identified by a C1q assay after heart transplantation.

    PubMed

    Farrero Torres, M; Pando, M J; Luo, C; Luikart, H; Valantine, H; Khush, K

    2017-09-22

    The development of donor-specific antibodies (DSA) to human leukocyte antigens (HLA) has been associated with acute rejection and allograft failure after heart transplantation. Not all DSA, however, can fix complement. To determine the association between complement-fixing DSA and heart transplant outcomes, we retrospectively analyzed results obtained using the C1q solid-phase assay that specifically detects complement-fixing DSA in parallel with the standard IgG assay in 121 adult heart transplant recipients. The 52 recipients who developed post-transplant DSA had a higher incidence of acute cellular rejection (58% vs. 19%, p<0.001) and antibody-mediated rejection (29% vs. 7%, p<0.001) than the 69 recipients without DSA. The 24 recipients with C1q+ DSA had more antibody mediated rejection than the 28 recipients with C1q- DSA (46% vs. 14%, p=0.012), but there was no difference in the incidence of acute cellular rejection between these two groups. Patients with post-transplant DSA had higher mortality than patients with no DSA (29% vs. 13%, p=0.031), mainly due to increased incidence of acute rejection. No differences in survival were found between recipients with C1q+ DSA and C1q- DSA. Routine monitoring of DSA post-transplant, and their characterization using the C1q assay, may provide prognostic information for acute rejection after heart transplantation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Desensitization for renal transplantation: depletion of donor-specific anti-HLA antibodies, preservation of memory antibodies, and clinical risks.

    PubMed

    Rogers, Natasha M; Eng, Hooi S; Yu, Raymond; Kireta, Svjetlana; Tsiopelas, Eleni; Bennett, Greg D; Brook, Nicholas R; Gillis, David; Russ, Graeme R; Coates, P Toby

    2011-01-01

    Desensitization protocols reduce donor-specific anti-HLA antibodies (DSA) and enable renal transplantation in patients with a positive complement-dependent cytotoxic cross-match (CDC-CXM). The effect of this treatment on protective antibody and immunoglobulin levels is unknown. Thirteen patients with end-stage renal disease, DSA and positive CDC-CXM underwent desensitization. Sera collected pre- and post-transplantation were analysed for anti-tetanus and anti-pneumococcal antibodies, total immunoglobulin (Ig) levels and IgG subclasses and were compared to healthy controls and contemporaneous renal transplant recipients treated with standard immunosuppression alone. Ten patients developed negative CDC-CXM and enzyme-linked immunosorbent assay (ELISA) and underwent successful transplantation. Eight recipients achieved good graft function without antibody-mediated or late rejection, BK virus or cytomegalovirus infection. One patient had primary non-function due to recurrent oxalosis, and one patient with immediate graft function died from septicaemia. Seven recipients required post-operative transfusion and three developed septicaemia. DSA remained negative by ELISA at 12 months, but were detectable by Luminex(®) . Anti-tetanus and anti-pneumococcal antibodies, total Ig and IgG subclasses were below the normal range but comparable to levels in renal transplant recipients who had not undergone desensitization. Desensitization protocols effectively reduce DSA and allow successful transplantation. Post-operative bleeding and short-term infectious risk is increased. Protective antibody and serum immunoglobulin levels are relatively preserved. © 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.

  15. Everolimus and Advagraf Ab Initio in Combined Liver and Kidney Transplant With Donor-Specific Antibodies: A Case Report.

    PubMed

    Tariciotti, L; Manzia, T M; Sforza, D; Anselmo, A; Tisone, G

    2016-11-01

    Although donor-specific antibodies are regarded as a contraindication for kidney transplantation, the data available for combined liver and kidney transplantation (cLKTx) are scarce, and there is no established therapeutic approach for this category of transplant recipients. De novo use of everolimus and a reduced dose of calcineurin inhibitor reportedly provides excellent kidney function compared with a standard regimen containing a calcineurin inhibitor. This strategy, however, has been applied in only some recipient categories. Here we report a case of A highly sensitized male patient who underwent a cLKTx and received everolimus with low-dose tacrolimus (once-daily prolonged-release formulation) as ab initio immunosuppressive treatment. The pretransplant panel-reactive antibody estimate was 97%, and multiple anti-HLA antibodies were detected at the time of transplantation. Thus far, patient and allograft survival have reached 2 years, with the recipient remaining on a regimen of immunosuppression with everolimus and low-dose tacrolimus, with no episodes of rejection. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies.

    PubMed

    Aubert, O; Bories, M-C; Suberbielle, C; Snanoudj, R; Anglicheau, D; Rabant, M; Martinez, F; Scemla, A; Legendre, C; Sberro-Soussan, R

    2014-06-01

    Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.

  17. The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation

    PubMed Central

    Otten, H G; Verhaar, M C; Borst, H P E; Eck, M; van Ginkel, W G J; Hené, R J; van Zuilen, A D

    2013-01-01

    Antibodies recognizing denatured human leucocyte antigen (HLA) can co-react with epitopes on intact HLA or recognize cryptic epitopes which are normally unaccessible to HLA antibodies. Their specificity cannot be distinguished by single antigen beads (SAB) alone, as they carry a mixture of intact and denatured HLA. In this study, we selected pretransplant sera containing donor-specific HLA class I antibodies (DSA) according to regular SAB analysis from 156 kidney transplant recipients. These sera were analysed using a SAB preparation (iBeads) which is largely devoid of denatured HLA class I, and SAB coated with denatured HLA class I antigens. A total of 241 class I DSA were found by regular SAB analysis, of which 152 (63%) were also found by iBeads, whereas 28 (11%) were caused by reactivity with denatured DNA. Patients with DSA defined either by regular SAB or iBeads showed a significantly lower graft survival rate (P = 0·007) compared to those without HLA class I DSA, whereas reactivity to exclusively denatured HLA was not associated with decreased graft survival. In addition, DSA defined by reactivity to class I SAB or class I iBeads occurred more frequently in female patients and in patients with historic HLA sensitization, whereas reactivity to denatured HLA class I was not associated with any of these parameters. Our data suggest that pretransplant donor-specific antibodies against denatured HLA are clinically irrelevant in patients already sensitized against intact HLA. PMID:23627692

  18. Impact of de novo donor-specific anti-HLA antibodies on grafts outcomes in simultaneous pancreas-kidney transplantation.

    PubMed

    Malheiro, Jorge; Martins, La Salete; Tafulo, Sandra; Dias, Leonídio; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2016-02-01

    De novo donor-specific antibodies (dDSA) relevance in simultaneous pancreas-kidney (SPK) transplantation has been scarcely investigated. We analyzed dDSA relationship with grafts outcomes in a long-term follow-up SPK-transplanted cohort. In 150 patients that received SPK transplant between 2000 and 2013, post-transplant anti-human leukocyte antigen (HLA) antibodies were screened and identified using Luminex-based assays in sera collected at 3, 6, and 12 months, then yearly. dDSA were detected in 22 (14.7%) patients at a median 3.1 years after transplant. Pretransplant anti-HLA sensitization (OR = 4.64), full HLA-DR mismatch (OR = 4.38), and previous acute cellular rejection (OR = 9.45) were significant risk factors for dDSA. dDSA were significantly associated with kidney (in association with acute rejection) and pancreas graft failure. In dDSA+ patients, those with at least one graft failure presented more frequently dDSA against class II or I + II (P = 0.011) and locusDQ (P = 0.043) and had a higher median dDSA number (P = 0.014) and strength (P = 0.030). Median time between dDSA emergence and pancreas and kidney graft failure was 5 and 12 months, respectively. Emergence of dDSA increased the risk of grafts failure in SPK-transplanted patients. Full HLA-DR mismatch was associated with dDSA emergence. dDSA characteristics might help identify patients at a higher risk of graft failure. © 2015 Steunstichting ESOT.

  19. [Effect of pre-transplant donor specific antibody on antibody-mediated rejection and graft dysfunction].

    PubMed

    Wang, Ning; Li, Wei; Zhang, Sheng

    2016-05-01

    目的:研究肾移植受者的术前供者特异性抗体(donor specific antibody,DSA)与其术后发生抗体介导的体液排斥反应(antibody-mediated rejection,AMR)及移植肾功能的关系。方法:选取符合要求的肾移植受者88例。术前采用Luminex流式法对肾移植受者进行DSA检测,并将受者分为DSA阳性组(n=20)与DSA阴性组(n=68)。随访时间为2年。术后参照Banff 2005标准对移植肾病理形态进行评估分级,并观察移植肾的情况。结果: DSA阳性组与阴性组AMR发生率分别为20.0%和1.5%,移植物丢失发生率分别为15.0%和1.5%,两组比较差异均有统计学意义(分别P<0.01,P<0.05);AMR受者最高DSA的荧光指数中值(mean fluorescence intensity,MFI)较非AMR受者差异明显(P<0.01);受试者工作特征(receiver operating characteristic,ROC)曲线显示肾移植术后受者发展为AMR的最高MFI阈值为7909.5。两组移植肾功能延迟回复的发生相比较,差异无统计学意义(P>0.05)。结论:肾移植术前检测DSA水平,可以预测AMR的发生风险和移植肾功能状态。最高DSA值的MFI截点(7909.5)能够预测AMR发生的风险。.

  20. Donor Specific Anti-HLA Antibody and Risk of Graft Failure in Haploidentical Stem Cell Transplantation

    PubMed Central

    Kongtim, Piyanuch; Cao, Kai; Ciurea, Stefan O.

    2016-01-01

    Outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT) using HLA-half matched related donors (haploidentical) have recently improved due to better control of alloreactive reactions in both graft-versus-host and host-versus-graft directions. The recognition of the role of humoral rejection in the development of primary graft failure in this setting has broadened our understanding about causes of engraftment failure in these patients, helped us better select donors for patients in need of AHSCT, and developed rational therapeutic measures for HLA sensitized patients to prevent this unfortunate event, which is usually associated with a very high mortality rate. With these recent advances the rate of graft failure in haploidentical transplantation has decreased to less than 5%. PMID:26904122

  1. Donor-specific HLA antibodies and graft function in kidney-transplanted children - the Vienna cohort.

    PubMed

    Rusai, Krisztina; Dworak, Johanna; Potemkina, Alexandra; Fischer, Gottfried; Csaicsich, Dagmar; Arbeiter, Klaus; Aufricht, Christoph; Müller-Sacherer, Thomas

    2016-06-01

    In the pediatric population, little is known on de novo DSA development, its impact on graft function, and association with suboptimal IS. We assessed the prevalence of de novo DSA in the Vienna cohort of 40 renal transplanted children and adolescents and prospectively followed its association with clinical parameters, graft function, and proteinuria for one yr. At the cross-sectional analysis (median post-transplant time of five yr), 17% of the patients had developed de novo DSA. All HLA-Ab were anti-HLA class II antibodies and persisted in 85% of the cases until the follow-up screening performed within one yr. Basic clinical and laboratory parameters did not differ between DSA-negative and DSA-positive patients at the time of HLA-Ab screening. Suboptimal IS due to reduced medication or non-adherence could not be proven in DSA-positive patients. The changes in eGFR did not differ during the prospective study period, but there was a significantly higher proteinuria in the DSA-positive patients during the follow-up. Our data demonstrate an overall prevalence of 17% of de novo DSA in a pediatric renal transplant cohort. During 12 months of prospective follow-up time, we could demonstrate a significant impact of de novo DSA presence on proteinuria. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. DONOR SPECIFIC ANTI-HLA ANTIBODIES DETECTION AND IMPACT IN KIDNEY TRANSPLANTATION.

    PubMed

    Azar, Hiba; Mourani, Chebl; Nehme Chelala, Dania; Moukarzel, Maroun

    2015-01-01

    Kidney transplantation is now accepted to be the best treatment for end-stage renal disease. Despite the improvement of immunosuppressive therapy, there is still actually substantial loss of allografts, in part due to uncontrolled humoral immunity. For many years, the primary technique for the detection of anti-HLA antibodies was the CDC (complement dependent cytotoxicity). The recent use of solid phase assays, mainly the Luminex technology allowed detection of antibodies at much lower levels, and it has been shown that these antibodies have negative impact on the graft survival. We herein review the principal techniques for anti-HLA detection and the different presentations of humoral rejection.

  3. Mechanisms of immunologic unresponsiveness induced by ultraviolet-irradiated donor-specific blood transfusions and peritransplant cyclosporine

    SciTech Connect

    Oluwole, S.F.; Chabot, J.; Pepino, P.; Reemtsma, K.; Hardy, M.A.

    1988-09-01

    Recipient pretreatment with UV-B irradiated donor-specific blood transfusions (UV-DST) combined with peritransplant cyclosporine on days 0, +1, and +2 leads to permanent cardiac allograft survival in the ACI-to-Lewis rat strain combination. This study investigates the mechanisms of immunologic unresponsiveness induced by UV-DST and CsA by examining several in vitro and in vivo parameters in long-term cardiac allograft recipients. The results of the in vitro studies demonstrate that thoracic duct lymphocytes (TDL) of treated and allografted Lewis rats respond less in a mixed lymphocyte reaction to donor splenic lymphocytes (SpL) by 69%, 75%, and 73% (P less than 0.001) at 30, 50, and 100 days after transplantation, respectively, compared with controls, while the response to a third-party (W/F) SpL is unimpaired. In coculture experiments, the TDL from treated recipients specifically suppressed the response of unmodified Lewis TDL to ACI SpL by 59% and 40% (P less than 0.01) at 30 and 50 days after transplantation, respectively, while responses to W/F SpL were suppressed by only 3-6%. The sera obtained from ungrafted rats transfused with UV-DST suppressed the MLR between unmodified Lewis TDL and ACI SpL by 31% (P less than 0.05) while the sera from UV-DST and CsA-treated and allografted rats specifically suppressed the MLR by 75%, 80% (P less than 0.001) and 37% (P less than 0.01) at 10, 30, and 50 days after transplantation, respectively. In vivo adoptive transfer of 10(4) donor-type dendritic cells (DC) into recipients of beating cardiac allografts at 40 or 60 days after transplantation led to rapid and acute allograft rejection, while the adoptive transfer of 10(8) unseparated SpL obtained at 50 days after transplantation from treated Lewis recipients to syngeneic naive hosts led to a modest but significant prolongation of ACI test cardiac allografts.

  4. An adjustable predictive score of graft survival in kidney transplant patients and the levels of risk linked to de novo donor-specific anti-HLA antibodies.

    PubMed

    Prémaud, Aurélie; Filloux, Matthieu; Gatault, Philippe; Thierry, Antoine; Büchler, Matthias; Munteanu, Eliza; Marquet, Pierre; Essig, Marie; Rousseau, Annick

    2017-01-01

    Most predictive models and scores of graft survival in renal transplantation include factors known before transplant or at the end of the first year. They cannot be updated thereafter, even in patients developing donor-specific anti-HLA antibodies and acute rejection.We developed a conditional and adjustable score for prediction of graft failure (AdGFS) up to 10 years post-transplantation in 664 kidney transplant patients. AdGFS was externally validated and calibrated in 896 kidney transplant patients.The final model included five baseline factors (pretransplant non donor-specific anti-HLA antibodies, donor age, serum creatinine measured at 1 year, longitudinal serum creatinine clusters during the first year, proteinuria measured at 1 year), and two predictors updated over time (de novo donor-specific anti-HLA antibodies and first acute rejection). AdGFS was able to stratify patients into four risk-groups, at different post-transplantation times. It showed good discrimination (time-dependent ROC curve at ten years: 0.83 (CI95% 0.76-0.89).

  5. Efficacy of plasmapheresis on donor-specific antibody reduction by HLA specificity in post–kidney transplant recipients

    PubMed Central

    Yamada, Chisa; Ramon, Daniel S.; Cascalho, Marilia; Sung, Randall S.; Leichtman, Alan B.; Samaniego, Milagros; Davenport, Robertson D.

    2016-01-01

    BACKGROUND Donor-specific antibodies (DSAs) to HLA antigens can cause acute antibody-mediated rejection (AMR) after kidney transplantation (Txp). Therapeutic plasma exchange (TPE) has been used for AMR treatment; however, DSA reduction rates are inconsistent. We investigated DSA reduction rates by HLA specificity and clinical outcome. STUDY DESIGN AND METHODS Sixty-four courses of TPE for 56 kidney Txp recipients with high DSA were investigated. Dates of TPE procedures and Txp, patients’ age, sex, race, creatinine (Cr), and mean fluorescent intensity (MFI) of DSA were retrieved. MFI reduction rate after one to three TPE and four to six TPE procedures were calculated by HLA DSA specificity in each patient, and the mean reduction rates were compared. The relationship of TPE treatment, MFI or Cr improvement rate, and graft age was also investigated. RESULTS Patients received a mean 6.0 TPE procedures. Most received intravenous immunoglobulin after TPE and immunosuppressives. Forty-two cases (65.6%) had DSA to HLA Class I and 54 cases (84.4%) to Class II, including 32 cases (50.0%) to both. Mean MFI reduction rates after one to three TPE and four to six TPE procedures were 25.7 and 37.1% in HLA Class I, 25.1 and 34.2% in Class II, and 14.3 and 19.9% in DR51-53. The mean Cr improvements at the end of TPE and 3 and 6 months after TPE were 3.41, −0.37, and −0.72%, respectively. CONCLUSION Six TPE procedures decreased DSA more than three TPE procedures, but reduction rate was lower by the second three TPE procedures than the first three TPE procedures. Although the mean Cr improvement was minimal, the treatment has good potential to stop further deterioration of kidney function. Better Cr improvement rate is correlated with the graft age. PMID:25385678

  6. Probe-Free Digital PCR Quantitative Methodology to Measure Donor-Specific Cell-Free DNA after Solid-Organ Transplantation.

    PubMed

    Goh, Su Kah; Muralidharan, Vijayaragavan; Christophi, Christopher; Do, Hongdo; Dobrovic, Alexander

    2017-03-01

    Donor-specific cell-free DNA (dscfDNA) is increasingly being considered as a noninvasive biomarker to monitor graft health and diagnose graft rejection after solid-organ transplantation. However, current approaches used to measure dscfDNA can be costly and/or laborious. A probe-free droplet digital PCR (ddPCR) methodology using small deletion/insertion polymorphisms (DIPs) was developed to circumvent these limitations without compromising the quantification of dscfDNA. This method was called PHABRE-PCR (Primer to Hybridize across an Allelic BREakpoint-PCR). The strategic placement of one primer to hybridize across an allelic breakpoint ensured highly specific PCR amplification, which then enabled the absolute quantification of donor-specific alleles by probe-free ddPCR. dscfDNA was serially measured in 3 liver transplant recipients. Donor and recipient genomic DNA was first genotyped against a panel of DIPs to identify donor-specific alleles. Alleles that differentiated donor-specific from recipient-specific DNA were then selected to quantify dscfDNA in the recipient plasma. Lack of amplification of nontargeted alleles confirmed that PHABRE-PCR was highly specific. In recipients who underwent transplantation, dscfDNA was increased at day 3, but decreased and plateaued at a low concentration by 2 weeks in the 2 recipients who did not develop any complications. In the third transplant recipient, a marked increase of dscfDNA coincided with an episode of graft rejection. PHABRE-PCR was able to quantify dscfDNA with high analytical specificity and sensitivity. The implementation of a DIP-based approach permits surveillance of dscfDNA as a potential measure of graft health after solid-organ transplantation. © 2016 American Association for Clinical Chemistry.

  7. Mixed Chimerism, Lymphocyte Recovery and Evidence for Early Donor-Specific Unresponsiveness in Patients Receiving CKBMT to Induce Tolerance

    PubMed Central

    LoCascio, Samuel A.; Morokata, Tatsuaki; Chittenden, Meredith; Preffer, Frederic I.; Dombkowski, David M.; Andreola, Giovanna; Crisalli, Kerry; Kawai, Tatsuo; Saidman, Susan L.; Spitzer, Thomas R.; Tolkoff-Rubin, Nina; Cosimi, A. Benedict; Sachs, David H.; Sykes, Megan

    2011-01-01

    Background We have previously reported operational tolerance in patients receiving HLA-mismatched combined kidney and bone marrow transplantation (CKBMT). We now report on transient multilineage hematopoietic chimerism and lymphocyte recovery in five patients receiving a modified CKBMT protocol, and evidence for early donor-specific unresponsiveness in one of these patients. Methods Five patients with end-stage renal disease received CKBMT from HLA-mismatched, haploidentical living related donors following modified non-myeloablative conditioning. Polychromatic flow cytometry (FCM) was used to assess multilineage chimerism where evaluable and lymphocyte recovery post-transplant. Limiting dilution analysis was used to assess helper-T-lymphocyte reactivity to donor antigens. Results Transient multilineage mixed chimerism was observed in all patients but chimerism became undetectable by 2 weeks post-CKBMT. A marked decrease in T and B lymphocyte counts immediately following transplant was followed by gradual recovery. Initially recovering T cells were depleted of CD45RA+/CD45RO− “naïve-like” cells, which have shown strong recovery in two patients and CD4/CD8 ratios increased immediately following transplant but then declined markedly. NK cells were enriched in the peripheral blood of all patients following transplant. For Subject 2, a pre-transplant limiting dilution assay revealed T helper cells recognizing both donor and third-party PBMCs. However, the anti-donor response was completely undetectable by Day 24, while third-party reactivity persisted. Conclusion These results characterize the transient multilineage mixed hematopoietic chimerism and recovery of lymphocyte subsets in patients receiving a modified CKBMT protocol. The observations are relevant to the mechanisms of donor-specific tolerance in this patient group. PMID:21085064

  8. Pretransplant donor-specific HLA antibodies detected by single antigen bead flow cytometry: risk factors and outcomes after kidney transplantation.

    PubMed

    Kanter Berga, J; Sancho Calabuig, A; Gavela Martinez, E; Puig Alcaraz, N; Beltran Catalan, S; Avila Bernabeu, A; Crespo Albiach, J; Montoro, J A; Pallardo Mateu, L M

    2012-11-01

    The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single antigen bead flow cytometry (SAB-FC) remains unclear. Our aim was to investigate the impact that pre-Tx DSAs detected by SAB-FC have on the early and late clinical outcomes. We retrospectively tested stored frozen pre-Tx sera from 222 deceased-donor kidney transplants performed between November 1997 and November 2006. All patients had a negative complement-dependent cytotoxicity (CDC) cross-match with the donor. Median follow up was 5.1 years. Twenty-two (10%) patients had pre-Tx HLA antibodies detected by CDC. Pre-Tx HLA antibodies were detected using SAB-FC in the sera of 46 (20.7%) patients; 36 (16.2%) of them presented pre-Tx DSAs, 18 had class I antibodies, 9 class II, and 9 patients presented both classes. Mean pre-Tx DSA class I/II was 2360/1972 (MFI) mean fluorescence index in non CDC-sensitized patients. Pre-Tx DSAs were associated with female sex, retransplants, and pretransplant transfusions. Patients with Pre-Tx DSAs more than 1000 MFI and negative CDC screening presented a higher percentage of delayed graft function (61.1% versus 38.9%), more episodes of acute vascular rejection (33.3% versus 13.7%), and chronic rejection as the cause of allograft failure (22.2% versus 9.7%) compared with non-pre-Tx DSAs patients. Five-year allograft survival was significantly worse in patients with pre-Tx DSA (68.5% versus 82%, P = .006) and in patients with pre-Tx DSA class II more than 1000 MFI (43% versus 82%, P = .009). We didn't find differences in patient survival. Pre-Tx DSAs detected by SAB-FC were more frequent in female recipients, and they were associated with acute vascular and chronic rejection and a poorer graft outcome. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Post-transplant donor-specific antibody production and graft outcome in kidney transplantation: results of sixteen-year monitoring by flow cytometry.

    PubMed

    Piazza, Antonina; Poggi, Elvira; Ozzella, Giuseppina; Borrelli, Laura; Scornajenghi, Alessandra; Iaria, Giuseppe; Tisone, Giuseppe; Adorno, Domenico

    2006-01-01

    Our data show that monitoring by sensitive flow cytometric techniques of the de novo production of anti-HLA antibodies in patients receiving kidney transplantation is a useful and noninvasive tool to identify the onset of an immune response towards the graft before any clinical manifestation of antibody-mediated graft injury. Consequently prospective posttransplant monitoring of anti-HLA donor-directed antibodies may offer the chance to realize an effective clinical intervention in order to prevent graft dysfunction and to prolong graft survival. The long follow-up period of the study allowed us to demonstrate a very low graft survival rate in patients who developed donor-specific HLA antibodies in comparison with patients who did not have antibodies, thus confirming the "humoral theory of transplantation". The posttransplant production of anti-HLA antibodies can predict not only graft failure but also chronic dysfunction of the graft. Moreover, our findings suggest that graft survival is influenced by the epitope- and locus-specificity of anti-HLA donor-directed antibodies. The interval between antibody appearance and loss of graft function was short in some patients but reached several years in others. Moreover, some patients showed consistent production of antibodies for many years and an uneventful clinical status. These findings suggest a mechanism of graft "accommodation" or the production of "harmless" antibodies. Immunosuppressive drug combinations able to inhibit T and B cell activation are useful tools to prevent the humoral immune response against graft and consequently to prolong graft survival.

  10. Antibodies to HLA-E may account for the non-donor-specific anti-HLA class-Ia antibodies in renal and liver transplant recipients.

    PubMed

    Ravindranath, Mepur H; Pham, Tho; Ozawa, Miyuki; Terasaki, Paul I

    2012-01-01

    The non-donor-specific anti-HLA-Ia antibodies correlate significantly with lower graft survival in organ transplant patients. Based on our earlier findings that anti-HLA-E murine monoclonal antibodies (MEM-E/02 and 3D12) reacted with different HLA-Ia alleles and the peptides shared by HLA-E and HLA class, Ia alleles inhibited the HLA-Ia reactivity of the anti-HLA-E antibodies in normal non-alloimmunized males, the possibility of that anti-HLA-E IgG may account for the non-donor-specific anti-HLA-Ia antibodies in the allograft recipients was examined by multiplex-Luminex®-immunoassay. About 73% of renal and 53% of liver transplant patients' sera with high level of anti-HLA-E IgG showed reactivity to different non-donor HLA-Ia alleles. About 50% renal and 52% liver allograft recipients' sera with low level of anti-HLA-E IgG had no reactivity to any HLA-Ia alleles; however, the IgG isolated from the same sera with protein-G columns showed the presence of anti-HLA-E IgG with HLA-Ia reactivity. Furthermore, both recombinant HLA-E and the IgG-free serum containing soluble HLA-E (sHLA-E) inhibited HLA-Ia reactivity of anti-HLA-E murine monoclonal IgG significantly. The data suggest that the HLA-Ia reactivity of the anti-HLA-E antibody accounts for the non-donor-specific anti-HLA-Ia antibodies. It is proposed that the sHLA-E heavy chain, shed in circulation after organ transplantation, may expose cryptic epitopes of HLA-E to elicit anti-HLA-E IgG antibodies, which may cross react with HLA-Ia alleles due to the peptide sequences shared between them. This study provides a new explanation for the presence of non-donor-specific antibodies for non-existing HLA-Ia alleles, frequently observed and correlated with survival in organ transplant recipients.

  11. Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts.

    PubMed

    Fan, Yong; Tajima, Asako; Goh, Saik Kia; Geng, Xuehui; Gualtierotti, Giulio; Grupillo, Maria; Coppola, Antonina; Bertera, Suzanne; Rudert, William A; Banerjee, Ipsita; Bottino, Rita; Trucco, Massimo

    2015-07-01

    One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering. Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses against ovalbumin on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells. Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine.

  12. Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts

    PubMed Central

    Fan, Yong; Tajima, Asako; Goh, Saik Kia; Geng, Xuehui; Gualtierotti, Giulio; Grupillo, Maria; Coppola, Antonina; Bertera, Suzanne; Rudert, William A; Banerjee, Ipsita; Bottino, Rita; Trucco, Massimo

    2015-01-01

    One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering. Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses against ovalbumin on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells. Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine. PMID:25903472

  13. Anti-human leukocyte antigen DQ antibodies in renal transplantation: Are we underestimating the most frequent donor specific alloantibodies?

    PubMed

    Carta, Paolo; Di Maria, Lorenzo; Caroti, Leonardo; Buti, Elisa; Antognoli, Giulia; Minetti, Enrico Eugenio

    2015-07-01

    The role of anti-human leukocyte antigens DQ region (HLA-DQ) in transplantation is historically less studied than HLA-DR and HLA class I regions, but several studies are demonstrating that anti HLA-DQ antibodies are among the most frequent anti HLA antibodies that develop after transplantation and can have great influence on the developing of humoral rejection and graft loss. In this article we review the gene structure and nomenclature of the HLA-DQ region, the role of anti HLA-DQ antibodies after and before transplantation and briefly the associations of particular HLA-DQ alleles and other diseases.

  14. De novo donor-specific anti-HLA antibodies after kidney transplantation are associated with impaired graft outcome independently of their C1q-binding ability.

    PubMed

    Kauke, Teresa; Oberhauser, Cornelia; Lin, Viviane; Coenen, Michaela; Fischereder, Michael; Dick, Andrea; Schoenermarck, Ulf; Guba, Markus; Andrassy, Joachim; Werner, Jens; Meiser, Bruno; Angele, Martin; Stangl, Manfred; Habicht, Antje

    2017-04-01

    Many aspects of post-transplant monitoring of donor-specific (DSA) and non-donor-specific (nDSA) anti-HLA antibodies on renal allograft survival are still unclear. Differentiating them by their ability to bind C1q may offer a better risk assessment. We retrospectively investigated the clinical relevance of de novo C1q-binding anti-HLA antibodies on graft outcome in 611 renal transplant recipients. Acute rejection (AR), renal function, and graft survival were assessed within a mean follow-up of 6.66 years. Post-transplant 6.5% patients developed de novo DSA and 11.5% de novo nDSA. DSA (60.0%; P < 0.0001) but not nDSA (34.1%, P = 0.4788) increased rate of AR as compared with controls (27.4%). C1q-binding anti-HLA antibodies did not alter rate of AR in both groups. Renal function was only significantly diminished in patients with DSAC1q(+) . However, DSA significantly impaired 5-year graft survival (65.2%; P < 0.0001) in comparison with nDSA (86.7%; P = 0.0054) and controls (90.7%). While graft survival did not differ between DSAC1q(-) and DSAC1q(+) recipients, 5-year allograft survival was reduced in nDSAC1q(+) (80.9%) versus nDSAC1q(-) (90.7%, P = 0.0251). De novo DSA independently of their ability to bind C1q are associated with diminished graft survival. © 2016 Steunstichting ESOT.

  15. De Novo Donor-Specific HLA Antibodies Developing Early or Late after Transplant Are Associated with the Same Risk of Graft Damage and Loss in Nonsensitized Kidney Recipients

    PubMed Central

    Cioni, Michela; Nocera, Arcangelo; Innocente, Annalisa; Tagliamacco, Augusto; Trivelli, Antonella; Basso, Sabrina; Quartuccio, Giuseppe; Fontana, Iris; Magnasco, Alberto; Drago, Francesca; Gurrado, Antonella; Guido, Ilaria; Compagno, Francesca; Garibotto, Giacomo; Klersy, Catherine; Verrina, Enrico; Ghiggeri, Gian Marco; Cardillo, Massimo

    2017-01-01

    De novo posttransplant donor-specific HLA-antibody (dnDSA) detection is now recognized as a tool to identify patients at risk for antibody-mediated rejection (AMR) and graft loss. It is still unclear whether the time interval from transplant to DSA occurrence influences graft damage. Utilizing sera collected longitudinally, we evaluated 114 consecutive primary pediatric kidney recipients grafted between 2002 and 2013 for dnDSA occurrence by Luminex platform. dnDSAs occurred in 39 patients at a median time of 24.6 months. In 15 patients, dnDSAs developed within 1 year (early-onset group), while the other 24 seroconverted after the first posttransplant year (late-onset group). The two groups were comparable when considering patient- and transplant-related factors, as well as DSA biological properties, including C1q and C3d complement-binding ability. Only recipient age at transplant significantly differed in the two cohorts, with younger patients showing earlier dnDSA development. Late AMR was diagnosed in 47% of the early group and in 58% of the late group. Graft loss occurred in 3/15 (20%) and 4/24 (17%) patients in early- and late-onset groups, respectively (p = ns). In our pediatric kidney recipients, dnDSAs predict AMR and graft loss irrespective of the time elapsed between transplantation and antibody occurrence. PMID:28367453

  16. De Novo Donor-Specific HLA Antibodies Developing Early or Late after Transplant Are Associated with the Same Risk of Graft Damage and Loss in Nonsensitized Kidney Recipients.

    PubMed

    Cioni, Michela; Nocera, Arcangelo; Innocente, Annalisa; Tagliamacco, Augusto; Trivelli, Antonella; Basso, Sabrina; Quartuccio, Giuseppe; Fontana, Iris; Magnasco, Alberto; Drago, Francesca; Gurrado, Antonella; Guido, Ilaria; Compagno, Francesca; Garibotto, Giacomo; Klersy, Catherine; Verrina, Enrico; Ghiggeri, Gian Marco; Cardillo, Massimo; Comoli, Patrizia; Ginevri, Fabrizio

    2017-01-01

    De novo posttransplant donor-specific HLA-antibody (dnDSA) detection is now recognized as a tool to identify patients at risk for antibody-mediated rejection (AMR) and graft loss. It is still unclear whether the time interval from transplant to DSA occurrence influences graft damage. Utilizing sera collected longitudinally, we evaluated 114 consecutive primary pediatric kidney recipients grafted between 2002 and 2013 for dnDSA occurrence by Luminex platform. dnDSAs occurred in 39 patients at a median time of 24.6 months. In 15 patients, dnDSAs developed within 1 year (early-onset group), while the other 24 seroconverted after the first posttransplant year (late-onset group). The two groups were comparable when considering patient- and transplant-related factors, as well as DSA biological properties, including C1q and C3d complement-binding ability. Only recipient age at transplant significantly differed in the two cohorts, with younger patients showing earlier dnDSA development. Late AMR was diagnosed in 47% of the early group and in 58% of the late group. Graft loss occurred in 3/15 (20%) and 4/24 (17%) patients in early- and late-onset groups, respectively (p = ns). In our pediatric kidney recipients, dnDSAs predict AMR and graft loss irrespective of the time elapsed between transplantation and antibody occurrence.

  17. Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction.

    PubMed

    Patel, Samir J; Suki, Wadi N; Loucks-DeVos, Jennifer; Graviss, Edward A; Nguyen, Duc T; Knight, Richard J; Kuten, Samantha A; Moore, Linda W; Teeter, Larry D; Gaber, Lillian W; Gaber, A Osama

    2016-08-01

    Lymphocyte-depleting induction lowers acute rejection (AR) rates among high-immunologic risk (HIR) renal transplant recipients, including African Americans (AAs), retransplants, and the sensitized. It is unclear whether different HIR subgroups experience similarly low rates of AR. We aimed to describe the incidence of AR and de novo donor-specific antibody (dnDSA) among HIR recipients categorized by age, race, or donor type. All received antithymocyte globulin (ATG) induction and triple maintenance immunosuppression. A total of 464 HIR recipients from 2007 to 2014 were reviewed. AR and dnDSA rates at 1 year for the entire population were 14% and 27%, respectively. AR ranged from 6.7% among living donor (LD) recipients to 30% in younger AA deceased donor (DD) recipients. De novo donor-specific antibody at 1 year ranged from 7% in older non-AA LD recipients to 32% in AAs. AA race remained as an independent risk factor for AR among DD recipients and for dnDSA among all HIR recipients. Development of both AR and dnDSA within the first year was associated with a 54% graft survival at 5 years and was an independent risk factor for graft loss. Despite utilization of recommended immunosuppression for HIR recipients, substantial disparities exist among subgroups, warranting further consideration of individualized immunosuppression in certain HIR subgroups.

  18. Living donor kidney transplantation in patients with donor-specific HLA antibodies enabled by anti-CD20 therapy and peritransplant apheresis.

    PubMed

    Klein, Katrin; Süsal, Caner; Schäfer, Sebastian M; Becker, Luis Eduardo; Beimler, Jörg; Schwenger, Vedat; Zeier, Martin; Schemmer, Peter; Macher-Goeppinger, Stephan; Scherer, Sabine; Opelz, Gerhard; Morath, Christian

    2013-01-01

    Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor-specific antibodies (DSA). Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization. Six patients were negative in CDC as well as ELISA screening but positive in Luminex for DSA. The 23 patients received a median of 8 apheresis treatments before and 5 treatments after transplantation. Induction therapy was performed with either thymoglobulin (N = 11) or basiliximab (N = 12). The 2-year graft survival rate was 100%. At last follow up, a median of 12 months after transplantation, median serum creatinine was 1.42 mg/dL, median MDRD-GFR 59.5 mL/min/1.73 m(2), and median urinary protein-to-creatinine ratio 0.12. Ten out of fourteen patients (71%) who had completed the first year after transplantation by the time of analysis had no DSA by day 360. Acute T-cell mediated rejection was diagnosed in one patient (4%), and antibody-mediated changes were found in 5 patients (22%). Four out of these 5 patients showed evidence of persistent (N = 2) or reemerging plus/minus de novo DSA (N = 2) on day 360, and the 2 patients with persistent DSA lost their allograft subsequently on days 750 and 810, respectively. Infectious complications were infrequent. Our previously described treatment algorithm for desensitization of living donor kidney transplant recipients with DSA results in good graft outcomes with a low rate of side effects. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. The impact of donor-specific antibodies on graft outcome in pediatric renal transplantation from deceased donors.

    PubMed

    Piątosa, Barbara; Kwiatkowska, Aneta; Rubik, Jacek; Jarmużek, Wioletta; Kluge, Przemysław; Grenda, Ryszard

    2011-01-01

    Despite prospective crossmatching and modern immunosuppression, early acute rejection is still present in cadaveric renal transplantation. The purpose of this study was to evaluate the incidence of preformed anti-donor antibodies, detected by 2 solid-phase techniques, and to analyze their impact on early renal allograft outcome. Flow crossmatch detecting the presence of anti-donor IgG and IgM antibodies was performed in pre-transplant sera of 279 patients with negative cytotoxic crossmatch. Screening for IgG antibodies detected by bead-based multiplex technique was performed in sera of 69 patients from the FCXM group. The incidence of early biopsy-proven rejection and graft failure within 3 months after transplantation was analyzed. Anti-donor IgG antibodies were detected in 33 patients (11.8%) by flow crossmatch and in 10 patients by multiplex (14.5%). IgM antibodies were detected in 23 patients (8.2%). All multiplex-positive sera were also positive for IgG by flow crossmatch, but in 18 cases no antibodies were found by multiplex technique. Biopsy-proven acute rejection within 3 months after transplantation was observed in 16 patients, and 5 allografts were lost due to immunological reasons. Presence of IgG antibodies was found to have no effect on early outcome, while the presence of IgM antibodies was associated with significantly higher rejection rate and immune-related graft failure. Anti-donor IgG antibodies detected by bead-based and cell-based technique have no impact on biopsy-proven rejection rate or graft failure. Anti-donor IgM detected by flow crossmatch have significant impact on early transplantation outcome.

  20. Histopathologic changes in anti-angiotensin II type 1 receptor antibody-positive kidney transplant recipients with acute rejection and no donor specific HLA antibodies.

    PubMed

    Lim, Mary Ann; Palmer, Matthew; Trofe-Clark, Jennifer; Bloom, Roy D; Jackson, Annette; Philogene, Mary Carmelle; Kamoun, Malek

    2017-04-01

    To determine the association of antibodies against angiotensin II type 1 receptor (AT1R Ab) and histopathologic changes seen in patients with kidney allograft rejection and negative donor specific HLA antibodies (DSA). Stored sera from 27 patients who had biopsy-proven rejection in the absence of DSA were tested for AT1R Ab. Biopsy slides of all patients were re-examined and classified according to Banff 2013 criteria. Histopathologic changes were compared between AT1R positive and negative patients. 75% of patients with positive pre-transplant AT1R Ab had antibody mediated rejection (AMR) compared to 37% of AT1R Ab-negative patients. A trend towards increased interstitial inflammation was observed in the AT1R Ab positive group (p=0.08). More patients in the AT1R Ab positive group had microcirculation inflammation (88% vs 58% with glomerulitis scores ≥1; 75% vs 58% with peritubular capillaritis scores ≥1). In kidney transplant recipients with rejection and no DSA, a higher incidence of AMR and worse inflammation scores are observed in the presence of positive pre-transplant AT1R antibodies. Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  1. Deleterious Impact of Donor-Specific Anti-HLA Antibodies Toward HLA-Cw and HLA-DP in Kidney Transplantation.

    PubMed

    Bachelet, Thomas; Martinez, Charlie; Del Bello, Arnaud; Couzi, Lionel; Kejji, Salima; Guidicelli, Gwendaline; Lepreux, Sébastien; Visentin, Jonathan; Congy-Jolivet, Nicolas; Rostaing, Lionel; Taupin, Jean-Luc; Kamar, Nassim; Merville, Pierre

    2016-01-01

    It is widely accepted that HLA donor-specific antibodies (DSA) are associated with antibody-mediated rejection and graft loss. However, in many transplant programs, preformed anti-HLA-Cw and anti-HLA-DP DSA are not considered in organ allocation policies because their clinical relevance is still uncertain. We analyzed the clinical impact of Cw/DP DSA through a retrospective study, comparing 48 patients transplanted with isolated preformed Cw/DP DSA (Cw/DP DSA group) with (i) 104 matched HLA-sensitized kidney transplant recipients with No DSA at D0 (No DSA group) and (ii) 47 kidney transplant recipients with preformed A, -B, -DR, -DQ DSA (A/B/DR/DQ DSA group). A positive flow cytometry crossmatch in the Cw/DP DSA group was more frequent than in the No DSA group and as frequent as in the A/B/DR/DQDSA group. Two years after transplantation, the biopsy-proven acute rejection-free survival was worse in the Cw/DP and A/B/DR/DQ DSA groups than in the No DSA group (65%, 84%, 93%, P = 0.001 and P = 0.05, respectively). Accordingly, graft survival was lower in the Cw/DP and the A/B/DR/DQ DSA groups than in the No DSA group (87%, 89%, 95%, P = 0.02 and P = 0.1, respectively). These results suggest that preformed anti-HLA-Cw and anti-HLA-DP DSA are as deleterious as anti-HLA A/B/DR/DQ DSA. It justifies their inclusion in kidney allocation programs and in immunological risk stratification algorithms.

  2. A donor-specific epigenetic classifier for acute graft-versus-host disease severity in hematopoietic stem cell transplantation.

    PubMed

    Paul, Dirk S; Jones, Allison; Sellar, Rob S; Mayor, Neema P; Feber, Andrew; Webster, Amy P; Afonso, Neuza; Sergeant, Ruhena; Szydlo, Richard M; Apperley, Jane F; Widschwendter, Martin; Mackinnon, Stephen; Marsh, Steven G E; Madrigal, J Alejandro; Rakyan, Vardhman K; Peggs, Karl S; Beck, Stephan

    2015-12-15

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological conditions. Acute graft-versus-host disease (aGVHD) is a prevalent immune-mediated complication following HSCT. Current diagnostic biomarkers that correlate with aGVHD severity, progression, and therapy response in graft recipients are insufficient. Here, we investigated whether epigenetic marks measured in peripheral blood of healthy graft donors stratify aGVHD severity in human leukocyte antigen (HLA)-matched sibling recipients prior to T cell-depleted HSCT. We measured DNA methylation levels genome-wide at single-nucleotide resolution in peripheral blood of 85 HSCT donors, matched to recipients with various transplant outcomes, with Illumina Infinium HumanMethylation450 BeadChips. Using genome-wide DNA methylation profiling, we showed that epigenetic signatures underlying aGVHD severity in recipients correspond to immune pathways relevant to aGVHD etiology. We discovered 31 DNA methylation marks in donors that associated with aGVHD severity status in recipients, and demonstrated strong predictive performance of these markers in internal cross-validation experiments (AUC = 0.98, 95% CI = 0.96-0.99). We replicated the top-ranked CpG classifier using an alternative, clinical DNA methylation assay (P = 0.039). In an independent cohort of 32 HSCT donors, we demonstrated the utility of the epigenetic classifier in the context of a T cell-replete conditioning regimen (P = 0.050). Our findings suggest that epigenetic typing of HSCT donors in a clinical setting may be used in conjunction with HLA genotyping to inform both donor selection and transplantation strategy, with the ultimate aim of improving patient outcome.

  3. Pre-Transplant Donor-Specific T-Cell Alloreactivity Is Strongly Associated with Early Acute Cellular Rejection in Kidney Transplant Recipients Not Receiving T-Cell Depleting Induction Therapy

    PubMed Central

    Crespo, Elena; Lucia, Marc; Cruzado, Josep M.; Luque, Sergio; Melilli, Edoardo; Manonelles, Anna; Lloberas, Nuria; Torras, Joan; Grinyó, Josep M.; Bestard, Oriol

    2015-01-01

    Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy. PMID:25689405

  4. Characteristics of donor-specific anti-HLA antibodies and outcome in renal transplant patients treated with a standardized induction regimen.

    PubMed

    Zecher, Daniel; Bach, Christian; Staudner, Christoph; Böger, Carsten A; Bergler, Tobias; Banas, Bernhard; Spriewald, Bernd M

    2017-04-01

    Pre-transplant donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have been associated with antibody-mediated rejection (AMR) and early kidney allograft loss. Uncertainties remain regarding the general applicability of these findings and the optimal induction therapy in DSA-positive patients. Pre-transplant sera from 174 patients receiving a crossmatch-negative kidney transplant were retrospectively analysed for DSA using Luminex technology. DSA with mean-fluorescence intensity (MFI) values above 500 were considered positive. All recipients received basiliximab induction and tacrolimus-based maintenance immunosuppression. DSA were monitored post-transplantation in patients with pre-transplant DSA. Antibody results were correlated with the incidence of rejection and graft loss. In total, 61/174 patients had pre-transplant DSA. We found a strong correlation between the presence of DSA against class I and II HLA and DSA MFI greater than 10 000. Both DSA patterns independently predicted an increased risk of early AMR (odds ratio 4.24 and 4.75, respectively, P < 0.05). The risk for AMR in patients with intermediate MFI (3000-10 000) gradually increased with increasing MFI but group sizes were too small to allow for final conclusions. The risk for AMR was comparable to nonsensitized patients in patients with only class I or II HLA-DSA or MFI below 3000. 5-year allograft survival was lowest in patients with simultaneous presence of class I and II HLA-DSA and MFI above 10 000 (45%) but was comparable between patients with only HLA class I or II or no DSA (90.0, 90.0 and 88.1%, respectively). AMR was the only independent predictor of graft loss. Undetectable DSA 14 days post-transplant predicted excellent long-term outcome. . The favourable outcome in the majority of DSA-positive patients despite non-depleting antibody induction and the poor outcome in patients with class I and II HLA-DSA and high DSA strength call for a differentiated therapeutic

  5. The prevalence and clinical significance of C1q-binding donor-specific anti-HLA antibodies early and late after kidney transplantation.

    PubMed

    Calp-Inal, Sumeyye; Ajaimy, Maria; Melamed, Michal L; Savchik, Christina; Masiakos, Peter; Colovai, Adriana; Akalin, Enver

    2016-01-01

    We aimed to determine the prevalence and clinical significance of complement-binding donor-specific antibodies (DSA) detected up to 30 years after kidney transplantation. Group 1 patients included 284 consecutive DSA negative patients who underwent kidney transplantation after 1 May 2009. Group 2 included 405 patients transplanted before this date and followed at our center with functioning allografts. DSA were tested using Luminex Single Antigen and the C1q assay. In Group 1 patients, who were monitored prospectively, 31 (11%) developed de novo DSA during a median follow-up of 2.5 (1.9, 3.6) years. Of these, 11 (4%) had C1q+ and 20 (7%) had C1q negative DSA. In Group 2 patients, 77 (19%) displayed DSA. Among these, 33 (8%) had C1q+ and 44 (11%) had C1q negative DSA. The incidence of acute antibody-mediated rejection (AMR) was significantly higher in C1q+DSA patients in both Group 1 (45%) and Group 2 (15%) compared with C1q negative DSA (5% and 2%) and DSA negative patients (1% and 3%; P < 0.001 and P = 0.001). The incidence of chronic AMR was 36% (Group 1) and 51% (Group 2) in patients with C1q+DSA. In contrast, chronic AMR occurred in 5% and 25% of C1q negative DSA, and 2% and 6% of DSA negative Group 1 and 2 patients, respectively (P < 0.001). Although the graft survival was lower in Group 1 C1q+DSA patients (73%) compared with C1q negative DSA (95%) and DSA negative (94%) patients, the difference was not statistically significant by Kaplan-Meier survival analysis (P = 0.21). Our results indicated that the presence of C1q+ DSA was associated with acute and chronic AMR. Copyright © 2015 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  6. IgM-Enriched Human Intravenous Immunoglobulin-Based Treatment of Patients With Early Donor Specific Anti-HLA Antibodies After Lung Transplantation

    PubMed Central

    Ius, Fabio; Sommer, Wiebke; Kieneke, Daniela; Tudorache, Igor; Kühn, Christian; Avsar, Murat; Siemeni, Thierry; Salman, Jawad; Erdfelder, Carolin; Verboom, Murielle; Kielstein, Jan; Tecklenburg, Andreas; Greer, Mark; Hallensleben, Michael; Blasczyk, Rainer; Schwerk, Nicolaus; Gottlieb, Jens; Welte, Tobias; Haverich, Axel; Warnecke, Gregor

    2016-01-01

    Background At our institution, until April 2013, patients who showed early donor specific anti-HLA antibodies (DSA) after lung transplantation were preemptively treated with therapeutic plasma exchange (tPE) and a single dose of Rituximab. In April 2013, we moved to a therapy based on IgM-enriched human immunoglobulins (IVIG), repeated every 4 weeks, and a single dose of Rituximab. Methods This observational study was designed to evaluate the short-term patient and graft survival in patients who underwent IVIG-based DSA treatment (group A, n = 57) versus contemporary patients transplanted between April 2013 and January 2015 without DSA (group C, n = 180), as well as to evaluate DSA clearance in IVIG-treated patients versus historic patients who had undergone tPE-based treatment (group B, n = 56). Patient records were retrospectively reviewed. Follow-up ended on April 1, 2015. Results At 6 months and 1 year of follow-up, group A had a survival similar to group C (P = 0.81) but better than group B (P = 0.008). Group A showed statistically nonsignificant trends toward improved freedom from pulsed-steroid therapy and biopsy-confirmed rejection over groups B and C. The DSA clearance was better in group A than group B at treatment end (92% vs 64%; P = 0.002) and last DSA control (90% vs 75%; P = 0.04). Conclusions Patients with new early DSA but without graft dysfunction that are treated with IVIG and Rituximab have similarly good early survival as contemporary lung transplant recipients without early DSA. The IVIG yielded increased DSA clearance compared with historic tPE-based treatment, yet spontaneous clearance of new DSA also remains common. PMID:26714123

  7. The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

    PubMed Central

    O'Leary, Jacqueline G.; Samaniego, Millie; Barrio, Marta Crespo; Potena, Luciano; Zeevi, Adriana; Djamali, Arjang; Cozzi, Emanuele

    2016-01-01

    Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance. PMID:26680372

  8. The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.

    PubMed

    OʼLeary, Jacqueline G; Samaniego, Millie; Barrio, Marta Crespo; Potena, Luciano; Zeevi, Adriana; Djamali, Arjang; Cozzi, Emanuele

    2016-01-01

    Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.

  9. Analysis of preformed donor-specific anti-HLA antibodies characteristics for prediction of antibody-mediated rejection in kidney transplantation.

    PubMed

    Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2015-03-01

    The relevance of preformed donor specific antibodies (DSA) detected by Luminex assays, with a negative complement-dependent cytotoxicity (CDC) crossmatch, remains unsettled in kidney transplantation (KT). We aimed to analyze the impact of preformed DSA characteristics on kidney graft outcomes. In 462 patients that received a kidney graft in our unit, between 2007 and 2012, pre-transplant sera were analyzed by Luminex screening assay to determine the presence of anti-human leukocyte antigen (HLA) antibodies and single-antigen bead assay [positive if mean fluorescence intensity (MFI) ≥ 1000] to assign anti-HLA specificities. Anti-HLA antibodies were present in 95 patients (20.6%), but only 40 (8.7%) had DSA. Antibody-mediated rejection (AMR) at 1-year was higher in patients with DSA (35.0%) than in those without them (0.9%) (P < 0.001). Only DSA with a MFI of >3000 were significantly associated with AMR occurrence. Receiver operator curves revealed that a MFI of >4900 in the highest DSA bead had a high sensitivity (85.7%) and that the sum of all DSA beads MFI > 11,000 had a high specificity (92.3%) for AMR prediction. Anti-thymocyte globulin versus basiliximab induction was more frequent in DSA+ AMR- (65.4%) versus DSA+ AMR+ (34.6%) patients (P = 0.072). Five-year censored graft survival was lower in DSA+ than in DSA- patients (respectively, 84.8% versus 94.9%, P = 0.006), although survival was only reduced in DSA+ AMR+ (68.8%) versus DSA+ AMR- (96.0%) patients (P = 0.038). Preformed DSA is associated with kidney graft loss, in relation with AMR occurrence. DSA strength may be used to improve immunological risk stratification of sensitized patients and their clinical management. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Determining donor-specific antibody C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation.

    PubMed

    Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2017-04-01

    Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.

  11. Relationship among C1q-fixing de novo donor specific antibodies, C4d deposition and renal outcome in transplant glomerulopathy.

    PubMed

    Messina, Maria; Ariaudo, Claudia; Praticò Barbato, Loredana; Beltramo, Silvia; Mazzucco, Gianna; Amoroso, Antonio; Ranghino, Andrea; Cantaluppi, Vincenzo; Fop, Fabrizio; Segoloni, Giuseppe Paolo; Biancone, Luigi

    2015-09-01

    The C1q-binding properties of donor specific antibodies (DSA) may be related to antibody-mediated rejection and poor outcome. We retrospectively studied 35 kidney transplant recipients with transplant glomerulopathy (TG) and de novo DSA (dnDSA). C1q dnDSA were measured in the serum stored at renal biopsy and the association among C1q-fixing dnDSA, C4d deposition and graft loss was examined. Of the 35 patients with dnDSA and TG, 15 (42.9%) had C1q-positive dnDSA and 20 (57.1%) had C1q-negative dnDSA. Ten out of 15 patients with C1q-positive dnDSA (66.6%) and 5 with C1q-negative dnDSA (25%) had C4d positive staining renal biopsies (P=0.02), being the C1q-negative dnDSA/C4d-negative TG 42.9% of the total. The C1q-positive dnDSA group has significantly higher IgG DSA Class II MFI than the C1q-negative dnDSA group (P=0.004). Patients with C4d deposits have significantly higher IgG DSA MFI for both Class I and Class II than those without C4d deposits (P=0.02). We found a trend toward higher graft loss in the C1q-positive dnDSA group (60%) versus the C1q-negative dnDSA group (40%) without a statistical significance (P=0.31). Our study provides further characterization of TG associated with dnDSA. The major part of dnDSA-associated TG was C1q-negative and the presence of C1q-fixing dnDSA did not significantly correlate with graft outcome. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Société Francophone d'Histocompatibilité et d'Immunogénétique (SFHI) and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) analysis.

    PubMed

    Ruggeri, Annalisa; Rocha, Vanderson; Masson, Emeline; Labopin, Myriam; Cunha, Renato; Absi, Lena; Boudifa, Ali; Coeffic, Brigitte; Devys, Anne; De Matteis, Muriel; Dubois, Valérie; Hanau, Daniel; Hau, Françoise; Jollet, Isabelle; Masson, Dominique; Pedron, Beatrice; Perrier, Pascale; Picard, Christophe; Ramouneau-Pigot, Annie; Volt, Fernanda; Charron, Dominique; Gluckman, Eliane; Loiseau, Pascale

    2013-07-01

    Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has

  13. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Société Francophone d’Histocompatibilité et d’Immunogénétique (SFHI) and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) analysis

    PubMed Central

    Ruggeri, Annalisa; Rocha, Vanderson; Masson, Emeline; Labopin, Myriam; Cunha, Renato; Absi, Lena; Boudifa, Ali; Coeffic, Brigitte; Devys, Anne; De Matteis, Muriel; Dubois, Valérie; Hanau, Daniel; Hau, Françoise; Jollet, Isabelle; Masson, Dominique; Pedron, Beatrice; Perrier, Pascale; Picard, Christophe; Ramouneau-Pigot, Annie; Volt, Fernanda; Charron, Dominique; Gluckman, Eliane; Loiseau, Pascale

    2013-01-01

    Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620–17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient’s screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient

  14. Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies.

    PubMed

    Kim, Jon Jin; Shaw, Olivia; Martin, Chloe; Michaelides, George; Balasubramaniam, Ramnath; Sebire, Neil J; Mamode, Nizam; Dorling, Anthony; Vaughan, Robert; Marks, Stephen D

    2017-09-16

    We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan-Meier estimator. Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R (2) 0.072; C3d: adjusted R (2) 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q-) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q-) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30-1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d-); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d-) years; HR 0.38; 95% CI 0.15-0.97; p = 0.04]. Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction.

  15. The utility of comprehensive assessment of donor specific anti-HLA antibodies in the clinical management of pediatric kidney transplant recipients.

    PubMed

    Gloor, James M

    2011-09-01

    Advances in anti-HLA antibody characterization have had a major impact on kidney transplantation. Comprehensive characterization of DSA has improved protocols for allosensitized transplant candidates, increasing access to acceptable donors. Sensitive and specific solid phase antibody detection assays have given important insight into the clinical characteristics of antibody-mediated allograft injury, resulting in the development of a classification system for acute AMR. In addition, important insights into the nature of chronic antibody-mediated allograft rejection have been achieved as a result of improvements in DSA characterization. Finally, assays initially developed as tools to detect DSA in the clinical setting have been employed in innovative research protocols, allowing the investigation of new therapeutic approaches. © 2010 John Wiley & Sons A/S.

  16. Donor MHC class I peptides in conjunction with self-epitopes induce donor-specific tolerance in a dose-dependent manner but unable to abrogate chronic rejection.

    PubMed

    Semiletova, N V; Shen, X-D; Feldman, D M; Busuttil, R W; Kupiec-Weglinski, J W; Ghobrial, R M

    2005-05-01

    Understanding specific tolerance mechanisms is a primary goal of transplantation science. We have previously shown that hosts treated with MHC class I protein have donor sequences in the alpha1-helix of the alpha1 domain on a background of self-epitopes, resulting in the development of donor-specific tolerance. However, the nature of class I alloantigenic determinants that regulate the alloimmune response remains unclear. The alpha1-helical sequence of RT1.A,1 which shares RT1.A(u) sequences, was substituted in the RT1.A(a) molecule to produce the composite [alpha1h(l/u)]-RT1.A(a) MHC class I allochimeric molecule. Immunodominant epitopes were identified within the hypervariable region of the alpha1 domain of RT1.A(a) (ACI), RT1.Al (Lewis, LEW), and RT1.A(u) (Wistar Furth [WF]). To clarify the mechanisms of tolerance development through presentation of donor-type immunogenic epitopes and cryptic self-epitopes we used synthetic peptides corresponding to donor immunogenic determinants with peptides derived from recipient self-sequences (RT1.A(a)--aa 10 to 49 P1 and 91 to 120 P3; and P2 RT1.A(l/u) 50 to 90). ACI recipients of LEW and WF cardiac allografts were injected through the portal vein (PV) at day 0 with four doses (2, 0.5, 0.25, and 0.125 mg/rat) of three peptide mixtures in conjunction with subtherapeutic CsA (10 mg/kg for 3 days). Allograft survival was strongly dose-dependent. Only low-dose regimens were consistent in tolerance induction, but such therapy did not abrogate development of chronic rejection (CR), unlike allochimeric therapy with soluble MHC class I protein. Different effects of protein or synthetic peptide therapies on development of CR suggest that development of specific tolerance is an active immunologic process and it depends on the form of allogeneic epitopes presented.

  17. Donor-specific differences in long-term outcomes of myeloablative transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia.

    PubMed

    Lee, S; Chung, N-G; Cho, B-S; Eom, K-S; Kim, Y-J; Kim, H-J; Min, C-K; Cho, S-G; Kim, D-W; Lee, J-W; Min, W-S; Park, C-W; Kim, C-C

    2010-12-01

    We analyzed long-term outcomes of myeloablative stem cell transplantation (SCT) in 292 adults with Philadelphia (Ph)-negative acute lymphoblastic leukemia (ALL). Donors were related (RD; n=132), unrelated (URD; n=68; 30 well-matched (WM), 19 partially matched (PM), 19 mismatched (MM)) and autologous (AUTO; n=92). After a median follow-up of 85 months, the risk of relapse was higher for AUTO-SCT than for RD-SCT (P<0.001). MM-URD-SCT yielded higher risk of non-relapse mortality than RD-SCT (P=0.010). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; P=0.010) or MM-URD (26.3%; P=0.036), whereas DFS from other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD and 57.0% for PM-URD). Other factors associated with poorer DFS included SCT beyond first complete remission (CR), older age and adverse cytogenetics. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in first CR, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. SCT using RD, WM-URD or PM-URD may be considered the best donor sources for adult high-risk Ph-negative ALL.

  18. Delayed Donor Bone Marrow Infusion Induces Liver Transplant Tolerance.

    PubMed

    Xie, Yan; Wu, Yang; Xin, Kang; Wang, Jiao-Jing; Xu, Hong; Ildstad, Suzanne T; Leventhal, Joseph; Yang, Guang-Yu; Zhang, Zheng; Levitsky, Josh

    2017-05-01

    Nonmyeloablative conditioning followed by donor bone marrow infusion (BMI) to induce tolerance has not been robustly tested in liver transplantation (LT) and may be unsafe at the time of LT. We hypothesized T cell-depleted BMI is effective in inducing tolerance when delayed after LT, resulting in potentially safer future clinical applications. Nonimmunosuppressed syngeneic (Lewis to Lewis) and allogeneic (ACI to Lewis) rat LT transplants were initially performed as controls. Three experimental allogeneic LT groups were treated with tacrolimus (TAC) for 3 to 4 weeks and then underwent: (1) TAC withdrawal alone; (2) nonmyeloablative conditioning (anti-αβTCR mAb + total body irradiation [300 cGy]) followed by TAC withdrawal; (3) Nonmyeloablative conditioning + donor BMI (100 × 10 T cell-depleted bone marrow cells) followed by TAC withdrawal. All group 1 recipients developed chronic rejection. Group 2 had long-term survival but impaired liver function and high donor-specific antibody (DSA) levels. In contrast, group 3 (conditioning + BMI) had long-term TAC-free survival with preserved liver function and histology, high mixed chimerism and blood/liver/spleen CD4 + CD25 + Foxp3+ regulatory T cells, and low DSA titers, similar to syngeneic grafts. While donor-specific tolerance was observed post-BMI, graft-versus-host disease was not. These results support that donor-specific tolerance can be achieved with BMI even when delayed after LT and this tolerance correlates with increased mixed chimerism, regulatory T cell generation, and diminished DSA.

  19. Impact of donor-specific antibodies on the outcomes of kidney graft: Pathophysiology, clinical, therapy

    PubMed Central

    Salvadori, Maurizio; Bertoni, Elisabetta

    2014-01-01

    Allo-antibodies, particularly when donor specific, are one of the most important factors that cause both early and late graft dysfunction. The authors review the current state of the art concerning this important issue in renal transplantation. Many antibodies have been recognized as mediators of renal injury. In particular donor-specific-Human Leukocyte Antigens antibodies appear to play a major role. New techniques, such as solid phase techniques and Luminex, have revealed these antibodies from patient sera. Other new techniques have uncovered alloantibodies and signs of complement activation in renal biopsy specimens. It has been acknowledged that the old concept of chronic renal injury caused by calcineurine inhibitors toxicity should be replaced in many cases by alloantibodies acting against the graft. In addition, the number of patients on waiting lists with preformed anti-human leukocyte antigens (HLA) antibodies is increasing, primarily from patients with a history of renal transplant failure already been sensitized. We should distinguish early and late acute antibody-mediated rejection from chronic antibody-mediated rejection. The latter often manifets late during the course of the post-transplant period and may be difficult to recognize if specific techniques are not applied. Different therapeutic strategies are used to control antibody-induced damage. These strategies may be applied prior to transplantation or, in the case of acute antibody-mediated rejection, after transplantation. Many new drugs are appearing at the horizon; however, these drugs are far from the clinic because they are in phase I-II of clinical trials. Thus the pipeline for the near future appears almost empty. PMID:24669363

  20. Prolongation of rat heart allografts by donor-specific blood transfusion treated with ultraviolet irradiation

    SciTech Connect

    Oluwole, S.F.; Iga, C.; Lau, H.; Hardy, M.A.

    1985-07-01

    The effect of donor-specific blood transfusion was compared to that of UVB-irradiated donor-specific blood transfusion on heart allograft survival in inbred rats with major histocompatibility differences. In one series ACI rats received heterotopic heart grafts from Lewis rats and 1 mL transfusion of donor-type blood at 1, 2, and 3 weeks prior to the transplantation. Fifty percent of the grafts were permanently accepted (survival greater than 200 days). Following UVB-irradiated donor-specific blood transfusion, 55% of the grafts survived indefinitely. In a mixed lymphocyte reaction ACI lymphocytes are weak responders to Lewis lymphocytes. In another series, Lewis rats received ACI hearts. Donor-specific transfusions at 1, 2, and 3 weeks prior to transplantation did not significantly alter the survival of heart allografts. Lewis lymphocytes react strongly to ACI stimulator cells in a mixed lymphocyte reaction. However, when the donor blood was UVB-irradiated prior to transfusion, the ACI allograft survival was significantly prolonged in this ACI-to-Lewis strain combination. When Lewis rats received W/F hearts following either donor-specific or UVB-irradiated donor-specific transfusions, the hearts' survival was similarly and significantly prolonged, but did not become permanent. Mixed lymphocyte reaction reveals that the stimulation index of Lewis lymphocytes against W/F lymphocytes is greater than that of ACI versus Lewis, but is less than that between Lewis responder cells against ACI stimulators.

  1. Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival

    PubMed Central

    Shen, Xiao-Fei; Jiang, Jin-Peng; Yang, Jian-Jun; Wang, Wei-Zhong; Guan, Wen-Xian; Du, Jun-Feng

    2016-01-01

    The induction of donor-specific transplant tolerance has always been a central problem for small bowel transplantation (SBT), which is thought to be the best therapy for end-stage bowel failure. With the development of new tolerance-inducing strategies, mixed chimerism induced by co-stimulation blockade has become most potent for tolerance of allografts, such as skin, kidney, and heart. However, a lack of clinically available co-stimulation blockers has hindered efficient application in humans. Furthermore, unlike those for other types of solid organ transplantation, strategies to induce robust mixed chimerism for intestinal allografts have not been fully developed. To improve current mixed chimerism induction protocols for future clinical application, we developed a new protocol using donor-specific regulatory T (Treg) cells from mice with heart allograft tolerance, immunosuppressive drugs which could be used clinically and low doses of irradiation. Our results demonstrated that donor-specific Treg cells acquired from tolerant mice after in vitro expansion generate stable chimerism and lead to acceptance of intestinal allograft. Increased intragraft Treg cells and clonal deletion contribute to the development of SBT tolerance. PMID:27909438

  2. Mixed chimerism to induce tolerance for solid organ transplantation

    SciTech Connect

    Wren, S.M.; Nalesnik, M.; Hronakes, M.L.; Oh, E.; Ildstad, S.T. )

    1991-04-01

    Chimerism, or the coexistence of tissue elements from more than one genetically different strain or species in an organism, is the only experimental state that results in the induction of donor-specific transplantation tolerance. Transplantation of a mixture of T-cell-depleted syngeneic (host-type) plus T-cell-depleted allogeneic (donor) bone marrow into a normal adult recipient mouse (A + B----A) results in mixed allogeneic chimerism. Recipient mice exhibit donor-specific transplantation tolerance, yet have full immunocompetence to recognize and respond to third-party transplantation antigens. After complete hematolymphopoietic repopulation at 28 days, animals accept a donor-specific skin graft but reject major histocompatibility complex (MHC) locus-disparate third-party grafts. We now report that permanent graft acceptance can also be achieved when the graft is placed at the time of bone marrow transplantation. Histologically, grafts were viable and had only minimal inflammatory changes. This model may have potential future clinical application for the induction of donor-specific transplantation tolerance.

  3. C1Q Assay Results in Complement-Dependent Cytotoxicity Crossmatch Negative Renal Transplant Candidates with Donor-Specific Antibodies: High Specificity but Low Sensitivity When Predicting Flow Crossmatch

    PubMed Central

    Castelán, Natalia; de Santiago, Adrián; Arvizu, Adriana; Gonzalez-Tableros, Norma; López, Mayra; Salcedo, Isaac; Vilatobá, Mario; Granados, Julio

    2016-01-01

    The aim of the present study was to describe the association of positive flow cross match (FXM) and C1q-SAB. Methods. In this observational, cross-sectional, and comparative study, patients included had negative AHG-CDC-XM and donor specific antibodies (DSA) and were tested with FXM. All pretransplant sera were tested with C1q-SAB assay. Results. A total of 50 donor/recipient evaluations were conducted; half of them had at least one C1q+ Ab (n = 26, 52%). Ten patients (20.0%) had DSA C1q+ Ab. Twenty-five (50%) FXMs were positive. Factors associated with a positive FXM were the presence of C1q+ Ab (DSA C1q+ Ab: OR 27, 2.80–259.56, P = 0.004, and no DSA C1q+ Ab: OR 5, 1.27–19.68, P = 0.021) and the DSA LABScreen-SAB MFI (OR 1.26, 95% CI 1.06–1.49, P = 0.007). The cutoff point of immunodominant LABScreen SAB DSA-MFI with the greatest sensitivity and specificity to predict FXM was 2,300 (sensitivity: 72% and specificity: 75%). For FXM prediction, DSA C1q+ Ab was the most specific (95.8%, 85–100) and the combination of DSA-MFI > 2,300 and C1q+ Ab was the most sensitive (92.0%, 79.3–100). Conclusions. C1q+ Ab and LABScreen SAB DSA-MFI were significantly associated with FXM. DSA C1q+ Ab was highly specific but with low sensitivity. PMID:27688904

  4. Sirolimus and tacrolimus coefficient of variation is associated with rejection, donor-specific antibodies, and nonadherence.

    PubMed

    Pizzo, Helen P; Ettenger, Robert B; Gjertson, David W; Reed, Elaine F; Zhang, Jennifer; Gritsch, H Albin; Tsai, Eileen W

    2016-12-01

    Immunosuppression medication nonadherence has been associated with donor-specific antibodies and treatment-refractory rejection. Drug-level monitoring is a practical direct marker for nonadherence, as variations indicate erratic ingestion of medication. We previously reported that high variability in tacrolimus trough levels determined by the percent coefficient of variation (CV %) and standard deviation (SD) were associated with biopsy-proven rejection. We hypothesized that the CV % and SD in patients on a sirolimus/low-dose tacrolimus regimen may associate with self-reported medication nonadherence, rejection and donor-specific antibodies. In this pilot feasibility study, we studied 37 biopsies in 23 pediatric renal transplant patients on both sirolimus and tacrolimus immunosuppression; CV %, SD, de novo donor-specific antibodies, rejection, and self-reported adherence were examined. A cut-off sirolimus CV % of 25 maximized the percentage of biopsies correctly classified as rejection (32 of 37, or 86 %, p = 0.001). A cut-off tacrolimus CV % of 31 maximized the percentage of correctly classified biopsies (25 of 37, or 68 %, p = 0.09). Among patients with both high sirolimus and tacrolimus CV %, 67 % developed de novo donor-specific antibodies (p = 0.002) with a DQ predominance and 71 % reported nonadherence (p = 0.05). In pediatric renal transplantation, sirolimus and tacrolimus CV % is a potential tool for monitoring patients at risk for allograft rejection and donor-specific antibodies secondary to medication nonadherence.

  5. Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen

    SciTech Connect

    Sharabi, Y.; Sachs, D.H.

    1989-02-01

    The use of allogeneic bone marrow transplantation as a means of inducing donor-specific tolerance across MHC barriers could provide an immunologically specific conditioning regimen for organ transplantation. However, a major limitation to this approach is the toxicity of whole body irradiation as currently used to abrogate host resistance and permit marrow engraftment. The present study describes methodology for abrogating host resistance and permitting marrow engraftment without lethal irradiation. Our preparative protocol involves administration of anti-CD4 and anti-CD8 mAbs in vivo, 300-rad WBI, 700-rad thymic irradiation, and unmanipulated fully MHC-disparate bone marrow. B10 mice prepared by this regimen developed stable mixed lymphohematopoetic chimerism without any clinical evidence of graft-vs.-host disease. Engraftment was accompanied by induction of specific tolerance to donor skin grafts (B10.D2), while third-party skin grafts (B10.BR) were promptly rejected. Mice treated with the complete regimen without bone marrow transplantation appeared healthy and enjoyed long-term survival. This study therefore demonstrates that stable mixed chimerism with donor-specific tolerance can be induced across an MHC barrier after a nonlethal preparative regimen, without clinical GVHD and without the risk of aplasia.

  6. [Renal transplantation without maintenance immunosuppression. Identical twins and kidney transplantation following a successful bone marrow graft].

    PubMed

    Hadi, Riad Abdel; Thomé, Gustavo Gomes; Ribeiro, Adriana Reginato; Manfro, Roberto Ceratti

    2015-01-01

    Renal transplantation without maintenance immunosuppression has been sporadically reported in the literature. The cases include non-adherent patients who discontinued their immunosuppressive medications, transplantation between identical twins, kidney transplantation after a successful bone marrow graft from the same donor and simultaneous bone marrow and kidney transplantation for the treatment of multiple myeloma with associated renal failure. There are also ongoing clinical trials designed to induce donor specific transplant tolerance with infusion of hematopoietic cells from the same kidney donor. Here we describe two cases of renal transplantation without immunosuppression as examples of situations described above.

  7. Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance.

    PubMed

    Leventhal, J; Miller, J; Abecassis, M; Tollerud, D J; Ildstad, S T

    2013-01-01

    The immunoregulatory properties of hematopoietic stem cells (HSCs) have been recognized for more than 60 years, beginning in 1945, when Owen reported that genetically disparate freemartin cattle sharing a common placenta were red blood cell chimeras. In 1953, Billingham, Brent, and Medawar demonstrated that murine neonatal chimeras prepared by infusion of donor-derived hematopoietic cells exhibited donor-specific tolerance to skin allografts. Various approaches using HSCs in organ transplantation have gradually brought closer to reality the dream of inducing donor-specific tolerance in organ transplant recipients. Several hurdles needed to be overcome, especially the risk of graft-versus-host disease (GVHD), the toxicity of ablative conditioning, and the need for close donor-recipient matching. For wide acceptance, HSC therapy must be safe and reproducible in mismatched donor-recipient combinations. Discoveries in other disciplines have often unexpectedly and synergistically contributed to progress in this area. This review presents a historic perspective of the quest for tolerance in organ transplantation, highlighting current clinical approaches.

  8. Association of Kidney Graft Loss With De Novo Produced Donor-Specific and Non-Donor-Specific HLA Antibodies Detected by Single Antigen Testing.

    PubMed

    Süsal, Caner; Wettstein, Daniel; Döhler, Bernd; Morath, Christian; Ruhenstroth, Andrea; Scherer, Sabine; Tran, Thuong H; Gombos, Petra; Schemmer, Peter; Wagner, Eric; Fehr, Thomas; Živčić-Ćosić, Stela; Balen, Sanja; Weimer, Rolf; Slavcev, Antonij; Bösmüller, Claudia; Norman, Douglas J; Zeier, Martin; Opelz, Gerhard

    2015-09-01

    The association of donor-specific HLA antibodies (DSA) with kidney graft failure has been addressed previously; however, the majority of studies were based on small numbers of patients with graft failure. We investigated 83 patients with failed kidney transplants for a possible association of de novo development and persistence or loss of pre-existing DSA with graft failure. Single Antigen Bead assay-detected DSA and non-DSA antibodies were compared between patients with graft loss and matched controls with functioning grafts. The incidence of weak de novo DSA or non-DSA at a mean fluorescence intensity of 500 or higher was higher in the graft loss than in the nonrejector group (76% vs 40%, P < 0.001). Because of the low number of patients developing de novo DSA, the DSA results did not reach statistical significance (only 22% of patients with graft loss developed de novo DSA). However, at all cutoffs, there was a significantly higher rate of graft loss in patients with de novo non-DSA. The incidence of strong pretransplant DSA that persist after transplantation was higher in the graft loss group (10% vs 1%, P = 0.034). When C1q-binding ability in sera of rejectors and nonrejectors with posttransplant de novo or persistent DSA was compared, none of the nonrejectors demonstrated C1q positivity, whereas 43% of patients with graft loss showed C1q-positive antibodies, although not necessarily donor-specific (P < 0.001). Our data show that the posttransplant presence of persisting or de novo HLA antibodies, especially if C1q binding, is associated with graft loss, even if the antibodies are not specific for mismatched donor HLA.

  9. Utility of protocol kidney biopsies for de novo donor-specific antibodies.

    PubMed

    Parajuli, Sandesh; Reville, Patrick K; Ellis, Thomas M; Djamali, Arjang; Mandelbrot, Didier A

    2017-08-14

    There is limited information about the role of protocol kidney biopsies for de novo donor-specific antibodies (dnDSA) in kidney transplant recipients, especially in those with stable graft function. We initiated a routine posttransplant DSA monitoring and surveillance biopsy program for dnDSA since 2014. We identified 45 kidney transplant recipients with dnDSA detected between January 2014 and February 2017 who underwent kidney biopsy within 60 days of detection of dnDSA. Twenty-nine (64%) had stable graft function and 16 (36%) had impaired graft function at the time of dnDSA detection. Even in the group with stable graft function, we found a high rate of rejection (53%) on biopsy. Eighty-eight percent of patients with impaired graft function had rejection. Those patients with impaired graft function had significantly lower estimated glomerular filtration rate at 12 months postbiopsy and at last follow-up. Those with impaired graft function had more graft failures; however, this result was not statistically significant. The high rate of asymptomatic rejection, and the fact that outcomes in asymptomatic patients are poor, is in support of the utility of surveillance biopsies in patients with dnDSA. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  10. Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

    PubMed Central

    Moss, Jill; Moran, Linda; Brookes, Paul; Santos-Nunez, Eva; McLean, Adam G.; Cairns, Thomas; Taube, David; Cook, Terence H.; Roufosse, Candice

    2016-01-01

    The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy–free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor–specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation. PMID:26614383

  11. Desensitization Protocol in Recipients of Deceased Kidney Donor With Donor-Specific Antibody-Low Titers.

    PubMed

    Kanter Berga, J; Sancho Calabuig, A; Gavela Martinez, E; Puig Alcaraz, N; Avila Bernabeu, A; Crespo Albiach, J; Molina Vila, P; Beltrán Catalan, S; Pallardó Mateu, L

    2016-11-01

    Kidney transplantation is the better option for end-stage renal disease (ESRD), but for patients with human leukocyte antigen (HLA) sensitization, the wait times are significantly longer than for patients without antibodies. Many desensitization protocols have been described involving strong immunosuppression, the use of apheresis, and B-cell-modulating therapies. We have designed a desensitization protocol from day 0 for deceased donor kidney transplantation. Our aim was to present our initial experience with five kidney transplant patients. All patients had a negative complement-dependent cytotoxicity cross-match. The desensitization protocol included five to seven doses of thymoglobulin (1.25 mg/kg) and three sessions of plasmapheresis (PP) within the first week after transplantation, with intravenous immunoglobulin (500 mg/kg) after each PP session and one dose of rituximab on day 8. The presence of donor-specific antibodies (DSA) was analyzed by use of Luminex technology; levels between 1000 and 3000 mean fluorescence intensity were considered for desensitization. The median age was 44 years and median renal replacement therapy time was 9 years. All recipients presented 1 to 3 DSA specificities. There were no severe side effects related to PP, infusion of intravenous immunoglobulin, or rituximab. The median follow-up period was 19.3 months. Median serum creatinine level at last follow-up was 1.7 mg/dL. A kidney biopsy was performed in all patients. Graft and patient survival was 100%. Until now, few data are available concerning whether HLA-incompatible kidney transplantation after desensitization would benefit patients with ERSD. The desensitization strategy using the combination of PP, low doses of intravenous immunoglobulin, and rituximab at our center resulted in a satisfactory clinical outcome. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

    PubMed

    Perera, M T; Silva, M A; Murphy, N; Briggs, D; Mirza, D F; Neil, D A H

    2013-12-01

    INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

  13. Many de novo donor-specific antibodies recognize β2 -microglobulin-free, but not intact HLA heterodimers.

    PubMed

    Michel, K; Santella, R; Steers, J; Sahajpal, A; Downey, F X; Thohan, V; Oaks, M

    2016-05-01

    Solid-phase single antigen bead (SAB) assays are standard of care for detection and identification of donor-specific antibody (DSA) in patients who receive solid organ transplantation (SOT). While several studies have documented the reproducibility and sensitivity of SAB testing for DSA, there are little data available concerning its specificity. This study describes the identification of antibodies to β(2) -microglobulin-free human leukocyte antigen (β(2) -m-fHLA) heavy chains on SAB arrays and provides a reassessment of the clinical relevance of DSA testing by this platform. Post-transplant sera from 55 patients who were positive for de novo donor-specific antibodies on a SAB solid-phase immunoassay were tested under denaturing conditions in order to identify antibodies reactive with β(2) -m-fHLA or native HLA (nHLA). Antibodies to β(2) -m-fHLA were present in nearly half of patients being monitored in the post-transplant period. The frequency of antibodies to β(2) -m-fHLA was similar among DSA and HLA antigens that were irrelevant to the transplant (non-DSA). Among the seven patients with clinical or pathologic antibody-mediated rejection (AMR), none had antibodies to β(2) -m-fHLA exclusively; thus, the clinical relevance of β(2) -m-fHLA is unclear. Our data suggests that SAB testing produces false positive reactions due to the presence of β(2) -m-fHLA and these can lead to inappropriate assignment of unacceptable antigens during transplant listing and possibly inaccurate identification of DSA in the post-transplant period.

  14. Racial Differences in Incident De Novo Donor-Specific Anti-HLA Antibody among Primary Renal Allograft Recipients.

    PubMed

    Everly, Matthew J; Briley, Kimberly P; Haisch, Carl E; Dieplinger, Georg; Bolin, Paul; Kendrick, Scott A; Morgan, Claire; Maldonado, Angela Q; Rebellato, Lorita M

    2017-02-17

    Controversy exists as to whether African American (AA) transplant recipients are at risk for developing de novo donor-specific anti-human leukocyte antigen (HLA) antibody (dnDSA). We studied 341 HLA-mismatched, primary renal allograft recipients who were consecutively transplanted between 3/1999 and 12/2010. Sera were collected sequentially pre- and post-transplant and tested for anti-HLA immunoglobulin G (IgG) via single antigen bead assay. Of the 341 transplant patients (225 AA and 116 non-AA), 107 developed dnDSA at a median of 9.2 months post-transplant. AA patients had a 5-year dnDSA incidence of 35%. This was significantly higher than the 5-year dnDSA incidence for non-AA patients (21%). DQ mismatch (risk) and receiving a living-related donor (LRD) transplant (protective) were transplant factors associated with dnDSA. Within the AA patient cohort, HLA-DQ mismatch, not-receiving a LRD transplant, non-adherence, and BK viremia were the most common factors associated with early dnDSA (occurring <24 months post-transplant). Non-adherence and pre-transplant diabetes history were the strong precursors to late dnDSA. Despite the higher rates of dnDSA in the AA cohort, post-dnDSA survival was the same in AA and non-AA patients. This study suggests that DQ matching, increasing LRD transplantation in AA patients, and minimizing under-immunosuppression will be key to preventing dnDSA. This article is protected by copyright. All rights reserved.

  15. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.

    PubMed

    Wekerle, T; Kurtz, J; Ito, H; Ronquillo, J V; Dong, V; Zhao, G; Shaffer, J; Sayegh, M H; Sykes, M

    2000-04-01

    Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.

  16. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients.

    PubMed

    Aubert, Olivier; Loupy, Alexandre; Hidalgo, Luis; Duong van Huyen, Jean-Paul; Higgins, Sarah; Viglietti, Denis; Jouven, Xavier; Glotz, Denis; Legendre, Christophe; Lefaucheur, Carmen; Halloran, Philip F

    2017-03-02

    Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop de novo DSA. However, how these processes compare in terms of allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR (n=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had de novo DSA. Compared with patients with preexisting DSA ABMR, patients with de novo DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition. De novo DSA ABMR was characterized by increased expression of IFNγ-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the de novo DSA ABMR (63% versus 34% at 8 years after rejection, respectively; P<0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified de novo DSA ABMR (hazard ratio [HR], 1.82 compared with preexisting DSA ABMR; 95% confidence interval [95% CI], 1.07 to 3.08; P=0.03); low eGFR (<30 ml/min per 1.73 m(2)) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23; P<0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09; P<0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79; P=0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for de novo DSA.

  17. Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

    PubMed Central

    Picarda, Elodie; Bézie, Séverine; Boucault, Laetitia; Autrusseau, Elodie; Kilens, Stéphanie; Martinet, Bernard; Daguin, Véronique; Donnart, Audrey; Charpentier, Eric; Anegon, Ignacio

    2017-01-01

    Rat and human CD4+ and CD8+ Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are nonredundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4+ and CD8+ Foxp3+ Tregs, while CD45RA/RB/RO are. Transient administration of a monoclonal antibody (mAb) targeting CD45RC in a rat cardiac allotransplantation model induced transplant tolerance associated with inhibition of allogeneic humoral responses but maintained primary and memory responses against cognate antigens. Anti-CD45RC mAb induced rapid death of CD45RChigh T cells through intrinsic cell signaling but preserved and potentiated CD4+ and CD8+ CD45RClow/– Tregs, which are able to adoptively transfer donor-specific tolerance to grafted recipients. Anti-CD45RC treatment results in distinct transcriptional signature of CD4+ and CD8+ CD45RClow/– Tregs. Finally, we demonstrate that anti-human CD45RC treatment inhibited graft-versus-host disease (GVHD) in immune-humanized NSG mice. Thus, short-term anti-CD45RC is a potent therapeutic candidate to induce transplantation tolerance in human. PMID:28194440

  18. Value of Donor-Specific Anti-HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss.

    PubMed

    Viglietti, Denis; Loupy, Alexandre; Vernerey, Dewi; Bentlejewski, Carol; Gosset, Clément; Aubert, Olivier; Duong van Huyen, Jean-Paul; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Zeevi, Adriana; Lefaucheur, Carmen

    2017-02-01

    The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor-specific anti-HLA antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post-transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post-transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post-transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category-free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P<0.001 and 0.93; 95% CI, 0.49 to 1.36; P<0.001, respectively) and post-transplant (category-free net reclassification index, 1.33; 95% CI, 1.03 to 1.62; P<0.001 and 0.95; 95% CI, 0.62 to 1.28; P<0.001, respectively). Thus, pre- and post-transplant DSA monitoring and characterization may improve individual risk stratification for kidney allograft loss. Copyright © 2017 by the American Society of Nephrology.

  19. Detection of donor-specific anti-HLA class I and II antibodies using antibody monitoring system.

    PubMed

    Yang, C W; Oh, E J; Lee, S B; Moon, I S; Kim, D G; Choi, B S; Park, S C; Choi, Y J; Park, Y J; Han, K

    2006-11-01

    The antibody monitoring system (AMS, GTI Inc) is a solid enzyme-linked immunosorbent assay (ELISA) crossmatch test for the detection of immunoglobulin G (IgG) antibody to donor-specific solubilized HLA class I and class II antigens. The objective of this study was to compare the results of the AMS assay with donor-specific anti-HLA IgG antibodies (DS-HLA Abs), as determined by ELISA panel reactive antibody (PRA) and the flow cytometric crossmatch test (FCXM). A total of 107 sera were screened for the presence of HLA Abs by ELISA PRA (LAT-M, One-Lambda Inc), the DS-HLA Abs were determined in 34 serum samples (31.8%) by an ELISA panel (LAT class I and class II, One-Lambda Inc) and FCXM. The FCXM and AMS assays were performed with matched lymphocytes from 56 donors. There was a significant degree of concordance (89.7%) between the two tests (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of AMS assay to detect DS-HLA Abs was 88.2%, 94.5%, 88.2%, and 94.5%, respectively. The AMS is a simple, objective test, which has several advantages over the cell-based crossmatch test, such as elimination of non-HLA antibody reactivity, elimination of non-donor-specific antibody reactivity, no need for viable cells, and preparation of the donor's HLA antigens in advance. In summary, this study suggested that AMS may be useful as a supportive crossmatch test or as a monitoring test after transplantation to detect class I or class II DS-HLA Abs.

  20. Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies

    PubMed Central

    Legris, Tristan; Picard, Christophe; Todorova, Dilyana; Lyonnet, Luc; Laporte, Cathy; Dumoulin, Chloé; Nicolino-Brunet, Corinne; Daniel, Laurent; Loundou, Anderson; Morange, Sophie; Bataille, Stanislas; Vacher-Coponat, Henri; Moal, Valérie; Berland, Yvon; Dignat-George, Francoise; Burtey, Stéphane; Paul, Pascale

    2016-01-01

    Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1+ cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of

  1. Facial tissue allograft transplantation.

    PubMed

    Siemionow, M Z; Demir, Y; Sari, A; Klimczak, A

    2005-01-01

    A hemifacial allograft transplant model was used to investigate the rationale for development of functional tolerance across an MHC barrier. Thirty hemiface transplantations were performed in five groups of six Lewis (RT1(1)) rat recipients each. Isografts were performed in group 1. Transplants were obtained from semiallogenic LBN(RT1(1+n)) in group 2 and from fully allogenic ACI(RT1(a)) in group 3 donors, which served as allograft rejection controls. Group 4 grafts using LBN donors and group 5 using ACI donors in addition received CsA monotherapy (16 mg/kg/d for 1 week) and maintained at 2 mg/kg/d. Signs of graft rejection were sought daily. Isograft controls survived indefinitely. All nontreated allografts were rejected within 5 to 8 days posttransplant. Eighty-three percent of face-transplant recipients from LBN donors and 67% from ACI donors did not show any signs of rejection up to 270 days and 200 days, respectively. Flow cytometry at day 63 in LBN recipients showed the presence of donor-specific chimerism for MHC class I RT1(n) antigens, namely 3.39% CD4/RT1(n); 1.01% CD8/RT1(n) T-lymphocytes; and 3.54% CD45RA/RT1(n) B-lymphocytes. In ACI recipients the chimerism test revealed 10.55% CD4/RT1(a) and 4.59% of CD8/RT1(a) T-lymphocytes. MLR assay at day 160 posttransplant revealed suppressed responses against LBN donor antigens in group 4, but moderate reactivity to ACI donor antigens in group 5. Functional tolerance toward hemifacial allograft transplants induced across MHC barrier using a CsA monotherapy protocol was associated with the presence of donor-specific chimerism in T- and B-cell subpopulations.

  2. Role of de novo donor-specific anti-HLA antibodies in kidney graft failure: A case-control study.

    PubMed

    Castro, A; Malheiro, J; Tafulo, S; Dias, L; Martins, L S; Fonseca, I; Beirão, I; Castro-Henriques, A; Cabrita, A

    2017-11-01

    The role of de novo donor-specific anti-human leukocyte antigen (anti-HLA) antibodies (dnDSA) within the pathways leading to graft failure remains not fully understood. We investigated 56 patients who were transplanted between 2002 and 2014 with kidney graft failure (cases), for a possible association of development of dnDSA with graft failure. The 56 patients with failed transplants were matched with 56 patients with a functioning graft at present for the variables deceased or living donor, transplant number, transplant year, recipient age and gender, donor age and gender, dialysis vintage time, transplant induction therapy. All patients had at least one serum collected 1 year before failure (in cases) or end of follow-up (in controls). Cases and controls were very well-matched in several baseline characteristics. Post-transplant anti-HLA antibodies were found in 84% of cases and only 36% of controls (P < .001), with 54% of cases and 16% of controls (P < .001) having dnDSA at time of detection. Chronic active antibody-mediated rejection was significantly more common (P < .001) in patients with dnDSA (61% vs 12%), in 53 (47%) patients that had at least one graft biopsy performed during follow-up. dnDSA was a significant risk factor (odds ratio [OR] = 6.06; P = .003) for graft failure in a multivariable conditional logistic regression model. dnDSA as a time-dependent variable, was also an independent predictor [hazard ratio (HR) = 2.46; P = .002] of graft failure in a multivariable Cox regression analysis. In both statistical approaches, only dnDSA-II (OR = 11.90; P = .006) (HR = 2.30; P = .014) was significantly associated with graft failure. Post-transplant dnDSA was clearly associated with graft loss, particularly if against HLA class II antigens. dnDSA detection should be a tool for post-transplant monitoring of kidney graft recipients, allowing for the identification of those with a higher risk of graft failure. © 2017 John Wiley & Sons A/S. Published by John

  3. Peritubular Capillary Basement Membrane Multilayering in Renal Allograft Biopsies of Patients With De Novo Donor-Specific Antibodies.

    PubMed

    de Kort, Hanneke; Willicombe, Michelle; Brookes, Paul; Moran, Linda B; Santos-Nunez, Eva; Galliford, Jack W; Taube, David; McLean, Adam G; Moss, Jill; Cook, H Terence; Roufosse, Candice

    2016-04-01

    Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronic antibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basement membrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies (dnDSA) as an early marker to predict long-term antibody-mediated injury. This is a retrospective cohort study with 151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean number of BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development were estimated in survival analyses. We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25 PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, in patients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a mean PTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation. The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score added significantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone. Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronic antibody-mediated injury.

  4. Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter?

    PubMed

    Crespo, Marta; Torio, Alberto; Mas, Virginia; Redondo, Dolores; Pérez-Sáez, Maria J; Mir, Marisa; Faura, Anna; Guerra, Rita; Montes-Ares, Olga; Checa, Maria D; Pascual, Julio

    2013-12-01

    Anti-HLA donor-specific antibodies (DSA) identified by single antigen bead array (SAB) are questioned for their excess in sensitivity and lack of event prediction after transplantation. We retrospectively evaluated specific types of preformed DSA (class I, class II or C1q-fixing) and their impact on graft survival. Kidney transplantations performed across negative CDC-crossmatch were included (n=355). Anti-HLA antibodies were tested using SAB to identify DSA and their capacity to fix C1q. Twenty-eight patients with pretransplant DSA(+) with MFI>2000 were selected to assess C1q fixation. DSA were C1q+ in 15 patients and C1q- in 13, without significant differences in demographics, acute rejection, graft loss or renal function. The maximum MFI of DSA in patients with C1q-fixing DSA was significantly higher (p=0.008). Patients with DSA class-I suffered more antibody-mediated rejection (AMR) and had worse graft survival than class-II. The capacity of DSA I to fix C1q did not correlate with rejection, graft function or graft loss. C1q testing in pretransplant sera with DSA was unable to predict acute antibody-mediated rejection or early graft loss, but the presence of DSA class I compared to DSA only class II did. Despite non-fixing complement in vitro, pretransplant C1q-negative DSA I can mediate rejection and graft loss. © 2013.

  5. A Novel Model on DST-Induced Transplantation Tolerance by the Transfer of Self-Specific Donor tTregs to a Haplotype-Matched Organ Recipient

    PubMed Central

    Mohr Gregoriussen, Angelica Maria; Bohr, Henrik Georg

    2017-01-01

    Donor-specific blood transfusion (DST) can lead to significant prolongation of allograft survival in experimental animal models and sometimes human recipients of solid organs. The mechanisms responsible for the beneficial effect on graft survival have been a topic of research and debate for decades and are not yet fully elucidated. Once we discover how the details of the mechanisms involved are linked, we could be within reach of a procedure making it possible to establish donor-specific tolerance with minimal or no immunosuppressive medication. Today, it is well established that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable for maintaining immunological self-tolerance. A large number of animal studies have also shown that Tregs are essential for establishing and maintaining transplantation tolerance. In this paper, we present a hypothesis of one H2-haplotype-matched DST-induced transplantation tolerance (in mice). The formulated hypothesis is based on a re-interpretation of data from an immunogenetic experiment published by Niimi and colleagues in 2000. It is of importance that the naïve recipient mice in this study were never immunosuppressed and were therefore fully immune competent during the course of tolerance induction. Based on the immunological status of the recipients, we suggest that one H2-haplotype-matched self-specific Tregs derived from the transfusion blood can be activated and multiply in the host by binding to antigen-presenting cells presenting allopeptides in their major histocompatibility complex (MHC) class II (MHC-II). We also suggest that the endothelial and epithelial cells within the solid organ allograft upregulate the expression of MHC-II and attract the expanded Treg population to suppress inflammation within the graft. We further suggest that this biological process, here termed MHC-II recruitment, is a vital survival mechanism for organs (or the organism in general) when attacked by an immune system. PMID:28270810

  6. A Novel Model on DST-Induced Transplantation Tolerance by the Transfer of Self-Specific Donor tTregs to a Haplotype-Matched Organ Recipient.

    PubMed

    Mohr Gregoriussen, Angelica Maria; Bohr, Henrik Georg

    2017-01-01

    Donor-specific blood transfusion (DST) can lead to significant prolongation of allograft survival in experimental animal models and sometimes human recipients of solid organs. The mechanisms responsible for the beneficial effect on graft survival have been a topic of research and debate for decades and are not yet fully elucidated. Once we discover how the details of the mechanisms involved are linked, we could be within reach of a procedure making it possible to establish donor-specific tolerance with minimal or no immunosuppressive medication. Today, it is well established that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable for maintaining immunological self-tolerance. A large number of animal studies have also shown that Tregs are essential for establishing and maintaining transplantation tolerance. In this paper, we present a hypothesis of one H2-haplotype-matched DST-induced transplantation tolerance (in mice). The formulated hypothesis is based on a re-interpretation of data from an immunogenetic experiment published by Niimi and colleagues in 2000. It is of importance that the naïve recipient mice in this study were never immunosuppressed and were therefore fully immune competent during the course of tolerance induction. Based on the immunological status of the recipients, we suggest that one H2-haplotype-matched self-specific Tregs derived from the transfusion blood can be activated and multiply in the host by binding to antigen-presenting cells presenting allopeptides in their major histocompatibility complex (MHC) class II (MHC-II). We also suggest that the endothelial and epithelial cells within the solid organ allograft upregulate the expression of MHC-II and attract the expanded Treg population to suppress inflammation within the graft. We further suggest that this biological process, here termed MHC-II recruitment, is a vital survival mechanism for organs (or the organism in general) when attacked by an immune system.

  7. Local Differentiation of Sugar Donor Specificity of Flavonoid Glycosyltransferase in Lamiales[W

    PubMed Central

    Noguchi, Akio; Horikawa, Manabu; Fukui, Yuko; Fukuchi-Mizutani, Masako; Iuchi-Okada, Asako; Ishiguro, Masaji; Kiso, Yoshinobu; Nakayama, Toru; Ono, Eiichiro

    2009-01-01

    Flavonoids are most commonly conjugated with various sugar moieties by UDP-sugar:glycosyltransferases (UGTs) in a lineage-specific manner. Generally, the phylogenetics and regiospecificity of flavonoid UGTs are correlated, indicating that the regiospecificity of UGT differentiated prior to speciation. By contrast, it is unclear how the sugar donor specificity of UGTs evolved. Here, we report the biochemical, homology-modeled, and phylogenetic characterization of flavonoid 7-O-glucuronosyltransferases (F7GAT), which is responsible for producing specialized metabolites in Lamiales plants. All of the Lamiales F7GATs were found to be members of the UGT88-related cluster and specifically used UDP-glucuronic acid (UDPGA). We identified an Arg residue that is specifically conserved in the PSPG box in the Lamiales F7GATs. Substitution of this Arg with Trp was sufficient to convert the sugar donor specificity of the Lamiales F7GATs from UDPGA to UDP-glucose. Homology modeling of the Lamiales F7GAT suggested that the Arg residue plays a critical role in the specific recognition of anionic carboxylate of the glucuronic acid moiety of UDPGA with its cationic guanidinium moiety. These results support the hypothesis that differentiation of sugar donor specificity of UGTs occurred locally, in specific plant lineages, after establishment of general regiospecificity for the sugar acceptor. Thus, the plasticity of sugar donor specificity explains, in part, the extraordinary structural diversification of phytochemicals. PMID:19454730

  8. Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction

    PubMed Central

    Acharya, Munjal M.; Martirosian, Vahan; Chmielewski, Nicole N.; Hanna, Nevine; Tran, Katherine K.; Liao, Alicia C.; Christie, Lori-Ann; Parihar, Vipan K.; Limoli, Charles L.

    2014-01-01

    The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as “chemobrain”, a condition that can persist long after the cessation of treatment in as many as 75% of survivors. While cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely impacts quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested one month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture. PMID:25687405

  9. Faecal microbiota transplantation protects against radiation-induced toxicity.

    PubMed

    Cui, Ming; Xiao, Huiwen; Li, Yuan; Zhou, Lixin; Zhao, Shuyi; Luo, Dan; Zheng, Qisheng; Dong, Jiali; Zhao, Yu; Zhang, Xin; Zhang, Junling; Lu, Lu; Wang, Haichao; Fan, Saijun

    2017-04-01

    Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation-induced toxicity. High-throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non-coding RNA expression profiles of host small intestines in a sex-specific fashion. Despite promoting angiogenesis, sex-matched FMT did not accelerate the proliferation of cancer cells in vivo FMT might serve as a therapeutic to mitigate radiation-induced toxicity and improve the prognosis of tumour patients after radiotherapy.

  10. Evaluation of C1q Status and Titer of De Novo Donor-Specific Antibodies as Predictors of Allograft Survival.

    PubMed

    Wiebe, C; Gareau, A J; Pochinco, D; Gibson, I W; Ho, J; Birk, P E; Blydt-Hansen, T; Karpinski, M; Goldberg, A; Storsley, L; Rush, D N; Nickerson, P W

    2017-03-01

    De novo donor-specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post-dnDSA graft loss was observed more frequently in recipients with C1q-positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.

  11. Propylthiouracil-induced acute liver failure: role of liver transplantation.

    PubMed

    Carrion, Andres F; Czul, Frank; Arosemena, Leopoldo R; Selvaggi, Gennaro; Garcia, Monica T; Tekin, Akin; Tzakis, Andreas G; Martin, Paul; Ghanta, Ravi K

    2010-01-01

    Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.

  12. Tolerance induction in composite facial allograft transplantation in the rat model.

    PubMed

    Demir, Yavuz; Ozmen, Selahattin; Klimczak, Aleksandra; Mukherjee, Abir Lal; Siemionow, Maria

    2004-12-01

    -positive CD8PE/RT1Ac-Cy7 T-cell population at day 63 after transplantation (1.00 percent). The mixed lymphocyte reaction assay at day 160 after transplantation revealed donor-specific tolerance to donor (Lewis-Brown Norway) antigens and strong reactivity to the third-party (ACI) alloantigens. In this study, donor-specific chimerism and functional tolerance were induced in hemifacial allograft transplants across the major histocompatibility complex barrier under cyclosporine A monotherapy protocol. This model will allow further studies on tolerance induction protocols.

  13. Cellular and Molecular Targeting for Nanotherapeutics in Transplantation Tolerance

    PubMed Central

    Hlavaty, Kelan A.; Luo, Xunrong; Shea, Lonnie D.; Miller, Stephen D.

    2015-01-01

    The induction of donor-specific tolerance to transplanted cells and organs, while preserving immune function as a whole, remains a highly sought after and elusive strategy for overcoming transplant rejection. Tolerance necessitates modulating a diverse array of cell types that recognize and respond to alloantigens, including antigen presenting cells and T lymphocytes. Nanotherapeutic strategies that employ cellular and biomaterial engineering represent an emerging technology geared towards the goal of inducing transplant tolerance. Nanocarriers offer a platform for delivering antigens of interest to specific cell types in order to achieve tolerogenic antigen presentation. Furthermore, the technologies also provide an opportunity for local immunomodulation at the graft site. Nanocarriers delivering a combination of antigens and immunomodulating agents, such as rapamycin, provide a unique technology platform with the potential to enhance outcomes for the induction of transplant tolerance. PMID:25805659

  14. Lansoprazole-induced acute allergic interstitial nephritis in a renal transplant recipient: a case report.

    PubMed

    Yildirim, Tolga; Yilmaz, Rahmi; Baydar, Dilek Ertoy; Kutlugun, Aysun Aybal; Aki, Tuncay; Turgan, Cetin

    2012-12-01

    Drug-induced interstitial nephritis is one of the causes of graft dysfunction in renal transplant recipients. Although commonly implicated as a cause of drug-induced interstitial nephritis in the general population, proton pump inhibitor-induced interstitial nephritis has not yet been reported in renal transplant recipients. Trimethoprim-sulfamethoxazole is responsible for most cases of interstitial nephritis in this population. Here, we describe the first case of proton pump inhibitor-related interstitial nephritis in a renal transplant recipient.

  15. Radiation-induced tumors in transplanted ovaries. [Mice

    SciTech Connect

    Covelli, V.; Di Majo, V.; Bassani, B.; Metalli, P.; Silini, G.

    1982-04-01

    A comparison was made of tumor induction in the ovaries of whole-body-irradiation mice (250-kV X rays, doses of 0.25-4.00 Gy) or in ovaries irradiated in vivo and then transplanted intramuscularly into castrated syngeneic hosts. The form of the dose-induction relationships was similar in the two cases, showing a steeply rising branch at doses up to 0.75 Gy followed by a maximum and an elevated plateau up to 4.00 Gy. A higher incidence of tumors in transplanted organs was apparent for doses up to the maximum, which was attributed to castration-induced hormonal imbalance. Specific death rate analysis of mice dying with ovarian tumors showed that in this system radiation acts essentially by decreasing tumor latency. Ovarian tumors were classified in various histological types and their development in time was followed by serial sacrifice. Separate analysis of death rate of animals carrying different tumor classes allowed further resolution of the various components of the tumor induction phenomenon. It was thus possible to show that the overall death rate analysis masks a true effect of induction of granulosa cell tumors in whole-body-irradiation animals. The transplantation technique offers little advantage for the study of radiation induction of ovarian tumor.

  16. Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor-specific anti-HLA antibodies: a cohort study.

    PubMed

    Béland, Marc-Antoine; Lapointe, Isabelle; Noël, Réal; Côté, Isabelle; Wagner, Eric; Riopel, Julie; Latulippe, Eva; Désy, Olivier; Béland, Stéphanie; Magee, Ciara N; Houde, Isabelle; De Serres, Sacha A

    2017-05-01

    The development of de novo anti-HLA donor-specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. Despite this, antibody screening post-transplant is not widespread, largely because the optimal management of patients with dnDSA remains undetermined. We hypothesized that in this population, calcineurin inhibitor blood levels would be an independent predictor of graft loss. We analyzed a cohort of unsensitized patients for whom anti-HLA antibody screening was performed prospectively post-transplant. During the screening period between January 2005 and April 2016, 42 patients developed dnDSA. There was no difference in the clinical characteristics or the histological scores of patients biopsied for clinical indication versus those biopsied solely due to detection of dnDSA. Cox modeling revealed a strong relationship between mean tacrolimus levels following dnDSA detection and graft loss, with a hazard ratio of 0.49 (95% CI, 0.33-0.75), which persisted following adjustment for established independent predictors (HR, 0.52, 95% CI, 0.30-0.89). Kaplan-Meier analysis by tertiles of tacrolimus levels and receiver operating curve analysis concurred to show that a threshold of 5.3 ng/ml could be predictive of graft loss. These data suggest that anti-HLA antibody monitoring post-transplant could guide maintenance immunosuppression and improve graft outcomes. © 2017 Steunstichting ESOT.

  17. Pyrintegrin Induces Soft Tissue Formation by Transplanted or Endogenous Cells

    PubMed Central

    Shah, Bhranti S.; Chen, Mo; Suzuki, Takahiro; Embree, Mildred; Kong, Kimi; Lee, Chang H.; He, Ling; Xiang, Lusai; Ahn, Jeffrey A.; Ding, Sheng; Mao, Jeremy J.

    2017-01-01

    Focal adipose deficiency, such as lipoatrophy, lumpectomy or facial trauma, is a formidable challenge in reconstructive medicine, and yet scarcely investigated in experimental studies. Here, we report that Pyrintegrin (Ptn), a 2,4-disubstituted pyrimidine known to promote embryonic stem cells survival, is robustly adipogenic and induces postnatal adipose tissue formation in vivo of transplanted adipose stem/progenitor cells (ASCs) and recruited endogenous cells. In vitro, Ptn stimulated human adipose tissue derived ASCs to differentiate into lipid-laden adipocytes by upregulating peroxisome proliferator-activated receptor (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), with differentiated cells increasingly secreting adiponectin, leptin, glycerol and total triglycerides. Ptn-primed human ASCs seeded in 3D-bioprinted biomaterial scaffolds yielded newly formed adipose tissue that expressed human PPARγ, when transplanted into the dorsum of athymic mice. Remarkably, Ptn-adsorbed 3D scaffolds implanted in the inguinal fat pad had enhanced adipose tissue formation, suggesting Ptn’s ability to induce in situ adipogenesis of endogenous cells. Ptn promoted adipogenesis by upregulating PPARγ and C/EBPα not only in adipogenesis induction medium, but also in chemically defined medium specifically for osteogenesis, and concurrently attenuated Runx2 and Osx via BMP-mediated SMAD1/5 phosphorylation. These findings suggest Ptn’s novel role as an adipogenesis inducer with a therapeutic potential in soft tissue reconstruction and augmentation. PMID:28128224

  18. Cyclosporine-A induced neurotoxicity after renal transplantation.

    PubMed

    Derici, U; Arinsoy, T; Sindel, S; Tali, T; Leventoglu, A; Sert, S

    2001-06-01

    Cyclosporine-A is a highly potent immunosuppressive agent for solid organ transplantation, but has many side effects including nephrotoxicity, hypertension, gum hyperplasia, hepatotoxicity, and neurotoxicity. Neurotoxicity is a less known toxic effect. The pathogenesis of this effect is unclear. However, it has been postulated that hypomagnesemia, hypocholesterolemia, corticosteroids, and/or neurotoxic substances can induce this syndrome. Also, it has been suggested that the endothelial damage caused by Cyclosporine-A may contribute to neuropeptide-mediated ischemia in the brain and lead to the development of neurological symptoms. In this report, we present a case with reversible neurologic deficits whose symptoms returned to normal after the cessation of cyclosporine-A.

  19. Promiscuous activity of ER glucosidase II discovered through donor specificity analysis of UGGT

    SciTech Connect

    Miyagawa, Atsushi; Totani, Kiichiro; Matsuo, Ichiro; Ito, Yukishige

    2010-12-17

    Research highlights: {yields} UGGT has a narrow donor specificity. {yields} UGGT gave several non-natural high-mannose-type glycans. {yields} G-II has a promiscuous activity as broad specificity hexosidase. -- Abstract: In glycoprotein quality control system in the endoplasmic reticulum (ER), UGGT (UDP-glucose:glycoprotein glucosyltransferase) and glucosidase II (G-II) play key roles. UGGT serves as a glycoprotein folding sensor by virtue of its unique specificity to glucosylate glycoproteins at incompletely folded stage. By using various UDP-Glc analogues, we first analyzed donor specificity of UGGT, which was proven to be rather narrow. However, marginal activity was observed with UDP-galactose and UDP-glucuronic acid as well as with 3-, 4- and 6-deoxy glucose analogues to give corresponding transfer products. Intriguingly, G-II smoothly converted all of them back to Man{sub 9}GlcNAc{sub 2}, providing an indication that G-II has a promiscuous activity as a broad specificity hexosidase.

  20. Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure.

    PubMed

    Iacob, Speranta; Cicinnati, Vito R; Lindemann, Monika; Heinemann, Falko M; Radtke, Arnold; Kaiser, Gernot M; Kabar, Iyad; Schmidt, Hartmut H J; Baba, Hideo A; Beckebaum, Susanne

    2015-09-01

    The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients. Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin-embedded liver tissue. Mean time period from LT to enrollment was 66.9 ± 51.9 months. Independent predictive factors for graft failure included donor-positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P < 0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P < 0.0001). Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens.

  1. Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival.

    PubMed

    Guidicelli, Gwendaline; Guerville, Florent; Lepreux, Sébastien; Wiebe, Chris; Thaunat, Olivier; Dubois, Valérie; Visentin, Jonathan; Bachelet, Thomas; Morelon, Emmanuel; Nickerson, Peter; Merville, Pierre; Taupin, Jean-Luc; Couzi, Lionel

    2016-02-01

    C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival. Copyright © 2016 by the American Society of Nephrology.

  2. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

    PubMed Central

    Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

    2016-01-01

    Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. PMID:26293822

  3. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury.

    PubMed

    Lefaucheur, Carmen; Viglietti, Denis; Bentlejewski, Carol; Duong van Huyen, Jean-Paul; Vernerey, Dewi; Aubert, Olivier; Verine, Jérôme; Jouven, Xavier; Legendre, Christophe; Glotz, Denis; Loupy, Alexandre; Zeevi, Adriana

    2016-01-01

    Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. Copyright © 2016 by the American Society of Nephrology.

  4. A case of tacrolimus-induced encephalopathy after kidney transplantation

    PubMed Central

    Kim, Myoung Uk; Kim, Sae Yoon; Son, Su Min

    2011-01-01

    We present a case of tacrolimus-induced encephalopathy after successful kidney transplantation. An 11-year-old girl presented with sudden onset of neurologic symptoms, hypertension, and psychiatric symptoms, with normal kidney function, after kidney transplantation. The symptoms improved after cessation of tacrolimus. Magnetic resonance imaging (MRI) showed acute infarction of the middle cerebral artery (MCA) territory in the right frontal lobe. Three days later, she had normal mental function and maintained normal blood pressure with left hemiparesis. Follow-up MRI was performed on D19, showing new infarct lesions at both cerebral hemispheres. Ten days later, MRI showed further improvement, but brain single photon emission computed tomography (SPECT) showed mild reduction of uptake in both the anterior cingulate gyrus and the left thalamus. One month after onset of symptoms, angiography showed complete resolution of stenosis. However, presenting as a mild fine motor disability of both hands and mild dysarthria, what had been atrophy at both centrum semiovale at 4 months now showed progression to encephalomalacia. There are two points of interest in this case. First, encephalopathy occurred after administration of tacrolimus and improved after discontinuation of the drug. Second, the development of right-side hemiplegia could not be explained by conventional MRI; but through diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT) of white matter tract, visualization was possible. PMID:21359060

  5. Bacterial Infections, Alloimmunity, and Transplantation Tolerance

    PubMed Central

    Ahmed, Emily B.; Daniels, Melvin; Alegre, Maria-Luisa; Chong, Anita S.

    2010-01-01

    Transplantation of solid organs across histocompatibility barriers in the absence of immunosuppression is invariably followed by acute allograft rejection. Although several immunosuppressive regimens have been developed to prevent allograft rejection, these global immunosuppressive agents effectively inhibit all T cells leaving the host vulnerable to infections. Thus a major goal in transplantation immunology is to induce donor-specific tolerance that results in the extended suppression of allograft-specific immune responses, while leaving the remainder of the immune system competent to fight infections and malignancies. Initial successes in identifying approaches that successfully induce transplantation tolerance in experimental models have led to a newer research focus of identifying potential barriers to the induction of such tolerance as well as events that may reverse established allograft tolerance. Both clinical and experimental studies have identified bacterial infections as a possible trigger of allograft rejection. Recently, experimental models of transplantation tolerance have identified that bacterial signals can promote acute allograft rejection either by preventing the induction of transplantation tolerance or by reversing tolerance after it has been stably established. This review summarizes experimental and clinical literature supporting the hypothesis that bacterial infections and innate immunity can qualitatively and quantitatively alter adaptive alloreactivity through effects on innate immune responses. PMID:21126661

  6. Alloreactive Regulatory T Cells Allow the Generation of Mixed Chimerism and Transplant Tolerance.

    PubMed

    Ruiz, Paulina; Maldonado, Paula; Hidalgo, Yessia; Sauma, Daniela; Rosemblatt, Mario; Bono, Maria Rosa

    2015-01-01

    The induction of donor-specific transplant tolerance is one of the main goals of modern immunology. Establishment of a mixed chimerism state in the transplant recipient has proven to be a suitable strategy for the induction of long-term allograft tolerance; however, current experimental recipient preconditioning protocols have many side effects, and are not feasible for use in future therapies. In order to improve the current mixed chimerism induction protocols, we developed a non-myeloablative bone-marrow transplant (NM-BMT) protocol using retinoic acid (RA)-induced alloantigen-specific Tregs, clinically available immunosuppressive drugs, and lower doses of irradiation. We demonstrate that RA-induced alloantigen-specific Tregs in addition to a NM-BMT protocol generates stable mixed chimerism and induces tolerance to allogeneic secondary skin allografts in mice. Therefore, the establishment of mixed chimerism through the use of donor-specific Tregs rather than non-specific immunosuppression could have a potential use in organ transplantation.

  7. Alloreactive Regulatory T Cells Allow the Generation of Mixed Chimerism and Transplant Tolerance

    PubMed Central

    Ruiz, Paulina; Maldonado, Paula; Hidalgo, Yessia; Sauma, Daniela; Rosemblatt, Mario; Bono, Maria Rosa

    2015-01-01

    The induction of donor-specific transplant tolerance is one of the main goals of modern immunology. Establishment of a mixed chimerism state in the transplant recipient has proven to be a suitable strategy for the induction of long-term allograft tolerance; however, current experimental recipient preconditioning protocols have many side effects, and are not feasible for use in future therapies. In order to improve the current mixed chimerism induction protocols, we developed a non-myeloablative bone-marrow transplant (NM-BMT) protocol using retinoic acid (RA)-induced alloantigen-specific Tregs, clinically available immunosuppressive drugs, and lower doses of irradiation. We demonstrate that RA-induced alloantigen-specific Tregs in addition to a NM-BMT protocol generates stable mixed chimerism and induces tolerance to allogeneic secondary skin allografts in mice. Therefore, the establishment of mixed chimerism through the use of donor-specific Tregs rather than non-specific immunosuppression could have a potential use in organ transplantation. PMID:26635810

  8. Circulating donor-specific anti-HLA antibodies are a major factor in premature and accelerated allograft fibrosis.

    PubMed

    Gosset, Clément; Viglietti, Denis; Rabant, Marion; Vérine, Jérôme; Aubert, Olivier; Glotz, Denis; Legendre, Christophe; Taupin, Jean-Luc; Duong Van-Huyen, Jean-Paul; Loupy, Alexandre; Lefaucheur, Carmen

    2017-09-01

    Addressing the causes of kidney allograft-accelerated aging is an important challenge for improving long-term transplant outcomes. Here we investigated the role of circulating donor-specific anti-HLA antibodies (HLA-DSAs) in the development and the progression of kidney allograft fibrosis with inclusion of traditional risk factors for allograft fibrosis. We prospectively enrolled 1539 consecutive kidney recipients transplanted in two centers and assessed interstitial fibrosis and tubular atrophy (IF/TA) in biopsies performed at one year post-transplantation. The HLA-DSAs and all traditional determinants of IF/TA were recorded at transplantation and within the first year post-transplantation, including histological diagnoses in 2260 "for cause" biopsies. This identified 498 (32%) patients with severe IF/TA (Banff IF/TA grade 2 or more). HLA-DSAs were significantly associated with severe IF/TA (adjusted odds ratio, 1.53; 95% confidence interval 1.16-2.01) after including 37 determinants. HLA-DSAs remained significantly associated with severe IF/TA in patients without antibody-mediated rejection (adjusted odds ratio 1.54; 1.11-2.14). HLA-DSAs were the primary contributor, being involved in 11% of cases, while T cell-mediated rejection, calcineurin-inhibitor toxicity, acute tubular necrosis, pyelonephritis, and BK virus-associated nephropathy were involved in 9%, 8%, 6%, 5%, and 4% of cases, respectively. One hundred fifty-four patients with HLA-DSA-associated severe IF/TA showed significantly increased microvascular inflammation, transplant glomerulopathy, C4d deposition in capillaries, and decreased allograft survival compared to 344 patients with severe IF/TA without HLA-DSAs. Three hundred seventy-eight patients with post-transplant HLA-DSAs exhibited significantly accelerated progression of IF/TA compared to 1161 patients without HLA-DSAs in the biopsies performed at one year post-transplant and beyond. Thus, circulating HLA-DSAs are major determinants of

  9. Voriconazole-Induced Periostitis & Enthesopathy in Solid Organ Transplant Patients: Case Reports

    PubMed Central

    Sircar, Monica; Kotton, Camille; Wojciechowski, David; Safa, Kassem; Gilligan, Hannah; Heher, Eliot; Williams, Winfred; Thadhani, Ravi; Tolkoff-Rubin, Nina

    2016-01-01

    Background Voriconazole is frequently used to treat fungal infections in solid organ transplant patients. Recently, there have been reports suggesting that prolonged voriconazole therapy may lead to periostitis. Aim Here we present two cases of voriconazole-induced periostitis in solid organ transplant patients. Case Presentation Voriconazole was given to two transplant patients-one with a liver transplant and the second with a heart transplant, to treat their fungal infections. Both developed voriconazole-induced toxicity. While undergoing voriconazole therapy, they had incapacitating bone pain. The liver transplant patient had to be taken off voriconazole, and the heart transplant patient succumbed to non-voriconazole related causes. Conclusions Voriconazole therapy in two solid organ transplant patients resulted in periostitis. We provide potential etiologies underlying voriconazole-induced periostitis, including fluoride toxicity, abnormalities in the pulmonary vascular bed leading to the production of downstream inflammatory mediators, and abnormal pharmacokinetics of hepatic drug metabolism. In addition to monitoring blood voriconazole trough levels, we suggest careful assessment for musculoskeletal pain in patients undergoing voriconazole treatment for two months or more, particularly if their daily dosages of voriconazole exceed 500 mg per day. Appropriate workup should include measurement of alkaline phosphatase, voriconazole trough and fluoride levels as well as a bone scan. Overall, early recognition of voriconazole-induced musculoskeletal toxicity is important for better morbidity outcomes. PMID:27990445

  10. Defining the immunogenicity and antigenicity of HLA epitopes is crucial for optimal epitope matching in clinical renal transplantation.

    PubMed

    Kramer, C S M; Roelen, D L; Heidt, S; Claas, F H J

    2017-07-01

    Transplantation of an human leukocyte antigen (HLA) mismatched graft can lead to the development of donor-specific antibodies (DSA), which can result in antibody mediated rejection and graft loss as well as complicate repeat transplantation. These DSA are induced by foreign epitopes present on the mismatched HLA antigens of the donor. However, not all epitopes appear to be equally effective in their ability to induce DSA. Understanding the characteristics of HLA epitopes is crucial for optimal epitope matching in clinical transplantation. In this review, the latest insights on HLA epitopes are described with a special focus on the definition of immunogenicity and antigenicity of HLA epitopes. Furthermore, the use of this knowledge to prevent HLA antibody formation and to select the optimal donor for sensitised transplant candidates will be discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Molecular diagnosis of antibody-mediated rejection in human kidney transplants.

    PubMed

    Sellarés, J; Reeve, J; Loupy, A; Mengel, M; Sis, B; Skene, A; de Freitas, D G; Kreepala, C; Hidalgo, L G; Famulski, K S; Halloran, P F

    2013-04-01

    Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

  12. [Fetal experimentation, transplantations, cosmetics and their connection with induced abortion].

    PubMed

    Redondo Calderón, José Luis

    2012-01-01

    The increase in induced abortion produces large numbers of cells, tissues and organs, which are used in several fields of Medicine, either in research or in treatment. The main uses are in Cardiology, Hematology, Metabolism, Embryology, Neurology, Immunology, Ophthalmology, Dermatology and Transplantations. Flavor enhancers and cosmetics also benefit. Utilitarianism has led to an increase in abortion-originated cell and tissue banks. Abortion is justified through the manipulation of language. Vested interests give rise to complicity in researchers and society as a whole. Abortion and tissue 'donation' cannot be split; since fresh tissues are involved there is a symbiotic relationship between them. Valid consent is not possible. A contradiction emerges, the nasciturus is not desired or valued but fetal organs are. When someone is deprived of his rights it is because another wants to enslave them. Research must have a moral base. Knowledge should not be increased at any price. Something that is legal and well intentioned is not always morally acceptable. The duty of omission is applicable. Means to achieve a goal must be ethical means. Educational efforts to restore respect for the human embryo and fetus must be promoted. Technical advances are not always in accordance with human nature and dignity. Research and treatment that do not resort to cells, tissues and organs obtained from induced abortions should be promoted.

  13. Composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin allotransplantation model of bone marrow transplantation.

    PubMed

    Bozkurt, Mehmet; Klimczak, Aleksandra; Nasir, Serdar; Zor, Fatih; Krokowicz, Lukasz; Siemionow, Maria

    2013-01-01

    Cellular and vascularized bone marrow cells have been used to induce donor-specific chimerism in various models of composite tissue allotransplantation. Although thymus transplantation has been reported in the literature, the effect of thymus transplantation on chimerism levels in vascularized bone containing composite tissue allotransplantation has not been reported. In this study, a new method for composite vascularized sternal bone marrow transplant model is descried that can be applied to augment chimerism after transplantation. A total of seven composite osseomusculocutaneous sternum, ribs, thymus, pectoralis muscles, and skin transplantations were performed in two groups. The first group (n = 5) was designed as an allotransplantation group and the second group (n = 2) was designed as an isotransplantation group. Composite osseomusculocutaneous sternum, ribs, thymus, and pectoralis muscles allografts were harvested on the common carotid artery and external jugular vein and a heterotopic transplantation was performed to the inguinal region of the recipient rat. Cyclosporine A monotherapy was administered in order to prevent acute and chronic allograft rejection. Animals sacrificed when any sign of rejection occurred. The longest survival was 156 day post-transplant. Assessment of bone marrow cells within sternum bone component and flow cytometry analysis of donor-specific chimerism in the peripheral blood of recipients were evaluated. Our results showed that this composite allograft carried 7.5 × 10(6) of viable hematopoietic cells within the sternum component. At day 7 post-transplant chimerism was developed in T-cell population and mean level was assessed at 2.65% for RT1(n) /CD4 and at 1.0% for RT1(n) /CD8. In this study, a new osseomusculocutaneous sternum, ribs, thymus, pectoralis muscle, and skin allotransplantation model is reported which can be used to augment hematopoietic activity for chimerism induction after transplantation.

  14. Folate antagonist, methotrexate induces neuronal differentiation of human embryonic stem cells transplanted into nude mouse retina.

    PubMed

    Hara, Akira; Taguchi, Ayako; Aoki, Hitomi; Hatano, Yuichiro; Niwa, Masayuki; Yamada, Yasuhiro; Kunisada, Takahiro

    2010-06-25

    Transplanted embryonic stem (ES) cells can be integrated into the retinas of adult mice as well-differentiated neuroretinal cells. However, the transplanted ES cells also have a tumorigenic activity as they have the ability for multipotent differentiation to various types of tissues. In the present study, human ES (hES) cells were transplanted into adult nude mouse retinas by intravitreal injections 20 h after intravitreal N-methyl-D-aspartate (NMDA) administration. After the transplantation of hES cells, the folate antagonist, methotrexate (MTX) was administrated in order to control the differentiation of the transplanted hES cells. Neuronal differentiation and teratogenic potential of hES cells were examined immunohistochemically 5 weeks after transplantation. The proliferative activity of transplanted cells was determined by both the mitotic index and the Ki-67 proliferative index. Disappearance of Oct-4-positive hES cells showing undifferentiated morphology was observed after intraperitoneal MTX treatment daily, for 15 days. Decreased mitotic and Ki-67 proliferative indices, and increased neuronal differentiation were detected in the surviving hES cells after the MTX treatment. These results suggest two important effects of intraperitoneal MTX treatment for hES cells transplanted into nude mouse retina: (1) MTX treatment following transplantation induces neuronal differentiation, and (2) MTX decreases proliferative activity and tumorigenic potential.

  15. Persistence of yellow fever vaccine-induced antibodies after solid organ transplantation.

    PubMed

    Wyplosz, B; Burdet, C; François, H; Durrbach, A; Duclos-Vallée, J C; Mamzer-Bruneel, M-F; Poujol, P; Launay, O; Samuel, D; Vittecoq, D; Consigny, P H

    2013-09-01

    Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Protein F-induced immune tolerance in liver transplantation in rats.

    PubMed

    Zhuang, Jianbin; Wang, Yijun; Du, Zhi; Wang, Sumei

    2014-05-01

    Liver-specific protein F is commonly used in liver transplantation studies for its allograft immunogenicity. The objective of this study was to investigate immune tolerance induced by protein F in liver transplantation in rats. Healthy inbred male Wistar and Sprague-Dawley (SD) rats were used in this study. The transplant recipient rats were randomly divided into three groups. The SD rats transplanted with liver tissues from SD rats or Wistar rats were defined as intragraft control group (Group A) or acute reaction group (Group B), respectively. The SD rats that received thymic administration of 4 mg protein F 1 week prior to transplantation with livers from Wistar rats were defined as protein F interference group (Group C). Kamada's two-cuff technique was utilized in the liver transplantation surgeries. The postoperative general condition, transplantation survival time, pathological examination, and serum IFN-γ level (quantified by ELISA) were recorded and compared to evaluate the immune response and outcomes in the recipient rats after liver transplantation. Group A rats exhibited good postoperative condition and prolonged survival (median survival time was 92 days). In contrast, Group B rats lost body weight rapidly after liver transplantation, and died starting at day 12 (median survival time was 15 days). Compared to Group B, Group C rats showed significantly longer survival (medium survival time was 71 days). Our findings indicate that protein F is an important transplantation antigen with allograft immunogenicity, which could successfully induce immune tolerance in liver transplantation.

  17. Transplanting mouse induced pluripotent stem cells into mouse otocysts in vivo.

    PubMed

    Takeda, Hiroki; Minoda, Ryosei; Miwa, Toru; Yamada, Takao; Ise, Momoko

    2017-03-27

    The otocyst is an attractive target for studying treatment strategies for genetic hearing loss and for understanding inner ear development. We have previously reported that trans-uterine supplemental gene therapy in vivo into the otocysts of mice, which had a loss of function mutation in a causative gene of deafness, was able to prevent putative hearing loss. We herein set out to clarify the feasibility of allogenic cell transplantation into the mouse otocysts in vivo. We transplanted naive mouse-derived induced pluripotent stem cells (miPSCs) into the otocysts of wild type mice or connexin (Cx) 30 deficient mice, at embryonic day 11.5 (E11.5). The transplanted m-iPSCs survived in the lumens of the inner ears at E13.5 and E15.5 in wild type mice. In the Cx30 deficient mouse, the transplanted cells survived similarly, with some of the transplanted cells migrating into the lining cells of the lumens of the inner ears at E13.5 and showing tumorigenic cell proliferation at E15.5. In addition, engrafted cells appear to be able to differentiate after the cell transplantation. Our results suggest that otocyst transplanted cells survived and differentiated. A Cx30 deficiency may facilitate cell migration. These findings may offer some hope for cell transplantation therapy for profound genetic hearing loss caused by a Cxs deficiency.

  18. Bone marrow transplantation in a patient with drug-induced aplastic anemia

    PubMed Central

    Banerjee, T. K.; Band, P. R.; Pabst, H.; Goldsand, G.; Armstrong, W. D.; Brown, J.; Hill, J. R.; Dossetor, J. B.

    1972-01-01

    A 23-year-old woman gravely ill with Pseudomonas septicemia secondary to presumed drug-induced bone marrow aplasia received marrow transplantation from two male HL-A identical sibling donors. She had a successful engraftment with excellent but temporary clinical improvement. Subsequently she succumbed to graft-versus-host disease manifested by Pseudomonas and Candida albicans septicemia, cytomegalovirus pneumonitis, three phases of dermatitis, nausea, vomiting, dysphagia, diarrhea, fever, edema and bone pain, with gradual but complete graft suppression by the 74th day after the transplantation. A second marrow transplant on the 70th day was unsuccessful. PMID:4403793

  19. Influence of donor specific HLA antibodies detected by Luminex in kidney graft survival: a multivariate analysis.

    PubMed

    Caro-Oleas, J L; González-Escribano, M F; Gentil-Govantes, M A; Acevedo, M J; González-Roncero, F M; Bernal-Blanco, G; Núñez-Roldán, A

    2013-05-01

    Some studies have demonstrated the clinical relevance of a positive virtual crossmatch in graft survival; nevertheless, other donor and recipient variables influence the outcome of the transplant. The aim of this study was to investigate the relevance of a positive virtual crossmatch in the graft survival performing a multivariate analysis including other pretransplant variables. A total of 879 deceased kidney transplantations were included. Univariate and multivariate analyses were performed using Cox regression model. After performing the multivariate analysis, a positive virtual crossmatch against class I (adjusted HR 6.613; 95% CI 3.222-13.573), class II (adjusted HR 2.419; 95% CI 1.170-5.002) and class I+II (adjusted HR 5.717; 95% CI 1.925-16.975) detected by single antigen Luminex was the variable conferring the greatest relative risk of graft loss. A positive virtual crossmatch predicts a worse kidney graft survival even after correction by other variables and therefore, transplantation of patients with positive virtual crossmatches should be avoided. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  20. Small bowel transplantation induces adrenergic hypersensitivity in ileal longitudinal smooth muscle in rats.

    PubMed

    Ohtani, N; Balsiger, B M; Anding, W J; Duenes, J A; Sarr, M G

    2000-01-01

    Our aim was to determine the effects of small bowel transplantation on contractility of longitudinal muscle in the rat ileum. Full-thickness longitudinal muscle strips from four groups of rats (naive controls, sham-operated controls, and 1 week and 8 weeks after syngeneic orthotopic small bowel transplantation) were studied in vitro. Neither baseline contractility nor response to neural blockade (tetrodotoxin) or adrenergic/cholinergic blockade differed among the groups. Although the dose response to the cholinergic agonist bethanechol and to nitric oxide did not differ among groups, the ED50 (negative log of concentration giving half-maximal effect) for the adrenergic agonist norepinephrine was increased l week and 8 weeks after transplantation, indicating a hypersensitivity response not blocked by tetrodotoxin. Nonadrenergic, noncholinergic inhibitory responses to electrical field stimulation were of greater amplitude and occurred at lesser frequencies (>/=5 Hz) 1 week after small bowel transplantation, but returned to control values 8 weeks postoperatively. These inhibitory responses were blocked by the nitric oxide synthase inhibitor L-NMMA but not by methylene blue, a nonspecific inhibitor of guanylate cyclase. Small bowel transplantation induces a persistent adrenergic denervation hypersensitivity at the muscle and appears to upregulate, at least transiently, other inhibitory mechanisms mediated by neural release of nitric oxide. Small bowel transplantation does not alter muscle response to cholinergic pathways. These alterations in smooth muscle contractility may affect gut function early after clinical small bowel transplantation.

  1. Basiliximab induced non-cardiogenic pulmonary edema in two pediatric renal transplant recipients.

    PubMed

    Dolan, Niamh; Waldron, Mary; O'Connell, Marie; Eustace, Nick; Carson, Kevin; Awan, Atif

    2009-11-01

    We report two cases of non-cardiogenic pulmonary edema as a complication of basiliximab induction therapy in young pediatric renal transplant patients identified following a retrospective review of all pediatric renal transplant cases performed in the National Paediatric Transplant Centre, Childrens University Hospital, Temple Street, Dublin, Ireland. Twenty-eight renal transplantations, of which five were living-related (LRD) and 23 were from deceased donors (DD), were performed in 28 children between 2003 and 2006. In six cases, transplantations were pre-emptive. Immunosuppression was induced pre-operatively using a combination of basiliximab, tacrolimus and methylprednisolone in all patients. Basiliximab induction was initiated 2 h prior to surgery in all cases and, in 26 patients, basiliximab was re-administered on post-operative day 4. Two patients, one LRD and one DD, aged 6 and 11 years, respectively, developed acute non-cardiogenic pulmonary edema within 36 h of surgery. Renal dysplasia was identified as the primary etiological factor for renal failure in both cases. Both children required assisted ventilation for between 4 and 6 days. While both grafts had primary function, the DD transplant patient subsequently developed acute tubular necrosis and was eventually lost within 3 weeks due to thrombotic microangiopathy and severe acute antibody-mediated rejection despite adequate immunosuppression. Non-cardiogenic pulmonary edema is a potentially devastating post-operative complication of basiliximab induction therapy in young pediatric patients following renal transplantation. Early recognition and appropriate supportive therapy is vital for patient and, where possible, graft survival.

  2. Engineering of bone marrow cells with fas-ligand protein-enhances donor-specific tolerance to solid organs.

    PubMed

    Askenasy, E M; Shushlav, Y; Sun, Z; Shirwan, H; Yolcu, E S; Askenasy, N

    2011-11-01

    Effective immunomodulation to induce tolerance to tissue/organ allografts is attained by infusion of donor lymphocytes endowed with killing capacity through ectopic expression of a short-lived Fas-ligand (FasL) protein. The same approach has proven effective in improving hematopoietic stem and progenitor cell engraftment. This study evaluates the possibility of substitution of immune cells for bone marrow cells (BMC) to induce FasL-mediated tolerance to solid organ grafts. Expression of FasL protein on BMC increased the survival of simultaneously grafted vascularized heterotopic cardiac grafts to 90%, as compared to 30% in recipients of naïve BMC. Similar results were obtained for skin allografts implanted into radiation chimeras at 1 week after bone marrow transplantation. Further reduction of preparative conditioning to busulfan resulted in acceptance of donor skin implanted at 2 weeks after transplantation of naïve and FasL-coated BMC, whereas third-party grafts were acutely rejected. The levels of donor chimerism were in the range of 0.7% to 12% at the time of skin grafting, with higher levels in recipients of FasL-coated BMC. It is concluded that FasL-mediated abrogation of alloimmune responses can be effectively attained with BMC. There is no threshold of donor chimerism, but tolerance to solid organs evolves during the process of donor-host mutual acceptance.

  3. Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient.

    PubMed

    Huh, Kyungmin; Joung, Ji Young; Jeong, Hyemin; Je, Dongmo; Cho, Yoon Young; Jang, Hye Ryoun; Huh, Wooseong

    2013-06-01

    Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients.

  4. Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient

    PubMed Central

    Huh, Kyungmin; Joung, Ji Young; Jeong, Hyemin; Je, Dongmo; Cho, Yoon Young; Jang, Hye Ryoun; Huh, Wooseong

    2013-01-01

    Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients. PMID:26877917

  5. Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant

    PubMed Central

    Kelpke, Stacey S.; Chen, Bo; Bradley, Kelley M.; Teng, Xinjun; Chumley, Phillip; Brandon, Angela; Yancey, Brett; Moore, Brandon; Head, Hughston; Viera, Liliana; Thompson, John A.; Crossman, David K.; Bray, Molly S.; Eckhoff, Devin E.; Agarwal, Anupam; Patel, Rakesh P.

    2012-01-01

    Renal injury induced by brain death is characterized by ischemia and inflammation and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 hours of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 hours of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain dead rats showed significant improvement in function over the first 2 to 4 days post transplantation compared to untreated brain dead animals. Gene microarray analysis after 2 hours of brain death without or with nitrite therapy showed the latter significantly altered the expression of about 400 genes. Ingenuity Pathway analysis indicated multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription and genes related to humoral immune responses. Thus, nitrite-therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function. PMID:22534964

  6. A Case Report of Drug-Induced Thrombocytopenia after Living Donor Liver Transplantation.

    PubMed

    Arai, Keisuke; Kuramitsu, Kaori; Fukumoto, Takumi; Kido, Masahiro; Takebe, Atsushi; Tanaka, Motofumi; Kinoshita, Hisoka; Ajiki, Tetsuo; Toyama, Hirochika; Asari, Sadaki; Goto, Tadahiro; Ku, Yonson

    2016-06-16

    There are few descriptions of severe thrombocytopenia during the early postoperative period after liver transplantation, and these have not been fully documented in the literature. Here, we report a case of drug-induced thrombocytopenia requiring transfusion of blood products after living donor liver transplantation. We determined that this was not caused by the interferon-free anti-viral therapy but by tacrolimus A 61-year-old woman with hepatitis C-related cirrhosis and hepatorenal syndrome underwent living donor liver transplantation using a left lobe graft from her son. After transplantation, immunosuppression consisted of tacrolimus and steroid. Seven weeks after transplantation, interferon-free therapy with daclatasvir and asunaprevir was started. Thirteen days thereafter, hepatitis C virus tested negative. However, the platelet count had begun to gradually decrease just before starting anti-viral therapy. Daclatasvir and asunaprevir were stopped because this was suspected to be a side-effect of these drugs, but the patient nonetheless went on to develop severe thrombocytopenia (platelet count 17,000/μL), which needed transfusions. Now suspecting tacrolimus as the inducer of this side effect, we changed to cyclosporin, after which the platelet count gradually recovered. Viral markers were still not detectable up to 2 months after discontinuation of the antiviral drugs. We conclude that when severe thrombocytopenia occurs, possible drug-induced thrombocytopenia as well as other disorders must be investigated.

  7. Vascular smooth muscle cell apoptosis promotes transplant arteriosclerosis through inducing the production of SDF-1α.

    PubMed

    Li, J; Liu, S; Li, W; Hu, S; Xiong, J; Shu, X; Hu, Q; Zheng, Q; Song, Z

    2012-08-01

    Transplant arteriosclerosis is a leading cause of late allograft loss. Medial smooth muscle cell (SMC) apoptosis is considered to be an important event in transplant arteriosclerosis. However, the precise contribution of medial SMC apoptosis to transplant arteriosclerosis and the underlying mechanisms remain unclear. We transferred wild-type p53 to induce apoptosis of cultured SMCs. We found that apoptosis induces the production of SDF-1α from apoptotic and neighboring viable cells, resulting in increased SDF-1α in the culture media. Conditioned media from Ltv-p53-transferred SMCs activated PI3K/Akt/mTOR and MAPK/Erk signaling in a SDF-1α-dependent manner and thereby promoted mesenchymal stem cell (MSC) migration and proliferation. In a rat aorta transplantation model, lentivirus-mediated BclxL transfer selectively inhibits medial SMC apoptosis in aortic allografts, resulting in a remarkable decrease of SDF-1α both in allograft media and in blood plasma, associated with diminished recruitment of CD90(+)CD105(+) double-positive cells and impaired neointimal formation. Systemic administration of rapamycin or PD98059 also attenuated MSC recruitment and neointimal formation in the aortic allografts. These results suggest that medial SMC apoptosis is critical for the development of transplant arteriosclerosis through inducing SDF-1α production and that MSC recruitment represents a major component of vascular remodeling, constituting a relevant target and mechanism for therapeutic interventions.

  8. Sodium nitrite protects against kidney injury induced by brain death and improves post-transplant function.

    PubMed

    Kelpke, Stacey S; Chen, Bo; Bradley, Kelley M; Teng, Xinjun; Chumley, Phillip; Brandon, Angela; Yancey, Brett; Moore, Brandon; Head, Hughston; Viera, Liliana; Thompson, John A; Crossman, David K; Bray, Molly S; Eckhoff, Devin E; Agarwal, Anupam; Patel, Rakesh P

    2012-08-01

    Renal injury induced by brain death is characterized by ischemia and inflammation, and limiting it is a therapeutic goal that could improve outcomes in kidney transplantation. Brain death resulted in decreased circulating nitrite levels and increased infiltrating inflammatory cell infiltration into the kidney. Since nitrite stimulates nitric oxide signaling in ischemic tissues, we tested whether nitrite therapy was beneficial in a rat model of brain death followed by kidney transplantation. Nitrite, administered over 2 h of brain death, blunted the increased inflammation without affecting brain death-induced alterations in hemodynamics. Kidneys were transplanted after 2 h of brain death and renal function followed over 7 days. Allografts collected from nitrite-treated brain-dead rats showed significant improvement in function over the first 2 to 4 days after transplantation compared with untreated brain-dead animals. Gene microarray analysis after 2 h of brain death without or with nitrite therapy showed that the latter significantly altered the expression of about 400 genes. Ingenuity Pathway Analysis indicated that multiple signaling pathways were affected by nitrite, including those related to hypoxia, transcription, and genes related to humoral immune responses. Thus, nitrite therapy attenuates brain death-induced renal injury by regulating responses to ischemia and inflammation, ultimately leading to better post-transplant kidney function.

  9. Pharmacological modulation of amphetamine-induced dyskinesia in transplanted hemi-parkinsonian rats.

    PubMed

    Smith, Gaynor A; Breger, Ludivine S; Lane, Emma L; Dunnett, Stephen B

    2012-10-01

    Foetal cell transplantation in patients with Parkinson's disease can induce motor complications independent of L-DOPA administration, known as graft-induced dyskinesia. In the 6-OHDA lesioned rat model of Parkinson's disease, post-transplantation abnormal movements can develop in response to an amphetamine challenge, a behaviour which is used to model graft-induced dyskinesia. Although L-DOPA-induced dyskinesia has been well characterised pharmacologically, we lack knowledge on the modulation of post-transplantation amphetamine-induced dyskinesia which may shed light on the mechanisms underlying graft-induced dyskinesia. We assessed a series of drugs effective at reducing L-DOPA-induced dyskinesia against post-transplantation amphetamine-induced dyskinesia. Agents include: dopaminergic antagonists (D₁: CP94253; D₂: SCH-22390; D₃: nafadotride), serotonergic agonists (5-HT(1A): 8-OH-DPAT; 5-HT(1B): CP94253), opioid antagonist (μ: naloxone), cannabinoid agonist (CB₁: WIN55, 212-2), adrenergic antagonist (α₁ and α₂: yohimbine) and glutamatergic antagonists (NMDA: amantadine and MK-801; mGluR5: MTEP; AMPA: IEM1460). Abnormal involuntary movements in response to amphetamine were decreased by SCH-22390, raclopride, CP94253 and 8-OH-DPAT, yet were unaltered by naloxone, WIN55, 212-2, yohimbine, amantadine, MTEP and IEM1460. Unusually, MK-801 increased the appearance of amphetamine-induced dyskinesia. The results suggest that dopaminergic, serotoninergic and glutamatergic systems are likely to have a fundamental role in the development of graft-induced dyskinesias, which are mechanistically distinct from L-DOPA-induced behvaviours. Importantly, the expression of D₁ and D₂ receptors was unrelated to the severity of AIMs.

  10. Waning of vaccine-induced immunity to measles in kidney transplanted children.

    PubMed

    Rocca, Salvatore; Santilli, Veronica; Cotugno, Nicola; Concato, Carlo; Manno, Emma Concetta; Nocentini, Giulia; Macchiarulo, Giulia; Cancrini, Caterina; Finocchi, Andrea; Guzzo, Isabella; Dello Strologo, Luca; Palma, Paolo

    2016-09-01

    Vaccine-preventable diseases are a significant cause of morbidity and mortality in solid organ transplant recipients who undergo immunosuppression after transplantation. Data on immune responses and long-term maintenance after vaccinations in such population are still limited.We cross-sectionally evaluated the maintenance of immune response to measles vaccine in kidney transplanted children on immunosuppressive therapy. Measles-specific enzyme-linked immunosorbent assay and B-cell enzyme-linked immunosorbent spot were performed in 74 kidney transplant patients (Tps) and in 23 healthy controls (HCs) previously vaccinated and tested for humoral protection against measles. The quality of measles antibody response was measured by avidity test. B-cell phenotype, investigated via flow cytometry, was further correlated to the ability of Tps to maintain protective humoral responses to measles over time.We observed the loss of vaccine-induced immunity against measles in 19% of Tps. Nonseroprotected children showed signs of impaired B-cell distribution as well as immune senescence and lower antibody avidity. We further reported as time elapsed between vaccination and transplantation, as well as the vaccine administration during dialysis are clinical factors affecting the maintenance of the immune memory response against measles.Tps present both quantitative and qualitative alterations in the maintenance of protective immunity to measles vaccine. Prospective studies are needed to optimize the vaccination schedules in kidney transplant recipients in order to increase the immunization coverage over time in this population.

  11. Pretransplant angiotensin II type 1-receptor antibodies are a risk factor for earlier detection of de novo HLA donor-specific antibodies.

    PubMed

    Cuevas, Eric; Arreola-Guerra, José M; Hernández-Méndez, Erick A; Salcedo, Isaac; Castelán, Natalia; Uribe-Uribe, Norma O; Vilatobá, Mario; Contreras-Saldívar, Alan G; Sánchez-Cedillo, Aczel I; Ramírez, Julia B; de Rungs, David; Granados, Julio; Morales-Buenrostro, Luis E; Alberú, Josefina

    2016-10-01

    Angiotensin II type 1 receptor antibodies (AT1Rabs) have been associated with significantly reduced graft survival. Earlier graft loss has been observed in patients who had pretransplant AT1Rabs and posttransplant donor-specific antibodies (DSA). The main goal of this retrospective cohort study was to examine the association between AT1Rabs and the time period to detection of de novo human leukocyte antigen (HLA-DSA) posttransplantation in living donor kidney transplant recipients (KTR). The analysis included 141 KTRs. Pretransplant frozen serum samples were tested for AT1Rabs by ELISA and HLA-DSA by SAB (Luminex) at both the pre- and post-KT time points. The median AT1Rab level was 9.13 U (interquartile range 5.22-14.33). After a mean follow-up period of 3.55 years, 48 patients were found to harbour de novo HLA-DSAs. The presence of AT1Rabs [hazard ratio (HR) 1.009, 95% confidence interval (CI) 1.002-1.01, P = 0.010], male-to-male transplantation (HR 2.57, 95% CI 1.42-4.67, P = 0.002) and antecedent borderline changes or acute cellular rejection (ACR) (HR 2.47, 95% CI 1.29-4.75, P = 0.006) were significantly associated with de novo DSA detection. A dose-dependent association between AT1Rab levels (<10 U, 10.1-16.9 U, 17-29.9 U and >30 U) and de novo DSA detection was observed (log-rank P = 0.0031). After multivariate analysis of AT1Rab levels (continuous variable), AT1Rabs >30 U, male-to-male transplantation, donor age, higher class I percentage of Panel Reactive Antibody and antecedent borderline changes or ACR remained as independent significant risk factors for the detection of de novo DSAs. The findings suggest that higher levels of pretransplant circulating antibodies against AT1R (>30 U) in kidney graft recipients constitute an independent risk factor for earlier de novo HLA-DSA detection during the posttransplant period. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  12. Bone and cartilage repair by transplantation of induced pluripotent stem cells in murine joint defect model.

    PubMed

    Uto, Sakura; Nishizawa, Satoru; Takasawa, Yutaka; Asawa, Yukiyo; Fujihara, Yuko; Takato, Tsuyoshi; Hoshi, Kazuto

    2013-01-01

    The establishment of cartilage regenerative medicine has been an important issue in the clinical field, because cartilage has the poor ability of self-repair. Currently, tissue engineering using autologous chondrocytes has risen, but we should investigate more appropriate cell sources that can be obtained without any quantitative limitation. In this study, we focused on induced pluripotent stem (iPS) cells, in which the ethical hurdle does not seem higher than that of embryonic stem cells. Mouse iPS cells were transplanted into the mouse joint defect model of the knee. Strains of the transplants and hosts were arranged to be either closest (homology 75% in genetic background) or identical (100%). For transplantation, we embedded the iPS cells within the collagen hydrogel in order to obtain the effective administration of the cells into defects, which induced the differentiation of the iPS cells. At 8 weeks of transplantation, although the iPS cells with a 75% homology to the host in the genetic background tended to form teratoma, those of 100% showed a joint regeneration. GFP immunohistochemistry proved that the transplanted iPS cells were responsible for the bone and cartilage repair. Taking these results together, the iPS cells are regarded as a promising cell source for the cartilage tissue engineering.

  13. Follicular T helper cells and humoral reactivity in kidney transplant patients

    PubMed Central

    de Graav, G N; Dieterich, M; Hesselink, D A; Boer, K; Clahsen-van Groningen, M C; Kraaijeveld, R; Litjens, N H R; Bouamar, R; Vanderlocht, J; Tilanus, M; Houba, I; Boonstra, A; Roelen, D L; Claas, F H J; Betjes, M G H; Weimar, W; Baan, C C

    2015-01-01

    Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4POSCXCR5POS T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu. PMID:25557528

  14. Detection of anti-HLA antibodies by solid-phase assay in kidney transplantation: friend or foe?

    PubMed

    Ferrari-Lacraz, S; Tiercy, J-M; Villard, J

    2012-05-01

    Pre-formed and de novo anti-human leukocyte antigen (HLA) antibodies induce antibody-mediated rejection and are also involved in mechanisms leading to chronic graft nephropathy. The detection of anti-HLA antibodies by solid-phase assay (SPA) has revolutionized the management of immunized patients before and after kidney transplantation. Characterized by high sensitivity and specificity, the clinical relevance of anti-HLA antibodies by SPA has to be clarified. The presence of donor-specific antibody at the epitope level, their titer, and the use of different crossmatch technologies could help to determine which of the anti-HLA antibodies are friends and which are foes in kidney transplantation. In this review, we summarize the current state of the art on this debated topic, and give clinical guidelines for the management of antibody detection pre- and post-transplantation, based on these evidences and our own clinical expertise. © 2012 John Wiley & Sons A/S.

  15. Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells.

    PubMed

    Tian, C; Bagley, J; Iacomini, J

    2006-09-01

    Genetic modification of hematopoietic stem cells (HSCs) resulting in a state of molecular chimerism can be used to induce donor-specific tolerance to allografts. However, the requirements for maintaining tolerance in molecular chimeras remain unknown. Here, we examined whether long-term expression of a retrovirally encoded alloantigen in hematopoietic cells is required to maintain donor-specific tolerance in molecular chimeras. To this end, mice were reconstituted with syngeneic bone marrow transduced with retroviruses carrying the gene encoding the allogeneic MHC class I molecule Kb. Following induction of molecular chimerism, mice were depleted of cells expressing Kb by administration of the anti-Kb monoclonal antibody Y-3. Mice that were effectively depleted of cells expressing the retrovirally encoded MHC class I antigen rejected Kb disparate skin allografts. In contrast, control molecular chimeras accepted Kb disparate skin allografts indefinitely. These data suggest maintenance of tolerance in molecular chimeras requires long-term expression of retrovirally transduced alloantigen on the progeny of retrovirally transduced HSCs.

  16. TLR agonists abrogate costimulation blockade-induced mixed chimerism and transplantation tolerance

    PubMed Central

    Miller, David M.; Thornley, Thomas; Pearson, Todd; Yamazaki, Masahiro; Brehm, Michael A.; Rossini, Aldo A.; Greiner, Dale L.

    2008-01-01

    We investigated the mechanisms by which toll-like receptor (TLR) agonists affect the induction of mixed chimerism and skin allograft survival in mice treated with costimulation blockade (CB). We report that TLR agonists prevent the generation of mixed chimerism by breaking tolerance in the alloreactive CD4+ and CD8+ T cell compartments, and that type I interferon (IFN) is important in this process. Understanding how environmental perturbations affect CB-induced transplantation tolerance may lead to more effective regimens that can be used as an approach for the treatment of type 1 diabetes, for which the transplantation of pancreatic islets is a promising therapy. PMID:19120285

  17. Detection of C3d-Binding Donor-Specific Anti-HLA Antibodies at Diagnosis of Humoral Rejection Predicts Renal Graft Loss

    PubMed Central

    Sicard, Antoine; Ducreux, Stéphanie; Rabeyrin, Maud; Couzi, Lionel; McGregor, Brigitte; Badet, Lionel; Scoazec, Jean Yves; Bachelet, Thomas; Lepreux, Sébastien; Visentin, Jonathan; Merville, Pierre; Fremeaux-Bacchi, Véronique; Morelon, Emmanuel; Taupin, Jean-Luc; Dubois, Valérie

    2015-01-01

    Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR<30 ml/min per 1.73 m2 (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss. PMID:25125383

  18. Successful transplant of mesenchymal stem cells in induced osteonecrosis of the ovine femoral head: preliminary results.

    PubMed

    Feitosa, Matheus Levi Tajra; Fadel, Leandro; Beltrão-Braga, Patrícia Cristina Baleeiro; Wenceslau, Cristiane Valverde; Kerkis, Irina; Kerkis, Alexandre; Birgel Júnior, Eduardo Harry; Martins, João Flávio Panattoni; Martins, Daniele dos Santos; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

    2010-10-01

    Evaluate the bone tissue recovery following transplantation of ovine mesenchymal stem cells (MSC) from bone marrow and human immature dental-pulp stem cells (hIDPSC) in ovine model of induced osteonecrosis of femoral head (ONFH). Eight sheep were divided in three experimental groups. First group was composed by four animals with ONFH induced by ethanol through central decompression (CD), for control group without any treatment. The second and third group were compose by two animals, six weeks after ONFH induction received transplantation of heterologous ovine MSC (CD + oMSC), and hIDPSC (CD + hIDPSC), respectively. In both experiments the cells were transplanted without application of any type of immunosupression protocol. Our data indicate that both cell types used in experiments were able to proliferate within injured site providing bone tissue recovery. The histological results obtained from CD+hIDPSC suggested that the bone regeneration in such animals was better than that observed in CD animals. Mesenchymal stem cell transplant in induced ovine osteonecrosis of femoral head by central decompression technique is safe, and apparently favors bone regeneration of damaged tissues.

  19. Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons.

    PubMed

    Tang, Yunshuo; Stryker, Michael P; Alvarez-Buylla, Arturo; Espinosa, Juan Sebastian

    2014-12-23

    GABAergic inhibition has been shown to play an important role in the opening of critical periods of brain plasticity. We recently have shown that transplantation of GABAergic precursors from the embryonic medial ganglionic eminence (MGE), the source of neocortical parvalbumin- (PV(+)) and somatostatin-expressing (SST(+)) interneurons, can induce a new period of ocular dominance plasticity (ODP) after the endogenous period has closed. Among the diverse subtypes of GABAergic interneurons PV(+) cells have been thought to play the crucial role in ODP. Here we have used MGE transplantation carrying a conditional allele of diphtheria toxin alpha subunit and cell-specific expression of Cre recombinase to deplete PV(+) or SST(+) interneurons selectively and to investigate the contributions of each of these types of interneurons to ODP. As expected, robust plasticity was observed in transplants containing PV(+) cells but in which the majority of SST(+) interneurons were depleted. Surprisingly, transplants in which the majority of PV(+) cells were depleted induced plasticity as effectively as those containing PV(+) cells. In contrast, depleting both cell types blocked induction of plasticity. These findings reveal that PV(+) cells do not play an exclusive role in ODP; SST(+) interneurons also can drive cortical plasticity and contribute to the reshaping of neural networks. The ability of both PV(+) and SST(+) interneurons to induce de novo cortical plasticity could help develop new therapeutic approaches for brain repair.

  20. Impact on mid-term kidney graft outcomes of pretransplant anti-HLA antibodies detected by solid-phase assays: Do donor-specific antibodies tell the whole story?

    PubMed

    Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2017-09-01

    The detrimental impact of preformed anti-HLA donor-specific antibodies (DSA) is well defined, contrarily to non-donor-specific antibodies (NDSA). We sought to evaluate their clinical impact in a cohort of 724 kidney graft recipients in whom anti-HLA antibodies were thoroughly screened and identified in pre-transplant sera by solid-phase assays. NDSA or DSA were detected in 100 (13.8%) and 47 (6.5%) recipients respectively, while 577 (79.7%) were non-allosensitized (NaS). Incidence of antibody-mediated rejection at 1-year was 0.7%, 4.0% and 25.5% in NaS, NDSA and DSA patients, respectively (NaS vs. NDSA P=0.004; NaS vs. DSA P<0.001; NDSA vs. DSA P<0.001). Graft survival was lowest in DSA (78.7%), followed by NDSA (88.0%) and NaS (93.8%) recipients (NaS vs. NDSA P=0.015; NaS vs. DSA P<0.001; NDSA vs. DSA P=0.378). Multivariable competing risk analysis confirmed both NDSA (sHR=2.19; P=0.025) and DSA (sHR=2.87; P=0.012) as significant predictors of graft failure. The negative effect of NDSA and DSA on graft survival was significant in patients receiving no induction (P=0.019) or an anti-IL-2 receptor antibody (P<0.001), but not in those receiving anti-thymocyte globulin (P=0.852). The recognition of the immunological risk associated with preformed DSA but also NDSA have important implications in patients' risk stratification, and may impact clinical decisions at transplant. Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  1. Pregnancy-Induced Sensitization Promotes Sex Disparity in Living Donor Kidney Transplantation.

    PubMed

    Bromberger, Bianca; Spragan, Danielle; Hashmi, Sohaib; Morrison, Alexander; Thomasson, Arwin; Nazarian, Susanna; Sawinski, Deirdre; Porrett, Paige

    2017-10-01

    The presence of sex disparity in living donor kidney transplantation (LDKT) remains controversial. To determine if women fall behind men in LDKT evaluation, we performed an intention to treat study of 2587 candidates listed for kidney transplant at a single transplant center over 7 years. We found that women and men kidney transplant candidates engaged an equivalent type and number of prospective living donors. However, sex-specific differences in sensitization history and histocompatibility reduced the rate of LDKT for women by 30%. Pregnancy-induced incompatibility with spouse donors was limiting given that spouses were among the individuals most likely to complete donation. Notably, participation in a kidney paired exchange program eliminated sex-based differences in LDKT. Collectively, these data suggest that pregnancy is a formidable biologic barrier for women and contributes uniquely to sex disparity in LDKT. Targeted efforts to improve transplant center participation in paired kidney exchanges may increase sex equity in LDKT. Copyright © 2017 by the American Society of Nephrology.

  2. Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain.

    PubMed

    Kawai, Hiromi; Yamashita, Toru; Ohta, Yasuyuki; Deguchi, Kentaro; Nagotani, Shoko; Zhang, Xuemei; Ikeda, Yoshio; Matsuura, Tohru; Abe, Koji

    2010-08-01

    Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5 x 10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

  3. The Spleen Is an Ideal Site for Inducing Transplanted Islet Graft Expansion in Mice

    PubMed Central

    Takahashi, Hiroyuki; Kodama, Shohta

    2017-01-01

    Alternative islet transplantation sites have the potential to reduce the marginal number of islets required to ameliorate hyperglycemia in recipients with diabetes. Previously, we reported that T cell leukemia homeobox 1 (Tlx1)+ stem cells in the spleen effectively regenerated into insulin-producing cells in the pancreas of non-obese diabetic mice with end-stage disease. Thus, we investigated the spleen as a potential alternative islet transplantation site. Streptozotocin-induced diabetic C57BL/6 mice received syngeneic islets into the portal vein (PV), beneath the kidney capsule (KC), or into the spleen (SP). The marginal number of islets by PV, KC, or SP was 200, 100, and 50, respectively. Some plasma inflammatory cytokine levels in the SP group were significantly lower than those of the PV group after receiving a marginal number of islets, indicating reduced inflammation in the SP group. Insulin contents were increased 280 days after islet transplantation compared with those immediately following transplantation (p<0.05). Additionally, Tlx1-related genes, including Rrm2b and Pla2g2d, were up-regulated, which indicates that islet grafts expanded in the spleen. The spleen is an ideal candidate for an alternative islet transplantation site because of the resulting reduced inflammation and expansion of the islet graft. PMID:28135283

  4. Does Renal Tubular Injury-Induced Local Tissue Hypoxia Involve Post-Transplantation Erythrocytosis?

    PubMed

    Unal, A; Ata, S; Karakurkcu, C; Ciraci, M Z; Kocyigit, I; Sipahioglu, M H; B Tokgoz; Oymak, O

    2017-10-01

    The pathogenesis of post-transplantation erythrocytosis (PTE) is not well understood and appears to be multifactorial. Our hypothesis in this study was that several factors, including toxicity of calcineurin inhibitor, immunologic factors, and chronic allograft nephropathy, can trigger local tissue hypoxia in peritubular interstitium, which is where production of erythropoietin (EPO) takes place. This local interstitial tissue hypoxia can cause an increase in renal EPO production, which induces the development of PTE. This cross-sectional study included 15 renal transplant recipients, in whom polycythemia developed after kidney transplantation, with elevated hematocrit level to >51%. Forty-eight age- and gender-matched renal transplant recipients with normal hematocrit level were included as the renal transplant control group. In addition, 13 age- and gender-matched healthy subjects were also included as the healthy control group. We used urine hypoxia-inducible factor-2 alpha (HIF-2α) levels to evaluate whether there is local tissue hypoxia in renal allograft. HIF-2α levels were measured by double antibody sandwich enzyme-linked immunosorbent assay (ELISA). Serum EPO and insulin-like growth factor-1 (IGF-1) levels were also measured. HIF-2α levels were significantly lower in the polycythemia group than the other two groups, but there was no significant difference between the healthy control group and the renal transplant control group with regard to HIF-2α levels. There was no significant difference among the 3 study groups in terms of levels of serum EPO and IGF-1. Local tissue hypoxia in renal allograft does not seem to play an important role in the development of PTE. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure.

    PubMed

    Cooper, Sheldon C; Aldridge, Roland C; Shah, Tahir; Webb, Kerry; Nightingale, Peter; Paris, Sue; Gunson, Bridget K; Mutimer, David J; Neuberger, James M

    2009-10-01

    Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated. Copyright 2009 AASLD

  6. Impact of preformed donor-specific antibodies against HLA class I on kidney graft outcomes: Comparative analysis of exclusively anti-Cw vs anti-A and/or -B antibodies

    PubMed Central

    Santos, Sofia; Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Carmo, Rute; Sampaio, Susana; Costa, Marta; Campos, Andreia; Pedroso, Sofia; Almeida, Manuela; Martins, La Salete; Henriques, Castro; Cabrita, António

    2016-01-01

    AIM To analyze the clinical impact of preformed antiHLA-Cw vs antiHLA-A and/or -B donor-specific antibodies (DSA) in kidney transplantation. METHODS Retrospective study, comparing 12 patients transplanted with DSA exclusively antiHLA-Cw with 23 patients with preformed DSA antiHLA-A and/or B. RESULTS One year after transplantation there were no differences in terms of acute rejection between the two groups (3 and 6 cases, respectively in the DSA-Cw and the DSA-A-B groups; P = 1). At one year, eGFR was not significantly different between groups (median 59 mL/min in DSA-Cw group, compared to median 51 mL/min in DSA-A-B group, P = 0.192). Moreover, kidney graft survival was similar between groups at 5-years (100% in DSA-Cw group vs 91% in DSA-A-B group, P = 0.528). The sole independent predictor of antibody mediated rejection (AMR) incidence was DSA strength (HR = 1.07 per 1000 increase in MFI, P = 0.034). AMR was associated with shortened graft survival at 5-years, with 75% and 100% grafts surviving in patients with or without AMR, respectively (Log-rank P = 0.005). CONCLUSION Our data indicate that DSA-Cw are associated with an identical risk of AMR and impact on graft function in comparison with “classical” class I DSA. PMID:28058219

  7. Carbon Monoxide Induces Cytoprotection in Rat Orthotopic Lung Transplantation via Anti-Inflammatory and Anti-Apoptotic Effects

    PubMed Central

    Song, Ruiping; Kubo, Masatoshi; Morse, Danielle; Zhou, Zhihong; Zhang, Xuchen; Dauber, James H.; Fabisiak, James; Alber, Sean M.; Watkins, Simon C.; Zuckerbraun, Brian S.; Otterbein, Leo E.; Ning, Wen; Oury, Tim D.; Lee, Patty J.; McCurry, Kenneth R.; Choi, Augustine M.K.

    2003-01-01

    Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and antiapoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1α and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation. PMID:12819027

  8. Tempering Allorecognition to Induce Transplant Tolerance With Chemically Modified Apoptotic Donor Cells

    PubMed Central

    McCarthy, D. P.; Bryant, J.; Galvin, J. P.; Miller, S. D.; Luo, X.

    2015-01-01

    The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI-SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice. PMID:25807873

  9. Tempering allorecognition to induce transplant tolerance with chemically modified apoptotic donor cells.

    PubMed

    McCarthy, D P; Bryant, J; Galvin, J P; Miller, S D; Luo, X

    2015-06-01

    The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI-SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice.

  10. Rapid dendritic cell activation and resistance to allotolerance induction in anti-CD154-treated mice receiving CD47-deficient donor-specific transfusion.

    PubMed

    Wang, Yuantao; Wang, Hui; Bronson, Roderick; Fu, Yaowen; Yang, Yong-Guang

    2014-03-01

    CD47-SIRPα signaling plays an important role in regulating macrophage and dendritic cell (DC) activation. Here we investigated the role of CD47 expression on donor cells in tolerance induction by combined treatment with donor-specific transfusion (DST) plus anti-CD154 mAb in a mouse model of fully MHC-mismatched heart allotransplantation. The majority of BALB/c recipient mice that received anti-CD154 and CD47(+/+) B6 splenocytes (DST) showed indefinite donor heart survival (median survival time, MST > 150 days). Donor heart survival was improved in anti-CD154-treated BALB/c mice that received CD47(+/-) (MST = 90 days) or CD47(-/-) B6 DST (MST = 42 days) when compared to the nontreated (MST = 7 days) and anti-CD154 alone-treated (MST = 15 days) controls, but significantly reduced when compared to mice receiving anti-CD154 plus CD47(+/+) B6 DST. Recipient mice treated with anti-CD154 plus CD47(-/-) or CD47(+/-) DST also showed significantly increased antidonor, but not anti-third-party, MLR responses compared to those receiving anti-CD154 and CD47(+/+) DST. Furthermore, CD47(-/-) DST induced rapid activation of CD11c(hi)SIRPα(hi)CD8α(-) DCs via a mechanism independent of donor alloantigens. These results demonstrated that CD47 expression on donor cells is essential to the success of tolerance induction by combined therapy with DST and CD40/CD154 blockade.

  11. Antagonistic effect of toll-like receptor signaling and bacterial infections on transplantation tolerance*

    PubMed Central

    Alegre, Maria-Luisa; Chen, Luqiu; Wang, Tongmin; Ahmed, Emily; Wang, Chyung-Ru; Chong, Anita

    2009-01-01

    The induction of donor-specific tolerance remains a major goal in the field of transplantation immunology. Therapies that target costimulatory molecules can induce tolerance to heart and pancreatic islet allografts in mouse models, but fail to do so following transplantation of skin or intestinal allografts. We have proposed that organs colonized by commensal bacteria such as skin, lung and intestine may be resistant to such therapies as a result of bacterial translocation at the time of transplantation, which may promote antigen-presenting cell (APC) maturation and the production of pro-inflammatory cytokines, consequently enhancing responses of alloreactive T cells. Our results indicate that the inability to sense signaling by most toll-like receptors (TLRs), as well as by interleukin (IL)-1R and IL-18R, as a result of genetic ablation of myeloid differentiation factor 88 (MyD88) promotes the acceptance of skin allografts. Conversely, TLR signals and infections by a model bacterium, Listeria monocytogenes (LM), at the time of transplantation can prevent the induction of transplantation tolerance. The effects of the TLR9 agonist CpG are MyD88-dependent, while the pro-rejection capacity of LM depends on the intracellular sensing of LM and the production of type I interferon (IFN). Therefore, transiently targeting these innate, pro-inflammatory pathways may have therapeutic value to promote transplantation tolerance. PMID:19424015

  12. Graft Immunocomplex Capture Fluorescence Analysis to Detect Donor-Specific Antibodies and HLA Antigen Complexes in the Allograft.

    PubMed

    Nakamura, Tsukasa; Ushigome, Hidetaka; Watabe, Kiyoko; Imanishi, Yui; Masuda, Koji; Matsuyama, Takehisa; Harada, Shumpei; Koshino, Katsuhiro; Iida, Taku; Nobori, Shuji; Yoshimura, Norio

    2017-04-01

    Immunocomplex capture fluorescence analysis (ICFA) is an attractive method to detect donor-specific anti-HLA antibodies (DSA) and HLA antigen complexes. Currently, antibody-mediated rejection (AMR) due to DSA is usually diagnosed by C4d deposition and serological DSA detection. Conversely, there is a discrepancy between these findings frequently. Thereupon, our graft ICFA technique may contribute to establish the diagnosis of AMR. Graft samples were obtained by a percutaneous needle biopsy. Then, the specimen was dissolved in PBS by the lysis buffer. Subsequently, HLA antigens were captured by anti-HLA beads. Then, DSA-HLA complexes were detected by PE-conjugated anti-human IgG antibodies, where DSA had already reacted with the allograft in vivo, analyzed by a Luminex system. A ratio (sample MFI/blank beads MFI) was calculated: ≥ 1.0 was determined as positive. We found that DSA-HLA complexes in the graft were successfully detected from only slight positive 1.03 to 79.27 in a chronic active AMR patient by graft ICFA. Next, positive graft ICFA had predicted the early phase of AMR (MFI ratio: 1.38) even in patients with no serum DSA. Finally, appropriate therapies for AMR deleted DSA deposition (MFI ratio from 0.3 to 0.7) from allografts. This novel application would detect early phase or incomplete pathological cases of AMR, which could lead to a correct diagnosis and initiation of appropriate therapies. Moreover, graft ICFA might address a variety of long-standing questions in terms of DSA. AMR: Antibody-mediated rejection; DSA: Donor-specific antibodies; ICFA: Immunocomplex capture fluorescence analysis.

  13. IVIg Treatment Reduces Catalytic Antibody Titers of Renal Transplanted Patients

    PubMed Central

    Mahendra, Ankit; Peyron, Ivan; Dollinger, Cécile; Gilardin, Laurent; Sharma, Meenu; Wootla, Bharath; Padiolleau-Lefevre, Séverine; Friboulet, Alain; Boquet, Didier; Legendre, Christophe; Kaveri, Srinivas V.

    2013-01-01

    Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy. PMID:23967092

  14. Safety and Efficacy of Transplantation with Allogeneic Skin Tumors to Treat Chemically-Induced Skin Tumors in Mice

    PubMed Central

    Zhang, Zhiwei; Sun, Hua; Zhang, Jianhua; Ge, Chunlei; Dong, Suwei; Li, Zhen; Li, Ruilei; Chen, Xiaodan; Li, Mei; Chen, Yun; Zou, Yingying; Qian, Zhongyi; Yang, Lei; Yang, Jinyan; Zhu, Zhitao; Liu, Zhimin; Song, Xin

    2016-01-01

    Background Transplantation with allogeneic cells has become a promising modality for cancer therapy, which can induce graft-versus-tumor (GVT) effect. This study was aimed at assessing the safety, efficacy, and tissue type GVT (tGVT) response of transplantation with allogeneic skin tumors to treat chemically-induced skin tumors in mice. Material/Methods FVB/N and ICR mice were exposed topically to chemicals to induce skin tumors. Healthy ICR mice were transplanted with allogeneic skin tumors from FVB/N mice to test the safety. The tumor-bearing ICR mice were transplanted with, or without, allogeneic skin tumors to test the efficacy. The body weights (BW), body condition scores (BCS), tumor volumes in situ, metastasis tumors, overall survival, and serum cytokines were measured longitudinally. Results Transplantation with no more than 0.03 g allogeneic skin tumors from FVB/N mice to healthy ICR mice was safe. After transplantation with allogeneic skin tumors to treat tumor-bearing mice, it inhibited the growth of tumors slightly at early stage, accompanied by fewer metastatic tumors at 24 days after transplantation (21.05% vs. 47.37%), while there were no statistically significant differences in the values of BW, BCS, tumor volumes in situ, metastasis tumors, and overall survival between the transplanted and non-transplanted groups. The levels of serum interleukin (IL)-2 were significantly reduced in the controls (P<0.05), but not in the recipients, which may be associated with the tGVT response. Conclusions Our results suggest that transplantation with allogeneic skin tumors is a safe treatment in mice, which can induce short-term tGVT response mediated by IL-2. PMID:27587310

  15. Subcutaneous fat transplantation alleviates diet-induced glucose intolerance and inflammation in mice.

    PubMed

    Hocking, Samantha L; Stewart, Rebecca L; Brandon, Amanda E; Suryana, Eurwin; Stuart, Ella; Baldwin, Emily M; Kolumam, Ganesh A; Modrusan, Zora; Junutula, Jagath R; Gunton, Jenny E; Medynskyj, Michael; Blaber, Sinead P; Karsten, Elisabeth; Herbert, Benjamin R; James, David E; Cooney, Gregory J; Swarbrick, Michael M

    2015-07-01

    Adipose tissue (AT) distribution is a major determinant of mortality and morbidity in obesity. In mice, intra-abdominal transplantation of subcutaneous AT (SAT) protects against glucose intolerance and insulin resistance (IR), but the underlying mechanisms are not well understood. We investigated changes in adipokines, tissue-specific glucose uptake, gene expression and systemic inflammation in male C57BL6/J mice implanted intra-abdominally with either inguinal SAT or epididymal visceral AT (VAT) and fed a high-fat diet (HFD) for up to 17 weeks. Glucose tolerance was improved in mice receiving SAT after 6 weeks, and this was not attributable to differences in adiposity, tissue-specific glucose uptake, or plasma leptin or adiponectin concentrations. Instead, SAT transplantation prevented HFD-induced hepatic triacylglycerol accumulation and normalised the expression of hepatic gluconeogenic enzymes. Grafted fat displayed a significant increase in glucose uptake and unexpectedly, an induction of skeletal muscle-specific gene expression. Mice receiving subcutaneous fat also displayed a marked reduction in the plasma concentrations of several proinflammatory cytokines (TNF-α, IL-17, IL-12p70, monocyte chemoattractant protein-1 [MCP-1] and macrophage inflammatory protein-1β [ΜIP-1β]), compared with sham-operated mice. Plasma IL-17 and MIP-1β concentrations were reduced from as early as 4 weeks after transplantation, and differences in plasma TNF-α and IL-17 concentrations predicted glucose tolerance and insulinaemia in the entire cohort of mice (n = 40). In contrast, mice receiving visceral fat transplants were glucose intolerant, with increased hepatic triacylglycerol content and elevated plasma IL-6 concentrations. Intra-abdominal transplantation of subcutaneous fat reverses HFD-induced glucose intolerance, hepatic triacylglycerol accumulation and systemic inflammation in mice.

  16. Induced pluripotent stem cells: An unlimited source of organs for transplantation.

    PubMed

    De Vos, J; Assou, S

    2016-12-07

    Organ production outside the human body could address the shortage of organs for transplantation. However, in vitro organ production is still a faraway perspective, particularly because of the difficulty in establishing an effective vascularization. A new emerging technology proposes to use carrier animals for the development of human organs. In this approach, induced pluripotent stem cells (iPSC) are injected in animal embryos to produce chimeric animals that contain autologous human organs.

  17. Clinical and molecular significance of microvascular inflammation in transplant kidney biopsies.

    PubMed

    Gupta, Anjali; Broin, Pilib Ó; Bao, Yi; Pullman, James; Kamal, Layla; Ajaimy, Maria; Lubetzky, Michelle; Colovai, Adriana; Schwartz, Daniel; de Boccardo, Graciela; Golden, Aaron; Akalin, Enver

    2016-01-01

    The diagnostic criteria for antibody-mediated rejection (AMR) are continuously evolving. Here we investigated the clinical and molecular significance of different Banff microvascular inflammation (MVI) scores in transplant kidney biopsies. A total of 356 patients with clinically indicated kidney transplant biopsies were classified into three groups based on MVI scores of 0, 1, 2, or more for Groups 1-3, respectively. Gene expression profiles were assessed using arrays on a representative subset of 93 patients. The incidence of donor-specific anti-HLA antibodies was increased from 25% in Group 1 to 36% in Group 2 and to 54% in Group 3. Acute and chronic AMR were significantly more frequent in Group 3 (15% and 35%) compared with the Group 2 (3% and 15%) and Group 1 (0% and 5%), respectively. Gene expression profiles showed increased interferon-γ and rejection-induced, cytotoxic and regulatory T-cell, natural killer cell-associated and donor-specific antibody (DSA)-selective transcripts in Group 3 compared with Groups 1 and 2. There was no significant difference in gene expression profiles between the Groups 1 and 2. Increased intragraft expression of DSA-selective transcripts was found in the biopsies of C4d- Group 3 patients. Thus, an MVI score of 2 or more was significantly associated with a histological diagnosis of acute and chronic antibody-mediated rejection. Hence, increased intragraft DSA-selective gene transcripts may be used as molecular markers for AMR, especially in C4d- biopsies.

  18. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium.

    PubMed

    Tang, Yao Liang; Zhao, Qiang; Zhang, Y Clare; Cheng, Leilei; Liu, Mingya; Shi, Jianhui; Yang, Yin Zeng; Pan, Chuizhen; Ge, Junbo; Phillips, M Ian

    2004-01-15

    Neovascularization induced by vascular endothelial growth factor (VEGF) represents an appealing approach for treating ischemic heart disease. However, VEGF therapy has been associated with transient therapeutic effects and potential risk for hemangioma growth. Adult mesenchymal stem cells (MSCs) derived from bone marrow are a promising source for tissue regeneration and repair. In order to achieve a safe and persistent angiogenic effect, we have explored the potential of autologous MSCs transplantation to enhance angiogenesis and cardiac function of ischemic hearts. One week after myocardial infarction induced by occlusion of left anterior descending artery, autologous MSCs expanded in vitro was administrated intramyocardially into the infarct area of the same donor rats. By 2 months, MSCs implantation significantly elevated VEGF expression levels, accompanied by increased vascular density and regional blood flow in the infarct zone. The neovascularization resulted in a decreased apoptosis of hypertrophied myocytes and markedly improved the left ventricular contractility (ejection fraction: 79.9+/-7.6% vs. 37.2+/-6.9% in control animals). Therefore, mechanisms underlying MSCs improvement of cardiac functions may involve neovascularization induced by differentiation of MSCs to endothelial cells and para-secretion of growth factors, in addition to the apoptosis reduction and previously reported cardiomyocytes regeneration. Two months after cell transplantation, there are significant improvement of left ventricular function. Hence, autologous MSCs transplantation may represent a promising therapeutic strategy free of ethical concerns and immune rejection, for neovascularization in ischemic heart diseases.

  19. Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells.

    PubMed

    Zhang, Chao; Cao, Jiani; Li, Xiaoyan; Xu, Haoyu; Wang, Weixu; Wang, Libin; Zhao, Xiaoyang; Li, Wei; Jiao, Jianwei; Hu, Baoyang; Zhou, Qi; Zhao, Tongbiao

    2016-09-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell (NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells (iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.

  20. Regression of Adjuvant-Induced Arthritis in Rats Following Bone Marrow Transplantation

    NASA Astrophysics Data System (ADS)

    van Bekkum, Dirk W.; Bohre, Els P. M.; Houben, Paul F. J.; Knaan-Shanzer, Shoshan

    1989-12-01

    Total body irradiation followed by bone marrow transplantation was found to be an effective treatment for adjuvant arthritis induced in rats. This treatment is most effective when applied shortly after the clinical manifestation of arthritis--i.e., 4-7 weeks after administration of Mycobacterium tuberculosis. Transplantation of bone marrow at a later stage results in a limited recovery, in that the inflammatory reaction regresses but the newly formed excessive bone is not eliminated. Local irradiation of the affected joints had no effect on the disease. It could also be excluded that the recovery of arthritis following marrow transplantation is due to lack of available antigen. Transplantation of syngeneic bone marrow is as effective as that of allogeneic bone marrow from a rat strain that is not susceptible to induction of adjuvant arthritis. The beneficial effect of this treatment cannot be ascribed to the immunosuppressive effect of total body irradiation, since treatment with the highly immunosuppressive drug Cyclosporin A resulted in a regression of the joint swelling but relapse occurred shortly after discontinuation of the treatment.

  1. Cytomegalovirus-induced gammadelta T cells associate with reduced cancer risk after kidney transplantation.

    PubMed

    Couzi, Lionel; Levaillant, Yann; Jamai, Abdellah; Pitard, Vincent; Lassalle, Regis; Martin, Karin; Garrigue, Isabelle; Hawchar, Omar; Siberchicot, François; Moore, Nicholas; Moreau, Jean-François; Dechanet-Merville, Julie; Merville, Pierre

    2010-01-01

    An increase in the number of blood gammadelta T cells follows cytomegalovirus (CMV) infection in kidney transplant recipients. These cells react against CMV-infected cells and tumor epithelial cells in vitro. We hypothesized that these CMV-induced gammadelta T cells play a protective role against cancer in kidney transplant recipients. We performed a longitudinal case-control study involving 18 recipients who developed cancer between 2 and 6 yr after transplantation and 45 recipients who did not. The median percentage of gammadelta T cells among total lymphocytes in patients with malignancies was significantly lower compared with that in control patients at 6, 12, and 18 mo before the diagnosis of cancer. Patients with a gammadelta T cell percentage of more than 4% were protected from cancer. An increase of the Vdelta2(neg) gammadelta T cell subset significantly associated with lower incidence of cancer only in recipients who experienced pre- or postgraft CMV infection. Finally, a retrospective follow-up of 131 recipients for 8 yr revealed that CMV-naive recipients had an approximately 5-fold higher risk of cancer compared with CMV-exposed patients. In summary, these results suggest a protective role of CMV exposure against cancer in kidney transplant recipients.

  2. An Evaluation of the Possible Protective Effects of Neonatal Striatal Transplants Against Kainic Acid-Induced Lesions

    PubMed Central

    Nash, David R.; Kaplan, Stanley M.; Norman, Andrew B.; Sanberg, Paul R.

    1991-01-01

    The present study examined the recent report that transplantation of neonatal striatal tissue into kainic acid (KA) lesioned striatum protected the contralateral striatum from a subsequent KA lesion. We did not find a significant difference in the survival rate of animals that received neonatal striatal transplants into a KA lesioned striatum followed by a subsequent lesion of the contralateral striatum compared to those animals that received bilateral KA-induced striatal lesions alone. The tissue transplants did not protect against the degeneration of striatal neurons induced by KA. Indeed, the survival rate was very low (25%) in the transplant groups. A second experiment was also performed to examine whether a neonatal striatal transplant might reduce the severe syndrome of aphagia and adipsia associated with KA lesions of the striatum. Animals that received the neonatal striatal transplants showed increased aphagia and adipsia compared to animals only receiving the KA lesion. Again, the transplant group had a very low survival rate (10%). The present study was unable to confirm that neonatal striatal transplants protect against KA lesions either by themselves or in conjunction with a recent KA lesion. PMID:1831050

  3. Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes

    PubMed Central

    Russo, Gianluca Luigi; Peruzzotti-Jametti, Luca; Rossi, Silvia; Sandrone, Stefano; Butti, Erica; De Ceglia, Roberta; Bergamaschi, Andrea; Motta, Caterina; Gallizioli, Mattia; Studer, Valeria; Colombo, Emanuela; Farina, Cinthia; Comi, Giancarlo; Politi, Letterio Salvatore; Muzio, Luca; Villani, Claudia; Invernizzi, Roberto William; Hermann, Dirk Matthias; Centonze, Diego

    2016-01-01

    Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory–inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke. SIGNIFICANCE STATEMENT Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster

  4. Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

    PubMed

    Bacigaluppi, Marco; Russo, Gianluca Luigi; Peruzzotti-Jametti, Luca; Rossi, Silvia; Sandrone, Stefano; Butti, Erica; De Ceglia, Roberta; Bergamaschi, Andrea; Motta, Caterina; Gallizioli, Mattia; Studer, Valeria; Colombo, Emanuela; Farina, Cinthia; Comi, Giancarlo; Politi, Letterio Salvatore; Muzio, Luca; Villani, Claudia; Invernizzi, Roberto William; Hermann, Dirk Matthias; Centonze, Diego; Martino, Gianvito

    2016-10-12

    Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke. Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic

  5. Bone marrow mesenchymal stem cell transplantation improves radiation-induced heart injury through DNA damage repair in rat model.

    PubMed

    Gao, Song; Zhao, Zhiying; Wu, Rong; Zeng, Yuecan; Zhang, Zhenyong; Miao, Jianing; Yuan, Zhengwei

    2017-03-01

    Radiotherapy is an effective form of therapy for most thoracic malignant tumors. However, myocardial injury resulting from the high doses of radiation is a severe complication. Here we aimed to study the possibility of reducing radiation-induced myocardial injury with mesenchymal stem cell (MSC) transplantation. We used MSCs extracted from bone marrow (BMSCs) to transplant via the tail vein into a radiation-induced heart injury (RIHI) rat model. The rats were divided into six groups: a Sham group, an IRR (irradiation) group, and four IRR + BMSCs transplantation groups obtained at different time points. After irradiation, BMSC transplantation significantly enhanced the cardiac function in rats. By analyzing the expression of PPAR-α, PPAR-γ, TGF-β, IL-6, and IL-8, we found that BMSC transplantation alleviated radiation-induced myocardial fibrosis and decreased the inflammatory reaction. Furthermore, we found that expression of γ-H2AX, XRCC4, DNA ligase4, and TP53BP1, which are associated with DNA repair, was up-regulated, along with increased secretion of growth factors SDF-1, CXCR4, VEGF, and IGF in rat myocardium in the IRR + BMSCs transplantation groups compared with the IRR group. Thus, BMSC transplantation has the potential to improve RIHI via DNA repair and be a new therapeutic approach for patients with myocardial injury.

  6. Tacrolimus-induced thrombotic microangiopathy in orthotopic liver transplant patients: case series of four patients.

    PubMed

    Nwaba, A; MacQuillan, G; Adams, L A; Garas, G; Delriviere, L; Augustson, B; DeBoer, B; Moody, H; Jeffrey, G P

    2013-03-01

    Thrombotic microangiopathy (TMA) is a potentially fatal complication in solid organ and bone marrow transplant patients, with reported incidence of 0.5-3% and mortality of about 75%. To emphasise the importance of early diagnosis and prompt commencement of therapy results in improved clinical outcomes. A retrospective study of all patients who underwent orthotopic liver transplantation (OLTX) at the Western Australian Liver Transplantation Service from May 1994 to December 2010 was conducted to identify patients who developed tacrolimus-induced TMA. We identified four patients with tacrolimus-induced TMA post-OLTX, derived from a cohort of 104 patients treated with tacrolimus in our institution. The mean age at diagnosis was 40 years, and the mean time of onset was 63 ± 7.5 weeks after OLTX. The indications for OLTX in the four patients were fulminant hepatic failure in three (Wilson disease, paracetamol overdose and post-partum thrombotic thrombocytopenic purpura) and hepatitis C virus-related cirrhosis. All patients had tacrolimus post-OLTX. At diagnosis, tacrolimus was discontinued in all patients, and three of the four patients underwent plasma exchange and all patients improved clinically. Mean duration of follow up was 15 ± 7.5 months. There was no mortality 6 months post-TMA. Early diagnosis with immediate discontinuation or conversion of calcineurin inhibitors and plasma exchange should be offered to OLTX patients with TMA as it results in good outcomes. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  7. Role of Stem Cells Transplantation in Tissue Regeneration After Acute or Chronic Acetaminophen Induced Liver Injury.

    PubMed

    Katselis, Charalampos; Apostolou, Konstantinos; Feretis, Themistoklis; Papanikolaou, Ioannis G; Zografos, George C; Toutouzas, Konstantinos; Papalois, Apostolos

    2016-01-01

    Acetaminophen-induced liver injury (APAP) is recognized as a frequent etiologic factor responsible for hepatic damage in the developed world. Management remains still elusive as treatment options are limited and their results are inconclusive. Consequently new strategies are explored at the experimental level. Mesenchymal stem cells (MSCs) present a promising modality as they can promote liver regeneration (LG) and compensate acute liver injury (ALI). Our research was focused on articles related to drug-induced liver injury, mechanisms of liver regeneration (LG) after Acute Liver Injury (ALI) and recent experimental protocols of Mesenchymal Stem Cells (MSCs) transplantation after chemical insult. All these studies are cited on Pubmed and MedLine. This review has three distinct sections. First recent developments in ALI pathogenesis are presented. The second section covers cellular pathways and histological findings relevant to liver regeneration. The final chapter analyzes MSCs transplantation protocols after ALI and interrelation between liver regeneration and hepatic differentiation of MSCs. Adipose tissue stem cells (ADSCs) and (MSCs) transplantation represents a promising modality in severe ALI management although many aspects remain to be clarified.

  8. Female qualities in males: vitellogenin synthesis induced by ovary transplants into the male silkworm, Bombyx mori.

    PubMed

    Yang, Congwen; Lin, Ying; Shen, Guanwang; Chen, Enxiang; Wang, Yanxia; Luo, Juan; Zhang, Haiyan; Xing, Runmiao; Xia, Qingyou

    2014-10-10

    Female qualities in males are common in vertebrates but have not been extensively reported in insects. Vitellogenin (Vg) is highly expressed in the female fat body and is generally required for the formation of yolk proteins in the insect egg. Vg upregulation is generally regarded as a female quality in female oviparous animals. In this study, we found that Bombyx mori Vg (BmVg) is especially highly expressed in the female pupa. Downregulation of the BmVg gene in the female pupa by RNA interference (RNAi) interfered with egg formation and embryonic development, showing the importance of BmVg in these processes. So, we used BmVg as a biomarker for female qualities in the silkworm. Hematoxylin-eosin staining and immunofluorescence histochemistry showed that ovary transplants induced BmVg synthesis in the male pupa fat body. Ovaries transplanted into male silkworms produced only a few eggs with deformed yolk granules. These results suggested that the amount of BmVg in the male silkworm was insufficient for eggs to undergo complete embryonic development. After 17-beta-estradiol was used to treat male pupae and male pupal fat bodies, BmVg was upregulated in vivo and in vitro. These findings indicated that the male silkworm has innate female qualities that were induced by a transplanted ovary and 17β-estradiol. However, in silkworms, female qualities in males are not as complete as in females.

  9. Effect of ultraviolet-B-irradiated donor-specific blood transfusions and peritransplant immunosuppression with cyclosporine on rat cardiac allograft survival

    SciTech Connect

    Oluwole, S.F.; Lau, H.T.; Reemtsma, K.; Hardy, M.A.

    1988-02-01

    We have previously demonstrated that pretreatment of ACI recipients with ultraviolet-irradiated donor-specific blood transfusion (UV-DST) leads to permanent cardiac allograft survival without further host immunosuppression (ACI rats are weak responders to Lewis lymphocytes in mixed-lymphocyte reaction). This study examines the effect of UV-DST and the timing of transfusions on ACI cardiac allograft survival in Lewis recipients with and without the addition of peritransplant cyclosporine (CsA) (20 mg/kg i.m.) given on days 0, +1, and +2 in relation to the time of transplantation. The mean survival time (MST) of ACI cardiac allografts in Lewis recipients was significantly increased to 33.6 +/- 5.7 days (P less than 0.001) by CsA treatment alone as compared to 6.5 +/- 0.5 days survival in control. When DST was given on day -3 combined with CsA, graft survival was increased to 42.0 +/- 9.3 days (P less than 0.01), as compared to 5.8 +/- 1.3 days when DST alone was used. When DST was irradiated with ultraviolet B (UV-DST) and administered on day -3 combined with peritransplant CsA, the MST was increased to 68.83 +/- 16.1 days as compared to an MST of 10.0 +/- 1.0 days in controls treated with UV-DST alone. When UV-DST was given on day -7 and combined with peritransplant CsA immunosuppression, the results were similar. However, when UV-DST was peritransplant CsA course, 4 of 6 recipients maintained their ACI heart allografts indefinitely (greater than 300 days) in contrast to the effect of UV-DST alone (MST of 13.5 days). Third-party (W/F) UV-irradiated blood transfusions were ineffective in prolonging ACI cardiac allografts in Lewis rats, regardless of whether the transfusions were given alone or in combination with peritransplant immunosuppression with CsA.

  10. Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss.

    PubMed

    Sicard, Antoine; Ducreux, Stéphanie; Rabeyrin, Maud; Couzi, Lionel; McGregor, Brigitte; Badet, Lionel; Scoazec, Jean Yves; Bachelet, Thomas; Lepreux, Sébastien; Visentin, Jonathan; Merville, Pierre; Fremeaux-Bacchi, Véronique; Morelon, Emmanuel; Taupin, Jean-Luc; Dubois, Valérie; Thaunat, Olivier

    2015-02-01

    Antibody-mediated rejection (AMR) is a major cause of kidney graft loss, yet assessment of individual risk at diagnosis is impeded by the lack of a reliable prognosis assay. Here, we tested whether the capacity of anti-HLA antibodies to bind complement components allows accurate risk stratification at the time of AMR diagnosis. Among 938 kidney transplant recipients for whom a graft biopsy was performed between 2004 and 2012 at the Lyon University Hospitals, 69 fulfilled the diagnosis criteria for AMR and were enrolled. Sera banked at the time of the biopsy were screened for the presence of donor-specific anti-HLA antibodies (DSAs) and their ability to bind C1q and C3d using flow bead assays. In contrast with C4d graft deposition, the presence of C3d-binding DSA was associated with a higher risk of graft loss (P<0.001). Despite similar trend, the difference did not reach significance with a C1q-binding assay (P=0.06). The prognostic value of a C3d-binding assay was further confirmed in an independent cohort of 39 patients with AMR (P=0.04). Patients with C3d-binding antibodies had worse eGFR and higher DSA mean fluorescence intensity. In a multivariate analysis, only eGFR <30 ml/min per 1.73 m(2) (hazard ratio [HR], 3.56; 95% confidence interval [CI], 1.46 to 8.70; P=0.005) and the presence of circulating C3d-binding DSA (HR, 2.80; 95% CI, 1.12 to 6.95; P=0.03) were independent predictors for allograft loss at AMR diagnosis. We conclude that assessment of the C3d-binding capacity of DSA at the time of AMR diagnosis allows for identification of patients at risk for allograft loss. Copyright © 2015 by the American Society of Nephrology.

  11. [CO-TRANSPLANTATION OF MOUSE EPIDERMIS AND DERMIS CELLS IN INDUCING HAIR FOLLICLE REGENERATION].

    PubMed

    Chen, Lin; Xi, Jiafei; Liu, Daqing; Zhang, Xiuyuan; Lü, Yang; Li, Jing; Wang, Jingxue; Zhou, Junnian; Nan, Xue; Yue, Wen; Pei, Xuetao

    2016-04-01

    To investigate the co-transplantation of C57-green fluorescent protein (GFP) mouse epidermis and dermis cells subcutaneously to induce the hair follicle regeneration. C57-GFP mouse epidermis and dermis were harvested for isolation the mouse epidermis and dermis cells. The morphology of epidermis and dermis mixed cells at ratio of 1:1 of adult mouse, dermis cells of adult mouse, cultured 3rd generation dermis cells were observed by fluorescence microscope. Immunocytochemistry staining was used to detect hair follicle stem cells markers in cultured 3rd generation dermis cells from new born C57-GFP mouse. And then the epidermis and dermis mixed cells of adult mouse (group A), dermis cells of adult mouse (group B), cultured 3rd generation dermis cells of new born mouse (group C), and saline (group D) were transplanted subcutaneously into Balb/c nude mice. The skin surface of nude mice were observed at 4, 5, 6 weeks of transplantation and hair follicle formation were detected at 6 weeks by immunohistochemistry staining. The isolated C57-GFP mouse epidermis and dermis cells strongly expressed the GFP under the fluorescence microscope. Immunocytochemistry staining for hair follicle stem cells markers in cultured 3rd generation dermis cells showed strong expression of Vimentin and α-smooth muscle actin, indicating that the cells were dermal sheath cells; some cells expressed CD133, Versican, and cytokeratin 15. After transplanted for 4-6 weeks, the skin became black at the injection site in group A, indicating new hair follicle formation. However, no color change was observed in groups B, C, and D. Immunohistochemical staining showed that new complete hair follicles structures formed in group A. GFP expression could be only observed in the hair follicle dermal sheath and outer root sheath in group B, and it could also be observed in the hair follicle dermal sheath, outer root sheath, dermal papilla cells, and sweat gland in group C. The expression of GFP was negative in

  12. Pretransplant human leukocyte antigen antibodies detected by single-antigen bead assay are a risk factor for long-term kidney graft loss even in the absence of donor-specific antibodies.

    PubMed

    Richter, Rudolf; Süsal, Caner; Köhler, Stefanie; Qidan, Sara; Schödel, Alicia; Holschuh, Lisa; Brzoska, Martin; Asbe-Vollkopf, Aida; Büttner, Stefan; Betz, Christoph; Herrmann, Eva; Gauer, Stefan; Seifried, Erhard; Geiger, Helmut; Seidl, Christian; Hauser, Ingeborg A

    2016-09-01

    Clinical relevance of ELISA- and single-antigen bead assay (SAB)-detected pretransplant HLA antibodies (SAB-HLA-Ab) for kidney graft survival was evaluated retrospectively in 197 patients transplanted between 2002 and 2009 at the University Clinic Frankfurt. Having adjusted for retransplantation and delayed graft function, a significantly increased risk for death-censored graft loss was found in patients with pretransplant SAB-HLA-Ab [HR: 4.46; 95% confidence interval (CI): 1.47-13.48; P = 0.008]. The risk for increased graft loss was also significant in patients with pretransplant SAB-HLA-Ab but without SAB-detected donor-specific Ab (SAB-DSA) (HR: 4.91; 95% CI of 1.43-16.991; P = 0.012). ELISA was not sufficient to identify pretransplant immunized patients with an increased risk for graft loss. In immunized patients, graft loss was predominantly present in patients who received transplants with a mismatch on the HLA-DR locus. In conclusion, even if our study is limited due to small sample size, the results show an increased risk for long-term graft loss in patients with pretransplant SAB-HLA, even in the absence of DSA. SAB-HLA-Ab-positive patients, being negative in ELISA or CDC assay, might profit from a well-HLA-DR-matched graft and intensified immunosuppression. © 2016 Steunstichting ESOT.

  13. Tuning the Phosphoryl Donor Specificity of Dihydroxyacetone Kinase from ATP to Inorganic Polyphosphate. An Insight from Computational Studies

    PubMed Central

    Sánchez-Moreno, Israel; Bordes, Isabel; Castillo, Raquel; Ruiz-Pernía, José Javier; Moliner, Vicent; García-Junceda, Eduardo

    2015-01-01

    Dihydroxyacetone (DHA) kinase from Citrobacter freundii provides an easy entry for the preparation of DHA phosphate; a very important C3 building block in nature. To modify the phosphoryl donor specificity of this enzyme from ATP to inorganic polyphosphate (poly-P); a directed evolution program has been initiated. In the first cycle of evolution, the native enzyme was subjected to one round of error-prone PCR (EP-PCR) followed directly (without selection) by a round of DNA shuffling. Although the wild-type DHAK did not show activity with poly-P, after screening, sixteen mutant clones showed an activity with poly-phosphate as phosphoryl donor statistically significant. The most active mutant presented a single mutation (Glu526Lys) located in a flexible loop near of the active center. Interestingly, our theoretical studies, based on molecular dynamics simulations and hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations, suggest that this mutation has an effect on the binding of the poly-P favoring a more adequate position in the active center for the reaction to take place. PMID:26610480

  14. Tuning the Phosphoryl Donor Specificity of Dihydroxyacetone Kinase from ATP to Inorganic Polyphosphate. An Insight from Computational Studies.

    PubMed

    Sánchez-Moreno, Israel; Bordes, Isabel; Castillo, Raquel; Ruiz-Pernía, José Javier; Moliner, Vicent; García-Junceda, Eduardo

    2015-11-24

    Dihydroxyacetone (DHA) kinase from Citrobacter freundii provides an easy entry for the preparation of DHA phosphate; a very important C3 building block in nature. To modify the phosphoryl donor specificity of this enzyme from ATP to inorganic polyphosphate (poly-P); a directed evolution program has been initiated. In the first cycle of evolution, the native enzyme was subjected to one round of error-prone PCR (EP-PCR) followed directly (without selection) by a round of DNA shuffling. Although the wild-type DHAK did not show activity with poly-P, after screening, sixteen mutant clones showed an activity with poly-phosphate as phosphoryl donor statistically significant. The most active mutant presented a single mutation (Glu526Lys) located in a flexible loop near of the active center. Interestingly, our theoretical studies, based on molecular dynamics simulations and hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) optimizations, suggest that this mutation has an effect on the binding of the poly-P favoring a more adequate position in the active center for the reaction to take place.

  15. Plasma protein corona modulates the vascular wall interaction of drug carriers in a material and donor specific manner.

    PubMed

    Sobczynski, Daniel J; Charoenphol, Phapanin; Heslinga, Michael J; Onyskiw, Peter J; Namdee, Katawut; Thompson, Alex J; Eniola-Adefeso, Omolola

    2014-01-01

    The nanoscale plasma protein interaction with intravenously injected particulate carrier systems is known to modulate their organ distribution and clearance from the bloodstream. However, the role of this plasma protein interaction in prescribing the adhesion of carriers to the vascular wall remains relatively unknown. Here, we show that the adhesion of vascular-targeted poly(lactide-co-glycolic-acid) (PLGA) spheres to endothelial cells is significantly inhibited in human blood flow, with up to 90% reduction in adhesion observed relative to adhesion in simple buffer flow, depending on the particle size and the magnitude and pattern of blood flow. This reduced PLGA adhesion in blood flow is linked to the adsorption of certain high molecular weight plasma proteins on PLGA and is donor specific, where large reductions in particle adhesion in blood flow (>80% relative to buffer) is seen with ∼60% of unique donor bloods while others exhibit moderate to no reductions. The depletion of high molecular weight immunoglobulins from plasma is shown to successfully restore PLGA vascular wall adhesion. The observed plasma protein effect on PLGA is likely due to material characteristics since the effect is not replicated with polystyrene or silica spheres. These particles effectively adhere to the endothelium at a higher level in blood over buffer flow. Overall, understanding how distinct plasma proteins modulate the vascular wall interaction of vascular-targeted carriers of different material characteristics would allow for the design of highly functional delivery vehicles for the treatment of many serious human diseases.

  16. Acquisition of humoral transplantation tolerance upon de novo emergence of B lymphocytes.

    PubMed

    Parsons, Ronald F; Vivek, Kumar; Rostami, Susan Y; Zekavat, Ghazal; Ziaie, Seyed M; Luo, Yanping; Koeberlein, Brigitte; Redfield, Robert R; Cancro, Michael P; Naji, Ali; Noorchashm, Hooman

    2011-01-01

    A major obstacle to transplantation tolerance is humoral immunity. In this paper, we demonstrate that the intrinsic developmental propensity of the B lymphocyte compartment for acquisition of self-tolerance can be harnessed to induce humoral unresponsiveness to transplanted alloantigens. In the current study, when transitional B cells developed in the presence of donor lymphoid cells, the mature B lymphocyte compartment failed to mount a donor-specific alloantibody response to an organ transplant--despite unrestrained acute T cell-mediated allograft rejection. Specifically, we generated an experimental system wherein a B6 strain B cell compartment developed de novo in the presence of F1 (B6xBALB/c) lymphoid cells and in a T cell-deficient setting. Following establishment of a steady-state B cell compartment, these B6 mice were transplanted with heterotopic cardiac allografts from allogeneic BALB/c donors. The mice were then inoculated with purified syngeneic B6 T cells. As expected, all cardiac allografts were acutely rejected. However, the B lymphocyte compartment of these mice was completely inert in its capacity to form a BALB/c-specific alloantibody response. Using an alloantigen-specific Ig transgenic system, we demonstrated that this profound degree of humoral tolerance was caused by clonal deletion of alloreactive specificities from the primary B cell repertoire. Thus, de novo B cell compartment development at the time of transplantation is of critical importance in recipient repertoire "remodeling" to a humoral tolerant state.

  17. Late presentation of adenovirus-induced hemorrhagic cystitis and ureteral obstruction in a kidney-pancreas transplant recipient

    PubMed Central

    Kuperman, Michael; Haley, Clinton; Barri, Yousri; Chandrakantan, Arun; Fischbach, Bernard; Melton, Larry; Rice, Kim; Saim, Muhammad; Yango, Angelito; Klintmalm, Goran; Rajagopal, Arthi

    2015-01-01

    We report a late presentation of adenovirus-induced renal allograft and bladder infection causing azotemia and hemorrhagic cystitis in a patient 5 years after simultaneous kidney-pancreas transplantation. Adenovirus has been increasingly recognized as a cause of morbidity and mortality in both solid organ and stem cell transplant recipients. We wish to emphasize the importance of early detection, as treatment options involve reduction of immunosuppression, followed by the addition of antiviral agents and supportive care. PMID:26424950

  18. Inducible and endothelial nitric oxide synthase expression during development of transplant arteriosclerosis in rat aortic grafts.

    PubMed Central

    Akyürek, L. M.; Fellström, B. C.; Yan, Z. Q.; Hansson, G. K.; Funa, K.; Larsson, E.

    1996-01-01

    In the vascular system, distinct isoforms of nitric oxide synthase (NOS) generate nitric oxide (NO), which acts as a biological messenger. Its role in the development of transplant arteriosclerosis (TA) is still unclear. To investigate whether NO is involved in TA, we studied the expression of NOS isoforms, inducible NOS (iNOS) and endothelial NOS (eNOS), by immunohistochemistry and in situ hybridization during the first two post-transplantation months and their relation with cold ischemia (1 to 24 hours) and reperfusion injury using an aortic transplantation model in the rat. We found an increased iNOS expression in the intima and adventitia and a decreased expression in the media, whereas eNOS expression was not significantly altered during the development of TA. Co-localization studies suggested that iNOS-positive cells were vascular smooth muscle cells, monocyte-derived macrophages, and endothelial cells. Prolonged ischemic storage time resulted in an increase in eNOS expression in the neointima. In situ hybridization showed iNOS mRNA expression by vascular cells in the neointima and media. NO produced by iNOS and eNOS may be involved, at least in part, in the pathogenesis of TA in aortic grafts. Additional studies are needed to confirm the modulatory mechanism of NO during the development of TA. Images Figure 3 Figure 4 Figure 6 PMID:8952533

  19. Operational tolerance in nonvascularized transplant models induced by AR-C117977, a monocarboxylate transporter inhibitor.

    PubMed

    Påhlman, Clara; Malm, Helene; Qi, Zhongquan; Veress, Béla; Ferguson, Douglas; Bundick, Robert; Murray, Clare; Donald, David; Ekberg, Henrik

    2008-10-27

    AR-C117977, a monocarboxylate transporter inhibitor, reduces immune responses both in vitro and in vivo, maintains long-term graft survival, and induces operational tolerance. To evaluate the immunosuppressive limitations of AR-C117977, this study was performed in nonvascularized transplant models noted for their refractive response to standard immunosuppressive agents. Rat skin was transplanted from DA(RT1avl) into PVG(RT1c) and the reverse. Mouse islet allotransplantation was performed with BALB/c H2d donors and C57Bl/6J H2b recipients. In the skin graft model, AR-C117977 monotherapy was associated with long-term skin graft survival in one rat strain combination. AR-C117977 and cyclosporine A (CsA) in combination resulted in significant prolongation of graft survival in both rat strains. CsA monotherapy did not prevent acute rejection in either strain. Islet allograft survival was moderately prolonged with CsA or AR-C117977. AR-C117977 is an efficient immunosuppressive drug in stringent rodent transplant models and further studies are warranted.

  20. Stimulation of local solid tumour development of the nonproducer Marek's disease tumour transplant JMV by virus-induced immunosuppression.

    PubMed

    Bulow, V V; Weiland, F

    1980-01-01

    Chickens could be protected against lethal lymphoblastic leukaemia due to the nonproducer JMV Marek's disease (MD) tumour transplant by infection with the herpesvirus of turkeys (HVT) or various strains of MD virus. However, solid JMV tumours developed in MD virus-infected birds at the site of intramuscular or subcutaneous transplantation, but tumours never developed at the site of MD virus inoculation. The incidence and extent of local tumour growth, the development of metastases and the inhibition of tumour regression were related to the pathogenicity of the MD virus strains used for pre-treatment of the chickens. Infection of chickens with reticulo-endotheliosis virus (REV-C) or with chick syncytial virus (CSV), which are nonprotective against MD virus or JMV transplants, stimulated local tumour development of the attenuated JMV-A variant of the JMV transplant. Chickens which did not reject local tumours died of visceral JMV tumour metastases. A direct helper mechanism of viral infection on the oncogenicity of transplants was excluded. The results suggested that virus-induced immunosuppression stimulated the development of local JMV tumours which never occurred in normal chickens. Immunity to the JMV transplant, including resistance to lethal leukaemia and successful regression of local tumours, did not coincide with immunity to MD virus-induced visceral lymphomas or nerve lesions. Vaccinal induced tumour immunity evidently was defective. The significance of these results is discussed with reference to immunological functions of MD tumour-specific antigens.

  1. Establishment of a surgically induced cryptorchidism canine recipient model for spermatogonial stem cell transplantation

    PubMed Central

    Lee, Won-Young; Lee, Ran; Song, Hyuk; Hur, Tai-Young; Lee, Seunghoon; Ahn, Jiyun

    2016-01-01

    Transplantation of spermatogonial stem cells (SSCs) in experimental animal models has been used to study germ line stem cell biology and to produce transgenic animals. The species-specific recipient model preparation is important for the characterization of SSCs and the production of offspring. Here, we investigated the effects of surgically induced cryptorchidism in dog as a new recipient model for spermatogonial stem cell transplantation. Artificially unilateral or bilateral cryptorchidism was induced in ten mature male dogs by surgically returning the testis and epididymis to the abdominal cavity. The testes and epididymides were collected every week after the induction of artificial cryptorchidism (surgery) for one month. To determine the effect of surgical cryptorchidism, the seminiferous tubule diameter was measured and immunohistochemistry using PGP9.5 and GATA4 antibodies was analyzed. The diameters of the seminiferous tubules of abdominal testes were significantly reduced compared to those of the scrotal testes. Immunohistochemistry results showed that PGP9.5 positive undifferentiated spermatogonia were significantly reduced after surgical cryptorchidism induction, but there were no significant changes in GATA-4 positive sertoli cells. To evaluate the testis function recovery rate, orchiopexy was performed on two dogs after 30 days of bilateral cryptorchidism. In the orchiopexy group, SCP3 positive spermatocytes were detected, and spermatogenesis was recovered 8 weeks after orchiopexy. In this study, we provided optimum experimental conditions and time for surgical preparation of a recipient canine model for SSC transplantation. Additionally, our data will contribute to recipient preparation by using surgically induced cryptorchidism in non-rodent species. PMID:28053620

  2. Mechanisms of transplantation tolerance in animals and humans.

    PubMed

    Sykes, Megan

    2009-05-15

    Donor-specific immune tolerance would avoid the toxicities of chronic immunosuppressive therapies while preventing graft rejection. Hematopoietic cell transplantation has shown preliminary success for intentional tolerance induction in pilot clinical trials. The mechanisms of tolerance in these trials and the animal studies leading up to them are discussed.

  3. Liver transplantation for acute hepatic failure due to chemotherapy-induced HBV reactivation in lymphoma patients

    PubMed Central

    Noterdaeme, Timothée; Longrée, Luc; Bataille, Christian; Deroover, Arnaud; Lamproye, Anne; Delwaide, Jean; Beguin, Yves; Honoré, Pierre; Detry, Olivier

    2011-01-01

    Hepatitis B (HBV) reactivation induced by chemotherapy is problem encountered recently in the management of malignant diseases. Chemotherapy-induced HBV reactivation may ultimately lead to terminal acute liver failure. Liver transplantation (LT) currently remains the only definitive treatment option for such cases, but is generally denied to patients suffering from malignancy. Here, the authors describe 2 cases of cancer-free and HBV graft re-infection-free survival after LT performed for terminal liver failure arising from HBV reactivation induced by chemotherapy for advanced stage lymphoma. These 2 cases, and some other reports in the literature, may suggest that patients suffering from hematologic malignancies and terminal liver disease can be considered for LT if the prognosis of their hematologic malignancy is good. PMID:21799656

  4. Inducible costimulatory molecule deficiency induced imbalance of Treg and Th17/Th2 delays rejection reaction in mice undergoing allogeneic tracheal transplantation

    PubMed Central

    Xu, Jingsong; Wu, Yu; Wang, Guifang; Qin, Yanghua; Zhu, Li; Tang, Gusheng; Shen, Qian

    2014-01-01

    Objective: This study aimed to investigate the role of inducible costimulatory molecule (ICOS) pathway in the rejection reaction of mice undergoing allogeneic tracheal transplantation. Methods: The bronchus was separated from wide-type (WT) BalB/c mice and transplanted into WT BalB/c mice, C57 mice and icos-/- mice to prepare the obliterative bronchiolitis (OB) animal model. The transplanted bronchus was pathologically examined; flow cytometry was done to detect the T cell subsets and activity of the bronchus and spleen of recipient mice. Results: 21 d after transplantation, evident rejection reaction was observed and the proportion of Th2 and Th17 cells increased significantly in the bronchus and spleen in C57 mice receiving allogeneic tracheal transplantation when compared with mice with autologous transplantation, but the proportion of Treg cells was comparable between them. When compared with WT BalB/c mice, the proportion of Th2, Th17 and Treg cells reduced markedly and rejection reaction was attenuated in icos-/- mice receiving tracheal transplantation, although rejection reaction was still noted. Conclusion: icos knockout may delay the rejection reaction after tracheal transplantation, which might be ascribed to the imbalance among Th2, Th17 and Treg cells. PMID:25628788

  5. Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation.

    PubMed

    Weiner, Joshua; Zuber, Julien; Shonts, Brittany; Yang, Suxiao; Fu, Jianing; Martinez, Mercedes; Farber, Donna L; Kato, Tomoaki; Sykes, Megan

    2017-10-01

    Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

  6. Complement-fixing donor-specific antibodies identified by a novel C1q assay are associated with allograft loss.

    PubMed

    Sutherland, Scott M; Chen, Ge; Sequeira, Flavia A; Lou, Calvin D; Alexander, Steven R; Tyan, Dolly B

    2012-02-01

    Long-term outcomes following renal transplantation remain disappointing. Recently, interest has focused on the antibody-mediated component of allograft injury and the deleterious effects of DSA. We applied a novel C1q solid-phase assay in parallel with the standard IgG SAB assay to identify DSA with the potential to activate complement by binding C1q. Among 193 consecutive renal transplants at our center, 19.2% developed de novo DSA following transplantation. Of the patients with DSA, 43% had antibodies that bound C1q in vitro [C1q+ DSA]. Patients with C1q+ DSA were more likely to develop allograft loss than patients with DSA that did not bind C1q (46.7% vs. 15%; p = 0.04); patients with C1q+ DSA were nearly six times more likely to lose their transplant than those with C1q- DSA. Additionally, patients with C1q+ DSA who underwent allograft biopsy were more likely to demonstrate C4d deposition (50% vs. 8%; p = 0.03) and meet criteria for acute rejection (60% vs. 17%; p = 0.02) when compared with patients with DSA that did not bind C1q. These data suggest that DSA with the ability to activate complement, as determined by this novel C1q assay, are associated with greater risk of acute rejection and allograft loss.

  7. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model

    PubMed Central

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-01-01

    Abstract Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29+, CD44+ and CD166+ after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a β-TCP/HA matrix comparable to the application of 60 μg/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with β-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering. PMID

  8. Directly auto-transplanted mesenchymal stem cells induce bone formation in a ceramic bone substitute in an ectopic sheep model.

    PubMed

    Boos, Anja M; Loew, Johanna S; Deschler, Gloria; Arkudas, Andreas; Bleiziffer, Oliver; Gulle, Heinz; Dragu, Adrian; Kneser, Ulrich; Horch, Raymund E; Beier, Justus P

    2011-06-01

    Bone tissue engineering approaches increasingly focus on the use of mesenchymal stem cells (MSC). In most animal transplantation models MSC are isolated and expanded before auto cell transplantation which might be critical for clinical application in the future. Hence this study compares the potential of directly auto-transplanted versus in vitro expanded MSC with or without bone morphogenetic protein-2 (BMP-2) to induce bone formation in a large volume ceramic bone substitute in the sheep model. MSC were isolated from bone marrow aspirates and directly auto-transplanted or expanded in vitro and characterized using fluorescence activated cell sorting (FACS) and RT-PCR analysis before subcutaneous implantation in combination with BMP-2 and β-tricalcium phosphate/hydroxyapatite (β-TCP/HA) granules. Constructs were explanted after 1 to 12 weeks followed by histological and RT-PCR evaluation. Sheep MSC were CD29(+), CD44(+) and CD166(+) after selection by Ficoll gradient centrifugation, while directly auto-transplanted MSC-populations expressed CD29 and CD166 at lower levels. Both, directly auto-transplanted and expanded MSC, were constantly proliferating and had a decreasing apoptosis over time in vivo. Directly auto-transplanted MSC led to de novo bone formation in a heterotopic sheep model using a β-TCP/HA matrix comparable to the application of 60 μg/ml BMP-2 only or implantation of expanded MSC. Bone matrix proteins were up-regulated in constructs following direct auto-transplantation and in expanded MSC as well as in BMP-2 constructs. Up-regulation was detected using immunohistology methods and RT-PCR. Dense vascularization was demonstrated by CD31 immunohistology staining in all three groups. Ectopic bone could be generated using directly auto-transplanted or expanded MSC with β-TCP/HA granules alone. Hence BMP-2 stimulation might become dispensable in the future, thus providing an attractive, clinically feasible approach to bone tissue engineering.

  9. Transfusion-induced bone marrow transplant rejection due to minor histocompatibility antigens.

    PubMed

    Patel, Seema R; Zimring, James C

    2013-10-01

    Traditionally, alloimmunization to transfused blood products has focused exclusively on recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunologic sequelae of alloimmunization have been antibody mediated effects (ie, hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection-under reduced intensity conditioning with HLA-matched or HLA-identical marrow. Bone marrow transplant of this nature is the only existing cure for a series of nonmalignant hematologic diseases (eg, sickle cell disease, thalassemias, etc); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion-induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or natural killer cells. In this case, rejection occurs in the absence of alloantibodies and would not be detected by existing immune-hematologic methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion, which current blood bank methodologies are unable to detect. © 2013.

  10. Foetal Cell Transplantation for Parkinson's Disease: Focus on Graft-Induced Dyskinesia.

    PubMed

    Tronci, Elisabetta; Fidalgo, Camino; Carta, Manolo

    2015-01-01

    Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson's disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID.

  11. [Fulminant hepatitis induced by disulfiram in a patient with alcoholic cirrhosis. Survival after liver transplantation].

    PubMed

    Vanjak, D; Samuel, D; Gosset, F; Derrida, S; Moreau, R; Soupison, T; Soulier, A; Bismuth, H; Sicot, C

    1989-12-01

    Fulminant hepatitis was observed in a 44-year-old patient with cirrhosis, 38 days after the beginning of a treatment by disulfiram. Hepatitis was associated with fever and hypereosinophilia. Liver transplantation was performed with success. We reviewed 15 previously published cases of disulfiram-induced hepatitis. They occurred from 10 to 180 days after the beginning of the treatment by disulfiram, aminotransferases were increased whereas alkaline phosphatases were not markedly changed; there was either focal or widespread necrosis. Fulminant hepatitis was observed mainly in patients with alcoholic chronic liver disease or in patients who continued to ingest disulfiram while jaundice was already present. An immunoallergic mechanism is thought to be responsible for disulfiram-induced hepatitis.

  12. Steroid-induced femoral head osteonecrosis in immune thrombocytopenia treatment with osteochondral autograft transplantation.

    PubMed

    Fotopoulos, Vasileios Ch; Mouzopoulos, George; Floros, Themistoklis; Tzurbakis, Matthaios

    2015-09-01

    Osteonecrosis of the femoral head is a devastating complication of steroid administration and has rarely been observed in the treatment of immune thrombocytopenia. The treatment of osteochondral defects in advanced stages of avascular necrosis (AVN), characterized by collapse of the subchondral bone, remains an unsolved burden in orthopedic surgery. In this report, we present a case of a 19-year-old female that was admitted in the Emergency Department with walking disability and painful hip joint movement due to steroid-induced femoral head osteonecrosis. Two years before she was diagnosed with immune thrombocytopenia, for which she received pulse steroid therapy with high dose of dexamethasone and underwent a splenectomy. This case report is the first to describe the use of osteochondral autograft transplantation as a treatment of steroid-induced AVN of the femoral head due to immune thrombocytopenia at the age of 19 years with very good clinical and radiological results 3 years postoperatively.

  13. Origin of enriched regulatory t cells in patients receiving combined kidney/bone marrow transplantation to induce transplantation tolerance.

    PubMed

    Sprangers, Ben; DeWolf, Susan; Savage, Thomas M; Morokata, Tatsuaki; Obradovic, Aleksandar; LoCascio, Samuel A; Shonts, Brittany; Zuber, Julien; Lau, Sai Ping; Shah, Ravi; Morris, Heather; Steshenko, Valeria; Zorn, Emmanuel; Preffer, Frederic I; Olek, Sven; Dombkowski, David M; Turka, Laurence A; Colvin, Robert; Winchester, Robert; Kawai, Tatsuo; Sykes, Megan

    2017-03-01

    We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney and bone marrow transplantation (CKBMT) that led to transient chimerism under a previously-published non-myeloablative conditioning regimen (Immune Tolerance Network study ITN036). Polychromatic flow cytometry (FCM) and high throughput sequencing of TCRβ hypervariable regions of DNA from peripheral blood T regulatory cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of regulatory T cells (CD3(+) CD4(+) CD25(high) CD127(low) Foxp3(+) ) in blood that resulted from peripheral proliferation (Ki67(+) ), possibly new thymic emigration (CD31(+) ) and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4(+) and CD8(+) cells predominated. A large fraction of the T cell clones detected in post-transplant biopsy specimens by TCR sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early post-transplant period may contribute to tolerance following CKBMT. Furthermore, most conventional T cell clones detected in immunologically quiescent post-transplant biopsies appear to be circulating cells in the microvasculature rather than infiltrating T cells. This article is protected by copyright. All rights reserved.

  14. Amelioration of penetrating ballistic-like brain injury induced cognitive deficits after neuronal differentiation of transplanted human neural stem cells.

    PubMed

    Spurlock, Markus S; Ahmed, Aminul Islam; Rivera, Karla N; Yokobori, Shoji; Lee, Stephanie W; Sam, Pingdewinde N; Shear, Deborah A; Hefferan, Michael P; Hazel, Thomas G; Johe, Karl K; Gajavelli, Shyam; Tortella, Frank C; Bullock, Ross

    2017-03-01

    Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies in penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread peri-lesional neurodegeneration, similar to that seen in humans following gunshot wound to head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Towards this, green fluorescent protein (GFP) labeled hNSCs (400,000 per animal) were transplanted in immunosuppressed Sprague Dawley (SD), Fisher, and athymic (ATN) PBBI rats one week after injury. Tacrolimus (3mg/kg two days prior to transplantation, then 1mg/kg/day), Methylprednisolone (10mg/kg on day of transplant, 1mg/kg/week thereafter), and Mycophenolate mofetil (30mg/kg/day) for seven days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8-weeks post transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16-weeks post-transplantation neither cell proliferation nor glial lineage markers expression was detected. Transplanted cell morphology was similar to neighboring host neurons and there was relatively little migration of cells from the peri-transplant site. By 16 weeks, GFP positive processes extended both rostro-caudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing internal capsule, extending ~13 mm caudally from transplantation site reaching into the brain stem. In a Morris water maze test at 8-weeks post-transplantation, animals with transplants had shorter latency to platform compared to vehicle treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits

  15. The Leuven Immunomodulatory Protocol Promotes T-Regulatory Cells and Substantially Prolongs Survival After First Intestinal Transplantation.

    PubMed

    Ceulemans, L J; Braza, F; Monbaliu, D; Jochmans, I; De Hertogh, G; Du Plessis, J; Emonds, M-P; Kitade, H; Kawai, M; Li, Y; Zhao, X; Koshiba, T; Sprangers, B; Brouard, S; Waer, M; Pirenne, J

    2016-10-01

    Intestinal transplantation (ITx) remains challenged by frequent/severe rejections and immunosuppression-related complications (infections/malignancies/drug toxicity). We developed the Leuven Immunomodulatory Protocol (LIP) in the lab and translated it to the clinics. LIP consists of experimentally proven maneuvers, destined to promote T-regulatory (Tregs)-dependent graft-protective mechanisms: donor-specific blood transfusion (DSBT); avoiding high-dose steroids/calcineurin-inhibitors; and minimizing reperfusion injury and endotoxin translocation. LIP was tested in 13 consecutive ITx from deceased donors (2000-2014) (observational cohort study). Recipient age was 37 years (2.8-57 years). Five-year graft/patient survival was 92%. One patient died at 9 months due to aspergillosis, another at 12 years due to nonsteroidal anti-inflammatory drug-induced enteropathy. Early acute rejection (AR) developed in two (15%); late AR in three (23%); all were reversible. No chronic rejection (CR) occurred. No malignancies developed and estimated glomerular filtration rate remained stable post-Tx. At last follow-up (3.5 years [0.5-12.5 years]), no donor-specific antibodies were detected and 11 survivors were total parenteral nutrition free with a Karnofsky score >90% in 8 recipients (follow-up >1 years). A high frequency of circulating CD4(+) CD45RA(-) Foxp3(hi) memory Tregs was found (1.8% [1.39-2.21]), comparable to tolerant kidney transplant (KTx) recipients and superior to stable immunosuppression (IS)-KTx, KTx with CR, and healthy volunteers. In this ITx cohort we show that DSBT in a low-inflammatory/pro-regulatory environment activates Tregs at levels similar to tolerant-KTx, without causing sensitization. LIP limits rejection under reduced IS and thereby prolongs long-term survival to an extent not previously attained after ITx. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Pathogen Stimulation History Impacts Donor-Specific CD8(+) T Cell Susceptibility to Costimulation/Integrin Blockade-Based Therapy.

    PubMed

    Badell, I R; Kitchens, W H; Wagener, M E; Lukacher, A E; Larsen, C P; Ford, M L

    2015-12-01

    Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8(+) memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data, therefore, demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation.

  17. Pathogen stimulation history impacts donor-specific CD8+ T cell susceptibility to costimulation/integrin blockade-based therapy

    PubMed Central

    Badell, IR; Kitchens, WH; Wagener, ME; Lukacher, AE; Larsen, CP; Ford, ML

    2017-01-01

    Recent studies have shown that the quantity of donor-reactive memory T cells is an important factor in determining the relative heterologous immunity barrier posed during transplantation. Here, we hypothesized that the quality of T cell memory also potently influences the response to costimulation blockade-based immunosuppression. Using a murine skin graft model of CD8+ memory T cell-mediated costimulation blockade resistance, we elicited donor-reactive memory T cells using three distinct types of pathogen infections. Strikingly, we observed differential efficacy of a costimulation and integrin blockade regimen based on the type of pathogen used to elicit the donor-reactive memory T cell response. Intriguingly, the most immunosuppression-sensitive memory T cell populations were composed primarily of central memory cells that possessed greater recall potential, exhibited a less differentiated phenotype, and contained more multi-cytokine producers. These data therefore demonstrate that the memory T cell barrier is dependent on the specific type of pathogen infection via which the donor-reactive memory T cells are elicited, and suggest that the immune stimulation history of a given transplant patient may profoundly influence the relative barrier posed by heterologous immunity during transplantation. PMID:26228897

  18. Rat Heterotopic Heart Transplantation Model to Investigate Unloading-Induced Myocardial Remodeling

    PubMed Central

    Fu, Xuebin; Segiser, Adrian; Carrel, Thierry P.; Tevaearai Stahel, Hendrik T.; Most, Henriette

    2016-01-01

    Unloading of the failing left ventricle in order to achieve myocardial reverse remodeling and improvement of contractile function has been developed as a strategy with the increasing frequency of implantation of left ventricular assist devices in clinical practice. But, reverse remodeling remains an elusive target, with high variability and exact mechanisms still largely unclear. The small animal model of heterotopic heart transplantation (hHTX) in rodents has been widely implemented to study the effects of complete and partial unloading on cardiac failing and non-failing tissue to better understand the structural and molecular changes that underlie myocardial recovery. We herein review the current knowledge on the effects of volume unloading the left ventricle via different methods of hHTX in rats, differentiating between changes that contribute to functional recovery and adverse effects observed in unloaded myocardium. We focus on methodological aspects of heterotopic transplantation, which increase the correlation between the animal model and the setting of the failing unloaded human heart. Last, but not least, we describe the late use of sophisticated techniques to acquire data, such as small animal MRI and catheterization, as well as ways to assess unloaded hearts under “reloaded” conditions. While giving regard to certain limitations, heterotopic rat heart transplantation certainly represents the crucial model to mimic unloading-induced changes in the heart and as such the intricacies and challenges deserve highest consideration. Careful translational research will further improve our knowledge of the reverse remodeling process and how to potentiate its effect in order to achieve recovery of contractile function in more patients. PMID:27807535

  19. Thoracic organ transplantation: laboratory methods.

    PubMed

    Patel, Jignesh K; Kobashigawa, Jon A

    2013-01-01

    Although great progress has been achieved in thoracic organ transplantation through the development of effective immunosuppression, there is still significant risk of rejection during the early post-transplant period, creating a need for routine monitoring for both acute antibody and cellular mediated rejection. The currently available multiplexed, microbead assays utilizing solubilized HLA antigens afford the capability of sensitive detection and identification of HLA and non-HLA specific antibodies. These assays are being used to assess the relative strength of donor specific antibodies; to permit performance of virtual crossmatches which can reduce the waiting time to transplantation; to monitor antibody levels during desensitization; and for heart transplants to monitor antibodies post-transplant. For cell mediated immune responses, the recent development of gene expression profiling has allowed noninvasive monitoring of heart transplant recipients yielding predictive values for acute cellular rejection. T cell immune monitoring in heart and lung transplant recipients has allowed individual tailoring of immunosuppression, particularly to minimize risk of infection. While the current antibody and cellular laboratory techniques have enhanced the ability to manage thoracic organ transplant recipients, future developments from improved understanding of microchimerism and graft tolerance may allow more refined allograft monitoring techniques.

  20. Expression of hypoxia-inducible factor-1α and hepatocyte growth factor in development of fibrosis in the transplanted kidney.

    PubMed

    Kellenberger, Terese; Marcussen, Niels; Nyengaard, Jens R; Wogensen, Lise; Jespersen, Bente

    2015-02-01

    Late renal graft loss is associated with interstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) is thought to facilitate fibrosis through interaction with TGF-β1, while hepatocyte growth factor (HGF) may act antifibrotic in the kidney allograft. The aim of this study was to investigate the expression of HIF-1α and HGF in protocol biopsies as possible prognostic biomarkers for renal fibrosis. Thirty-nine renal transplant recipients were included in the study. Protocol biopsies performed 1 and 2 years after transplantation were used for immunohistochemistry analysis. The correlation between HIF-1α/HGF and the Banff score was analysed. In addition, progression in renal fibrosis and graft survival among recipients with high or low expression of HIF-1α/HGF after transplantation was compared. There was no significant correlation between fibrosis and the HIF-1α expression 1 and 2 years after transplantation, but an inverse significant correlation between the HGF expression and the fibrosis score 1 year after transplantation was shown. Even when adjusting for human leucocyte antigen mismatches, there was a significant relationship between fibrosis and HGF expression. Graft survival was not significantly correlated to HIF-1α or HGF at 1 year, although the trend was towards better graft survival with high HGF. HGF may have antifibrotic effects in human renal transplants. (Central.Denmark.Region.Committee number: 1-10-72-318-13).

  1. Amelioration of Hyperbilirubinemia in Gunn Rats after Transplantation of Human Induced Pluripotent Stem Cell-Derived Hepatocytes

    PubMed Central

    Chen, Yong; Li, Yanfeng; Wang, Xia; Zhang, Wei; Sauer, Vanessa; Chang, Chan-Jung; Han, Bing; Tchaikovskaya, Tatyana; Avsar, Yesim; Tafaleng, Edgar; Madhusudana Girija, Sanal; Tar, Krisztina; Polgar, Zsuzsanna; Strom, Stephen; Bouhassira, Eric E.; Guha, Chandan; Fox, Ira J.; Roy-Chowdhury, Jayanta; Roy-Chowdhury, Namita

    2015-01-01

    Summary Hepatocyte transplantation has the potential to cure inherited liver diseases, but its application is impeded by a scarcity of donor livers. Therefore, we explored whether transplantation of hepatocyte-like cells (iHeps) differentiated from human induced pluripotent stem cells (iPSCs) could ameliorate inherited liver diseases. iPSCs reprogrammed from human skin fibroblasts were differentiated to iHeps, which were transplanted into livers of uridinediphosphoglucuronate glucuronosyltransferase-1 (UGT1A1)-deficient Gunn rats, a model of Crigler-Najjar syndrome 1 (CN1), where elevated unconjugated bilirubin causes brain injury and death. To promote iHep proliferation, 30% of the recipient liver was X-irradiated before transplantation, and hepatocyte growth factor was expressed. After transplantation, UGT1A1+ iHep clusters constituted 2.5%–7.5% of the preconditioned liver lobe. A decline of serum bilirubin by 30%–60% and biliary excretion of bilirubin glucuronides indicated that transplanted iHeps expressed UGT1A1 activity, a postnatal function of hepatocytes. Therefore, iHeps warrant further exploration as a renewable source of hepatocytes for treating inherited liver diseases. PMID:26074313

  2. 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

  3. Intratracheal transplantation of endothelial progenitor cells attenuates smoking-induced COPD in mice

    PubMed Central

    Shi, Zhihui; Chen, Yan; Cao, Jun; Zeng, Huihui; Yang, Yue; Chen, Ping; Luo, Hong; Peng, Hong; Cai, Shan; Guan, Chaxiang

    2017-01-01

    Background Endothelial progenitor cells (EPCs) might play a protective role in COPD. The aim of this study was to investigate whether intratracheal allogeneic transplantation of bone-marrow-derived EPCs would attenuate the development of smoking-induced COPD in mice. Methods Isolated mononuclear cells from the bone marrow of C57BL/6J mice were cultured in endothelial cell growth medium-2 for 10 days, yielding EPCs. A murine model of COPD was established by passive 90-day exposure of cigarette smoke. On day 30, EPCs or phosphate-buffered saline alone was administered into the trachea. On day 90, EPCs or 30 μL phosphate-buffered saline alone was administered into the trachea, and on day 120, inflammatory cells, antioxidant activity, apoptosis, matrix metalloproteinase (MMP)-2, and MMP-9 were measured. Results After EPC treatment, the lung function of the mice had improved compared with the untreated mice. Mean linear intercept and destructive index were reduced in the EPCs-treated group compared with the untreated group. In addition, the EPCs-treated mice exhibited less antioxidant activity in bronchoalveolar lavage fluid compared with the untreated mice. Moreover, decreased activities of MMP-2, MMP-9, and TUNEL-positive cells in lung tissues were detected in EPCs-treated mice. Conclusion Intratracheal transplantation of EPCs attenuated the development of pulmonary emphysema and lung function disorder probably by alleviating inflammatory infiltration, decelerating apoptosis, inhibiting proteolytic enzyme activity, and improving antioxidant activity. PMID:28360519

  4. Combined treatment with MSC transplantation and neutrophil depletion ameliorates D-GalN/LPS-induced acute liver failure in rats.

    PubMed

    Zhao, Xin; Shi, Xiaolei; Zhang, Zhiheng; Ma, Hucheng; Yuan, Xianwen; Ding, Yitao

    2016-12-01

    The imbalance of immunity is an important pathogenesis of acute liver failure (ALF). Neutrophils are the hallmark of acute inflammation, which have an essential role in immune regulation. Mesenchymal stem cell (MSC) transplantation is a promising therapy in ALF treatment. Recent studies indicated a considerable connection between MSCs and neutrophils in immune regulation. To investigate changes in neutrophils in ALF rats after MSC transplantation, and to explore the therapeutic effect and mechanism of the combined treatment with MSC transplantation and neutrophil depletion in ALF. We employed monotherapy and the combination therapy with MSCs and anti-PMN serum in D-galactosamine (D-GalN)/lipopolysaccharides (LPS)-induced ALF rats. Rats were sacrificed at 6, 12 and 24h, respectively. Blood samples and liver tissues were collected. Hepatic injury, inflammatory cytokines (TNF-α, IL-1β and IL-10), chemokines (CXCL1 and CXCL2), the number and activity of neutrophils and animal survival were assessed at fixed times. MSC transplantation can effectively improve the liver function of ALF rats and reduce the number and activity of neutrophils in both peripheral blood and liver. Compared with MSC transplantation alone, anti-PMN treatment and co-treatment had a better result in diminishing neutrophils. The co-treatment also exhibited a better therapeutical effect in ALF rats compared with monotherapy. In this process, the expressions of inflammatory cytokines in the liver were consistent with liver function. The regulation of the neutrophil-related microenvironment is affected in D-GalN/LPS-induced ALF rats after MSC transplantation. The combined treatment with MSC transplantation and neutrophil depletion may have a better therapeutic effect in ALF rats. Copyright © 2016. Published by Elsevier Masson SAS.

  5. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model.

    PubMed

    Desmarets, Maxime; Cadwell, Chantel M; Peterson, Kenneth R; Neades, Renee; Zimring, James C

    2009-09-10

    When successful, human leukocyte antigen (HLA)-matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex-matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8(+) T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.

  6. Improvement of Carbon Tetrachloride-Induced Acute Hepatic Failure by Transplantation of Induced Pluripotent Stem Cells without Reprogramming Factor c-Myc

    PubMed Central

    Chang, Hua-Ming; Liao, Yi-Wen; Chiang, Chih-Hung; Chen, Yi-Jen; Lai, Ying-Hsiu; Chang, Yuh-Lih; Chen, Hen-Li; Jeng, Shaw-Yeu; Hsieh, Jung-Hung; Peng, Chi-Hsien; Li, Hsin-Yang; Chien, Yueh; Chen, Szu-Yu; Chen, Liang-Kung; Huo, Teh-Ia

    2012-01-01

    The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl4)-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl4-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl4-treated mice. CCl4-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases. PMID:22489170

  7. Seasonal and pollution-induced variations in biomarkers of transplanted mussels within the Beagle Channel.

    PubMed

    Giarratano, Erica; Gil, Mónica N; Malanga, Gabriela

    2011-06-01

    The occurrence of biomarker variations linked to environmental factors makes it difficult to distinguish the effect of pollution. In an attempt to evaluate spatial and seasonal effects of environmental parameters on biomarker responses, mussels Mytilus edulis chilensis coming from an aquaculture farm were transplanted to several points within Ushuaia Bay (Beagle Channel) for 6 weeks in summer and winter. Activities of superoxide dismutase, catalase, glutathione-S-transferase and levels of lipid peroxidation were measured in gills and digestive gland. Cu, Zn, Fe, Cd and Pb concentrations were also assessed. Results indicated a significant effect of seasons on biological responses as well as in metal bioaccumulation showing the influence of natural factors such as dissolved oxygen, temperature and food availability. The interdependence of those environmental factors is important for the homeostasis of thermoconformers, especially regarding their oxidative metabolism and should also be taken into consideration to distinguish natural from pollution-induced variations.

  8. Amlodipine-induced gingival overgrowth in a child after liver transplant

    PubMed Central

    Guollo, André; Vivas, Ana Paula Molina; Lopes, Rodrigo Nascimento; Porta, Gilda

    2016-01-01

    Drug-induced gingival overgrowth (GO) has been associated with phenytoin, cyclosporine, and calcium channel blocker therapies. This study reports the case of an 11-year-old girl who was referred for evaluation of GO, which had occurred over the last 6 months. Her medical history included a liver transplant due to biliary atresia 3 years ago, immunosuppressive therapy, and hypertension, which is why she was started on a daily intake of amlodipine. The intraoral examination showed generalized GO, and the treatment consisted of a gingivectomy. Subsequently, amlodipine was replaced with captopril and oral hygiene instructions. There was no recurrence of GO after 28 months of follow-up. Although GO may be related to the chronic use of amlodipine, such an association is uncommon in pediatrics, and the treatment consists of the replacement of medication combined with a surgical approach and plaque control. PMID:27818959

  9. Bidirectional homeostatic plasticity induced by interneuron cell death and transplantation in vivo.

    PubMed

    Howard, MacKenzie Allen; Rubenstein, John L R; Baraban, Scott C

    2014-01-07

    Chronic changes in excitability and activity can induce homeostatic plasticity. These perturbations may be associated with neurological disorders, particularly those involving loss or dysfunction of GABA interneurons. In distal-less homeobox 1 (Dlx1(-/-)) mice with late-onset interneuron loss and reduced inhibition, we observed both excitatory synaptic silencing and decreased intrinsic neuronal excitability. These homeostatic changes do not fully restore normal circuit function, because synaptic silencing results in enhanced potential for long-term potentiation and abnormal gamma oscillations. Transplanting medial ganglionic eminence interneuron progenitors to introduce new GABAergic interneurons, we demonstrate restoration of hippocampal function. Specifically, miniature excitatory postsynaptic currents, input resistance, hippocampal long-term potentiation, and gamma oscillations are all normalized. Thus, in vivo homeostatic plasticity is a highly dynamic and bidirectional process that responds to changes in inhibition.

  10. Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization.

    PubMed

    Espinosa-Heidmann, Diego G; Malek, Goldis; Mettu, Priyatham S; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K; Hu, Peng; Spiga, Maria-Grazia; Cousins, Scott W

    2013-11-13

    Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow-derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+). Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization.

  11. Bone Marrow Transplantation Transfers Age-Related Susceptibility to Neovascular Remodeling in Murine Laser-Induced Choroidal Neovascularization

    PubMed Central

    Espinosa-Heidmann, Diego G.; Malek, Goldis; Mettu, Priyatham S.; Caicedo, Alejandro; Saloupis, Peter; Gach, Sarah; Dunnon, Askia K.; Hu, Peng; Spiga, Maria-Grazia; Cousins, Scott W.

    2013-01-01

    Purpose. Neovascular remodeling (NVR), the progression of small capillaries into large-caliber arterioles with perivascular fibrosis, represents a major therapeutic challenge in neovascular age-related macular degeneration (AMD). Neovascular remodeling occurs after laser-induced choroidal neovascularization (CNV) in aged but not young mice. Additionally, bone marrow–derived cells, including macrophages, endothelial precursor cells, and mesenchymal precursor cells, contribute to CNV severity. In this study, we investigated the impact of aged bone marrow transplantation (BMT) on the degree of fibrosis, size, and vascular morphology of CNV lesions in a mouse model of laser-induced CNV. Methods. Young (2 months) and old (16 months) mice were transplanted with green fluorescent protein (GFP)-labeled bone marrow isolated from either young or old donors. Laser CNV was induced 1 month following transplant, and eyes were analyzed via choroidal flat mounts and immunohistochemistry 1 month postlaser. The identity of cells infiltrating CNV lesions was determined using specific markers for the labeled transplanted cells (GFP+), macrophages (F4/80+), perivascular mesenchymal-derived cells (smooth muscle actin, SMA+), and endothelial cells (CD31+). Results. Bone marrow transplantation from aged mice transferred susceptibility to NVR into young recipients. Inversely, transplantation of young marrow into old mice prevented NVR, preserving small size and minimal fibrosis. Mice with NVR demonstrated a greater relative contribution of marrow-derived SMA+ perivascular mesenchymal cells as compared to other cells. Conclusions. Our findings indicate that the status of bone marrow is an important determining factor of neovascular severity. Furthermore, we find that perivascular mesenchymal cells, rather than endothelial cells, derived from aged bone marrow may contribute to increased CNV severity in this murine model of experimental neovascularization. PMID:24135751

  12. Substantial early loss of induced pluripotent stem cells following transplantation in myocardial infarction.

    PubMed

    Martens, Andreas; Rojas, Sebastian V; Baraki, Hassina; Rathert, Christian; Schecker, Natalie; Zweigerdt, Robert; Schwanke, Kristin; Rojas-Hernandez, Sara; Martin, Ulrich; Saito, Shunsuke; Schmitto, Jan D; Haverich, Axel; Kutschka, Ingo

    2014-11-01

    The limited success of cardiac stem cell therapy has lately generated discussion regarding its effectiveness. We hypothesized that immediate cell loss after intramyocardial injection significantly obscures the regenerative potential of stem cell therapy. Therefore, our aim was to assess the distribution and quantity of induced pluripotent stem cells after intramyocardial delivery using in vivo bioluminescence analysis. In this context, we wanted to investigate if the injection of different cell concentrations would exert influence on cardiac cell retention. Murine-induced pluripotent stem cells were transfected for luciferase reporter gene expression and transplanted into infarcted myocardium in mice after left anterior descending coronary artery ligation. Cells were delivered constantly in aqueous media (15 μL) in different cell concentrations (group A, n = 10, 5.0 × 10(5) cells; group B, n = 10, 1.0 × 10(6) cells). Grafts were detected using bioluminescence imaging. Organ explants were imaged 10 min after injection to quantify early cardiac retention and cell biodistribution. Bioluminescence imaging showed a massive early displacement from the injection site to the pulmonary circulation, leading to lung accumulation. Mean cell counts of explanted organs in group A were 7.51 × 10(4) ± 4.09 × 10(3) (heart), 6.44 × 10(4) ± 2.48 × 10(3) (left lung), and 8.06 × 10(5) ± 3.61 × 10(3) (right lung). Respective cell counts in group B explants were 1.69 × 10(5) ± 7.69 × 10(4) (heart), 2.11 × 10(5) ± 4.58 × 10(3) (left lung), and 3.25 × 10(5) ± 9.35 × 10(3) (right lung). Applying bioluminescence imaging, we could unveil and quantify massive early cardiac stem cell loss and pulmonary cell accumulation following intramyocardial injection. Increased injection concentrations led to much higher intracardiac cell counts; however, pulmonary biodistribution of transplanted cells still persisted. Therefore, we recommend applying tissue engineering techniques for

  13. 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.

  14. Unique molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation.

    PubMed

    Taner, Timucin; Park, Walter D; Stegall, Mark D

    2017-02-20

    Kidney allografts transplanted simultaneously with liver allografts from the same donor are known to be immunologically privileged. This is especially evident in recipients with high levels of donor-specific anti-HLA antibodies. Here we investigated the mechanisms of liver's protective impact using gene expression in the kidney allograft. Select solitary kidney transplant or simultaneous liver-kidney transplant recipients were retrospectively reviewed and separated into four groups: 16 cross-match negative kidney transplants, 15 cross-match positive kidney transplants, 12 cross-match negative simultaneous liver-kidney transplants, and nine cross-match-positive simultaneous liver-kidney transplants. Surveillance biopsies of cross-match-positive kidney transplants had increased expression of genes associated with donor-specific antigens, inflammation, and endothelial cell activation compared to cross-match-negative kidney transplants. These changes were not found in cross-match-positive simultaneous liver-kidney transplant biopsies when compared to cross-match-negative simultaneous liver-kidney transplants. In addition, simultaneously transplanting a liver markedly increased renal expression of genes associated with tissue integrity/metabolism, regardless of the cross-match status. While the expression of inflammatory gene sets in cross-match-positive simultaneous liver-kidney transplants was not completely reduced to the level of cross-match-negative kidney transplants, the downstream effects of donor-specific anti-HLA antibodies were blocked. Thus, simultaneous liver-kidney transplants can have a profound impact on the kidney allograft, not only by decreasing inflammation and avoiding endothelial cell activation in cross-match-positive recipients, but also by increasing processes associated with tissue integrity/metabolism by unknown mechanisms.

  15. Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in β amyloid-induced neurodegeneration.

    PubMed

    Esposito, Giuseppe; Sarnelli, Giovanni; Capoccia, Elena; Cirillo, Carla; Pesce, Marcella; Lu, Jie; Calì, Gaetano; Cuomo, Rosario; Steardo, Luca

    2016-03-04

    Alzheimer's disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD.

  16. Cardiac allograft acceptance after localized bone marrow transplantation by isolated limb perfusion in nonmyeloablated recipients.

    PubMed

    Askenasy, Nadir; Yolcu, Esma S; Shirwan, Haval; Wang, Zhiliang; Farkas, Daniel L; Yoleuk, Esma S

    2003-01-01

    Donor-specific tolerance to cardiac grafts may be induced by hematopoietic chimerism. This study evaluates the potential of localized bone marrow transplantation (BMT) performed by isolated limb (IL) perfusion to induce tolerance to secondary cardiac grafts without myeloablative conditioning. BALB/c recipients (H2d) preconditioned with lethal and sublethal doses of busulfan were injected i.v. and IL with 10(7) whole bone marrow cells (wBMCs) from B10 donors (H2(b)). Two hours after IL infusion of PKH-labeled wBMCs into myeloablated hosts, there were few labeled cells in the host peripheral blood (p < 0.001 versus i.v.) and femurs of the infused limb contained 57% +/- 7% PKH-labeled blasts (p < 0.001 versus 8% +/- 0.6% after i.v.). Femurs of the noninfused limbs contained 60-70 PKH-labeled blasts (p < 0.001 versus i.v.-BMT) after 2 days and 47% +/- 5% of 0.32 x 10(7) donor cells (p < 0.001 versus 78% +/- 4% of 1.2 x 10(7) donor cells in infused femurs) after 4 weeks. The survival rates of myeloablated hosts were 90% and 80% after i.v. and IL infusion, respectively, and the chimeras had 78%-84% donor peripheral blood cells. In recipients conditioned with 35 mg/g busulfan, the levels of donor chimerism in peripheral blood were 33% +/- 4% and 21% +/- 4% at 3 weeks after i.v.- and IL-BMT, respectively. Transplantation of donor-matched (H2(b)) secondary vascularized hearts in these chimeras after 3 weeks resulted in graft survival for periods exceeding 8 weeks, while third-party (H2(k)) allografts were acutely rejected (p < 0.001 versus H2(b)). These data indicate that IL perfusion is a reliable alternative procedure for establishment of hematopoietic chimerism and donor-specific tolerance without myeloablative conditioning.

  17. Kidney post-transplant monitoring of urinary glycosaminoglycans/proteoglycans and monokine induced by IFN-γ (MIG).

    PubMed

    De Muro, Pierina; Faedda, Rossana; Masala, Antonio; Lepedda, Antonio Junior; Zinellu, Elisabetta; Ciccarese, Milco; Cossu, Maria; Pala, Pier Giorgio; Satta, Rita Pasqualina; Formato, Marilena

    2013-02-01

    Allograft rejection during the first year after renal transplantation can lead to persistent allograft dysfunction and reduced long-term graft survival. Thus, it is important to define early predictors of kidney damage, less invasive than allograft biopsy. Urinary glycosaminoglycan/proteoglycan concentration and distribution, N-acetyl-β-(D)-glucosaminidase (NAG), and monokine induced by IFN-γ (MIG) levels were evaluated in the immediate post-transplant and during a 1-year follow-up. We observed increased urinary levels of MIG, urinary trypsin inhibitor and its degradation products, the lack of urinary heparan sulfate excretion, and the decreased chondroitin sulfate relative content at day 1 post-transplant in most patients who developed complications in the postoperative period. Moreover, urinary MIG levels showed significant correlations with NAG, C-reactive protein, and GFR at day 1 post-transplant. The monitoring of glycosaminoglycan/proteoglycan urinary pattern and the levels of urine MIG could serve as useful markers for predicting possible complications of transplantation, unraveling an early inflammatory state, on whose basis the immunosuppressive therapy could be appropriately modified.

  18. Activation and amplification of c-Ki-ras in a chemically induced transplantable human pancreas carcinoma

    SciTech Connect

    Parsa, I.; Maheshwari, K.K.

    1986-03-01

    Increasing evidence suggests that carcinogenesis is associated with the stepwise activation of oncogenes. The c-Ki-ras oncogene has been demonstrated in several human solid tumors and is shown to be amplified in tumor cell lines. The authors have probed endonuclease cleaved human pancreas (HP) DNAs and DNAs from an in vitro induced transplantable human pancreas carcinoma (HP-T1) for the presence and/or amplification of c-Ki-ras oncogene. The DNAs were cleaved with BamHI, BgIII, EcoRI, HhaI, HinfI, KpnI, PSTI, PvuII, SaII, SstI, TaqI or XbaI and were subjected to Southern blot analysis using /sup 32/P-labelled EcoRI fragments from HiHi3 clone. The hybridization profiles were similar in both DNAs when digested with BamHI, BgIII, HinfI, KpnI, SaII, SstI, or TaqI. The EcoRI cleaved DNAs from HP and HP-T1 revealed two hybridizing fragments of 6.8 and 3.0 kbp. The 3.0 kbp fragments in DNA from HP-T1 showed more than a 100 folds enhancement as compared to that of HP. The 6.8 hybridizing fragments also appeared 10 fold greater in HP-T1 DNA. Similar enhancements were also present in HP-T1 DNA cleaved with PstI and PvuII. Preliminary results from comparison of poly(A)/sup +/RNAs, prepared from total HP and HP-T1 RNAs, by Northern blot analysis using the same probe reflect similar enhancement in RNA from transplantable pancreas carcinoma.

  19. Survival and differentiation of transplanted neural stem cells derived from human induced pluripotent stem cells in a rat stroke model.

    PubMed

    Jensen, Matthew B; Yan, Hongmei; Krishnaney-Davison, Rajeev; Al Sawaf, Abdullah; Zhang, Su-Chun

    2013-05-01

    Although administration of various stem cells has shown promise in stroke models, neural stem cells (NSCs) derived from human induced pluripotent stem cells (iPSCs) have advantages over other cell types. We studied whether these cells could survive, differentiate, and improve stroke recovery in an ischemic stroke model. Human iPSCs were induced in vitro to an early NSC stage. One week after focal cerebral ischemia, 20 rats received cells or vehicle by intracerebral injection. Graft cell fate, infarct volume, and behavioral deficits were assessed. Graft cells were found in 8 of the transplanted rats (80%), with estimated mean graft cell numbers nearly double the amount transplanted 1 month later. Graft cells also expressed markers of NSCs in 5 rats (63%), neurons in all 8 rats (100%), rare astrocytes in 4 rats (50%), and signs of proliferation in 4 rats (50%), but no tumor formation was observed. Stroke volume and behavioral recovery were similar between the groups. To our knowledge, this is the first report of transplantation of NSCs derived from human iPSCs in a stroke model. Human iPSC-derived NSCs survived in the postischemic rat brain and appeared to differentiate, primarily into neurons. This cell transplantation approach for stroke appears to be feasible, but further optimization is needed. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  20. Polyomavirus BK Induces Inflammation via Up-regulation of CXCL10 at Translation Levels in Renal Transplant Patients with Nephropathy.

    PubMed

    Kariminik, Ashraf; Dabiri, Shahriar; Yaghobi, Ramin

    2016-08-01

    Polyomavirus BK-associated nephropathy (BKAN) is an important mechanism for renal losing after kidney transplantation. It seems that Polyomavirus BK can induce nephropathy by direct cell lysis and stimulation of the immune system and induction of inflammation. CXCL10 is a pro-inflammatory cytokine which stimulates the migration and activation of immune cells to the infected sites. Therefore, the aim of the current study was to evaluate the messenger RNA (mRNA) and protein levels of CXCL10 in the Polyomavirus BK-infected and Polyomavirus BK-non-infected post renal transplanted nephropathic patients in comparison to healthy controls. In this cross-sectional study, Polyomavirus BK-infected post renal transplanted nephropathic patients, Polyomavirus BK-non-infected post renal transplanted nephropathic patients, and healthy controls were enrolled to evaluate mRNA and protein levels of CXCL10 by real-time PCR and ELISA techniques, respectively. mRNA levels of CXCL10 were not significantly different among participants, while serum levels of CXCL10 were significantly elevated in the Polyomavirus BK-infected patients when compared to non-infected patients as well as controls and in non-infected patients when compared to healthy controls. Due to the results, it seems that Polyomavirus BK may potentially induce renal losing through stimulation of inflammation via increasing translation of CXCL10, as a pro-inflammatory chemokine.

  1. Ephedra-Treated Donor-Derived Gut Microbiota Transplantation Ameliorates High Fat Diet-Induced Obesity in Rats

    PubMed Central

    Wang, Jing-Hua; Kim, Bong-Soo; Han, Kyungsun; Kim, Hojun

    2017-01-01

    Changes in gut microbiota (GM) are closely associated with metabolic syndrome, obesity, type 2 diabetes and so on. Several medicinal herbs, including Ephedra sinica (Es), have anti-obesity effects that ameliorate metabolic disorders. Therefore, in this study we evaluated whether Es maintains its anti-obesity effect through Es-altered gut microbiota (EsM) transplantation. GM was isolated from cecal contents of Es treated and untreated rats following repeated transplants into obese rats via oral gavage over three weeks. High-fat-diet (HFD)-induced obese rats transplanted with EsM lost significant body weight, epididymal fat, and perirenal fat weight, but no remarkable changes were observed in abdominal fat, liver, cecum weight and food efficiency ratio. In addition, treatment with EsM also significantly lowered the fasting blood glucose, serum insulin level, and insulin resistance index. Meanwhile, EsM transplantation significantly reduced gene expression of proinflammatory cytokines interleukin-1 and monocyte chemotactic protein-1. Rats treated with EsM also showed changed GM composition, especially blautia, roseburia and clostridium, significantly reduced the level of endotoxin and markedly increased the acetic acid in feces. Overall, our results demonstrated that EsM ameliorates HFD-induced obesity and related metabolic disorders, like hyperglycemia and insulin resistance, and is strongly associated with modulating the distribution of GM, enterogenous endotoxin and enteral acetic acid. PMID:28545248

  2. Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice.

    PubMed

    Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A

    1995-08-01

    Hyperglycemia-induced beta-cell dysfunction may be an important component in the pathogenesis of non-insulin-dependent diabetes mellitus. However, most available data in this field were obtained from rodent islets. To investigate the relevance of this hypothesis for human beta-cells in vivo, human pancreatic islets were transplanted under the renal capsule of nude mice. Experimental groups were chosen so that grafted islets were exposed to either hyper- or normoglycemia or combinations of these for 4 or 6 wk. Grafts of normoglycemic recipients responded with an increased insulin release to a glucose stimulus during perfusion, whereas grafts of hyperglycemic recipients failed to respond to glucose. The insulin content of the grafts in the latter groups was only 10% of those observed in controls. Recipients initially hyperglycemic (4 wk), followed by 2 wk of normoglycemia regained a normal graft insulin content, but a decreased insulin response to glucose remained. No ultrastructural signs of beta-cell damage were observed, with the exception of increased glycogen deposits in animals hyperglycemic at the time of killing. It is concluded that prolonged exposure to a diabetic environment induces a long-term secretory defect in human beta-cells, which is not dependent on the size of the islet insulin stores.

  3. Impairment of glucose-induced insulin secretion in human pancreatic islets transplanted to diabetic nude mice.

    PubMed Central

    Jansson, L; Eizirik, D L; Pipeleers, D G; Borg, L A; Hellerström, C; Andersson, A

    1995-01-01

    Hyperglycemia-induced beta-cell dysfunction may be an important component in the pathogenesis of non-insulin-dependent diabetes mellitus. However, most available data in this field were obtained from rodent islets. To investigate the relevance of this hypothesis for human beta-cells in vivo, human pancreatic islets were transplanted under the renal capsule of nude mice. Experimental groups were chosen so that grafted islets were exposed to either hyper- or normoglycemia or combinations of these for 4 or 6 wk. Grafts of normoglycemic recipients responded with an increased insulin release to a glucose stimulus during perfusion, whereas grafts of hyperglycemic recipients failed to respond to glucose. The insulin content of the grafts in the latter groups was only 10% of those observed in controls. Recipients initially hyperglycemic (4 wk), followed by 2 wk of normoglycemia regained a normal graft insulin content, but a decreased insulin response to glucose remained. No ultrastructural signs of beta-cell damage were observed, with the exception of increased glycogen deposits in animals hyperglycemic at the time of killing. It is concluded that prolonged exposure to a diabetic environment induces a long-term secretory defect in human beta-cells, which is not dependent on the size of the islet insulin stores. Images PMID:7635965

  4. Villous atrophy induced by mycophenolate mofetil in renal-transplant patients.

    PubMed

    Kamar, Nassim; Faure, Patrick; Dupuis, Emmanuel; Cointault, Olivier; Joseph-Hein, Karine; Durand, Dominique; Moreau, Jacques; Rostaing, Lionel

    2004-09-01

    Leucopenia and diarrhoea are the main side effects observed after the use of mycophenolate mofetil (MMF) in renal-transplant patients. The mechanism of diarrhoea remains unknown. We report on four cases presenting with severe diarrhoea, which appeared, respectively, at 4, 10, 24, and 66 months after MMF therapy had been started. All patients presented with weight loss and biological signs of malabsorption syndrome. Oesophago-gastroduodenoscopy revealed duodenal villous atrophy, which was confirmed by pathology examination. Anti-endomysium antibodies were negative. In all patients, diarrhoea disappeared within 1 month of MMF withdrawal without a gluten-free diet. A control oesophago-gastroduodenoscopy was performed in one patient 6 months later and was considered normal. None of the patients showed evidence of cytomegalovirus in enterocytes or cytomegalovirus-positive viraemia. In conclusion, villous atrophy induced by MMF might be one of the mechanisms of diarrhoea. It is mandatory to differentiate coeliac disease from MMF-induced villous atrophy because, in the latter case, a gluten-free diet is not required.

  5. Transfusion Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens

    PubMed Central

    Patel, Seema R; Zimring, James C

    2014-01-01

    Traditionally, alloimmunization to transfused blood products has focused exclusively upon recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunological sequelae of alloimmunization have been antibody mediated effects (i.e. hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc.). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection - under reduced intensity conditioning with HLA matched or HLA identical marrow. BMT of this nature is the only existing cure for a series of non-malignant hematological diseases (e.g. sickle cell disease, thalassemias, etc.); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or NK cells. In this case, rejection occurs in the absence of alloantibodies, and would not be detected by existing immune-hematological methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion which current blood bank methodologies are unable to detect. PMID:24090731

  6. Preclinical Studies of Induced Pluripotent Stem Cell-Derived Astrocyte Transplantation in ALS

    DTIC Science & Technology

    2012-10-01

    Pluripotent Stem Cell -Derived Astrocyte Transplantation in ALS PRINCIPAL INVESTIGATOR: Nicholas J. Maragakis, M.D...Pluripotent Stem Cell -Derived Astrocyte Transplantation in ALS 5b. GRANT NUMBER W81XWH-10-1-0520 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...into astrocytes following transplantation. 15. SUBJECT TERMS Stem Cells , iPS cells , astrocytes, familial ALS 16. SECURITY CLASSIFICATION OF

  7. Kidney transplantation at the University of Pennsylvania: 1998-2008.

    PubMed

    Porrett, Paige M; Kamoun, Malek; Parsons, Ron; Bloom, Roy; Goral, Simin; Reese, Peter; Grossman, Robert; Baluarte, Jorge; Bleicher, Melissa; Doyle, Alden; Markmann, James F; Levine, Matt; Barker, Clyde; Olthoff, Kim; Naji, Ali; Shaked, Abraham; Abt, Peter

    2009-01-01

    Kidney transplantation at the University of Pennsylvania has grown substantially over the past 11 years. Although our transplant volume has increased primarily as a consequence of multiorgan transplants as well as the utilization of historically "marginal" allografts, our post-transplantation outcomes remain excellent in both children and adults. We attribute these outcomes to technical improvements in tissue typing and donor-recipient crossmatching, modification of immunosuppression protocols, and rigorous donor and recipient selection. In the next decade, we hope to substantially expand our living donor program and refine our overall donor and recipient selection process such that we maintain excellent post-transplant outcomes in the face of aging and increasingly comorbid donors and recipients. We further predict significant changes in post-transplant management of kidney recipients with respect to immunosuppression regimens. In particular, we anticipate the modulation of immunosuppression regimens in recipients with high titers of donor-specific antibody and the integration of B-cell specific immunosuppression into post-transplant patient care. Only time will tell whether such therapies will 1) improve long-term outcomes, 2) allow us to diminish the degree of non-specific pharmacologic immunosuppression currently in use, 3) or even promote donor-specific tolerance in kidney transplant recipients.

  8. Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice.

    PubMed

    Sun, Liang-Liang; Liu, Tian-Jin; Li, Limei; Tang, Wei; Zou, Jun-Jie; Chen, Xiang-Fang; Zheng, Jiao-Yang; Jiang, Bei-Ge; Shi, Yong-Quan

    2017-04-01

    Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting β-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, β-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of β-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing β-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes.

  9. Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice

    PubMed Central

    Sun, Liang-Liang; Liu, Tian-Jin; Li, Limei; Tang, Wei; Zou, Jun-Jie; Chen, Xiang-Fang; Zheng, Jiao-Yang; Jiang, Bei-Ge; Shi, Yong-Quan

    2017-01-01

    Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting β-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, β-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of β-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing β-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes. PMID:28290605

  10. Early Acute Antibody-Mediated Rejection of a Negative Flow Crossmatch 3rd Kidney Transplant with Exclusive Disparity at HLA-DP

    PubMed Central

    Mierzejewska, Beata; Schroder, Paul M.; Baum, Caitlin E.; Blair, Annette; Smith, Connie; Duquesnoy, Rene J.; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A.; Stepkowski, Stanislaw

    2014-01-01

    Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA. PMID:24755353

  11. Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP.

    PubMed

    Mierzejewska, Beata; Schroder, Paul M; Baum, Caitlin E; Blair, Annette; Smith, Connie; Duquesnoy, Rene J; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A; Stepkowski, Stanislaw

    2014-08-01

    Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.

  12. Mechanisms of defective glucose-induced insulin release in human pancreatic islets transplanted to diabetic nude mice.

    PubMed

    Eizirik, D L; Jansson, L; Flodström, M; Hellerström, C; Andersson, A

    1997-08-01

    We have previously observed that human islets, transplanted under the kidney capsule of hyperglycemic nude mice, show a longlasting impairment in glucose-induced insulin release. To investigate the cause(s) of this phenomenon, we transplanted human islets into normoglycemic or alloxan-diabetic nude mice for a 4- to 6-week period. In a third experimental group, aimed at evaluating reversibility of hyperglycemia effects, diabetic nude mice bearing a human islet graft were cured by a second intrasplenic transplant of mouse islets, and the human islets were exposed to a further 2 weeks of normoglycemia. Four to 6 weeks of hyperglycemia induced a severe impairment of glucose- and arginine-induced insulin release, as demonstrated by perfusion of the graft-bearing kidney. This defective release was not restored by a subsequent 2-week period of normoglycemia, and it was accompanied by normal (pro)insulin biosynthesis, glucose oxidation, and expression of insulin messenger RNA. Taken together with our previous study, these observations indicate that impaired glucose metabolism, depletion of insulin messenger RNA, decreased (pro)insulin biosynthesis, increased glycogen accumulation, and depletion of insulin reserves cannot explain the deleterious effects of the diabetic state on human islet insulin release. This, and the similar inhibition of glucose- and arginine-induced insulin release, suggest that prolonged hyperglycemia may exert its deleterious effect on insulin release at a step distal to closure of ATP-sensitive K-channels.

  13. Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants

    PubMed Central

    Peranteau, William H.; Hayashi, Satoshi; Abdulmalik, Osheiza; Chen, Qiukan; Merchant, Aziz; Asakura, Toshio

    2015-01-01

    Sickle cell disease (SCD) and thalassemias (Thal) are common congenital disorders, which can be diagnosed early in gestation and result in significant morbidity and mortality. Hematopoietic stem cell transplantation, the only curative therapy for SCD and Thal, is limited by the absence of matched donors and treatment-related toxicities. In utero hematopoietic stem cell transplantation (IUHCT) is a novel nonmyeloablative transplant approach that takes advantage of the immunologic immaturity and normal developmental properties of the fetus to achieve mixed allogeneic chimerism and donor-specific tolerance (DST). We hypothesized that a combined strategy of IUHCT to induce DST, followed by postnatal nonmyeloablative same donor “booster” bone marrow (BM) transplants in murine models of SCD and Thal would result in high levels of allogeneic engraftment and donor hemoglobin (Hb) expression with subsequent phenotypic correction of SCD and Thal. Our results show that: (1) IUHCT is associated with DST and low levels of allogeneic engraftment in the murine SCD and Thal models; (2) low-level chimerism following IUHCT can be enhanced to high-level chimerism and near complete Hb replacement with normal donor Hb with this postnatal “boosting” strategy; and (3) high-level chimerism following IUHCT and postnatal “boosting” results in phenotypic correction in the murine Thal and SCD models. This study supports the potential of IUHCT, combined with a postnatal nonmyelablative “boosting” strategy, to cure Thal and SCD without the toxic conditioning currently required for postnatal transplant regimens while expanding the eligible transplant patient population due to the lack of a restricted donor pool. PMID:26124498

  14. Correction of murine hemoglobinopathies by prenatal tolerance induction and postnatal nonmyeloablative allogeneic BM transplants.

    PubMed

    Peranteau, William H; Hayashi, Satoshi; Abdulmalik, Osheiza; Chen, Qiukan; Merchant, Aziz; Asakura, Toshio; Flake, Alan W

    2015-09-03

    Sickle cell disease (SCD) and thalassemias (Thal) are common congenital disorders, which can be diagnosed early in gestation and result in significant morbidity and mortality. Hematopoietic stem cell transplantation, the only curative therapy for SCD and Thal, is limited by the absence of matched donors and treatment-related toxicities. In utero hematopoietic stem cell transplantation (IUHCT) is a novel nonmyeloablative transplant approach that takes advantage of the immunologic immaturity and normal developmental properties of the fetus to achieve mixed allogeneic chimerism and donor-specific tolerance (DST). We hypothesized that a combined strategy of IUHCT to induce DST, followed by postnatal nonmyeloablative same donor "booster" bone marrow (BM) transplants in murine models of SCD and Thal would result in high levels of allogeneic engraftment and donor hemoglobin (Hb) expression with subsequent phenotypic correction of SCD and Thal. Our results show that: (1) IUHCT is associated with DST and low levels of allogeneic engraftment in the murine SCD and Thal models; (2) low-level chimerism following IUHCT can be enhanced to high-level chimerism and near complete Hb replacement with normal donor Hb with this postnatal "boosting" strategy; and (3) high-level chimerism following IUHCT and postnatal "boosting" results in phenotypic correction in the murine Thal and SCD models. This study supports the potential of IUHCT, combined with a postnatal nonmyelablative "boosting" strategy, to cure Thal and SCD without the toxic conditioning currently required for postnatal transplant regimens while expanding the eligible transplant patient population due to the lack of a restricted donor pool.

  15. Detection of antibodies against HLA-C epitopes in patients with rejected kidney transplants.

    PubMed

    Duquesnoy, Rene J; Marrari, Marilyn

    2011-04-15

    Although HLA-C matching is not considered in kidney transplantation, several reports have shown that anti-HLA-C antibodies are associated with rejection and graft failure. DNA-based typing methods can now accurately determine HLA-C compatibility and sensitive assays such as Luminex with single alleles can identify HLA-C antibodies. HLA-C displays considerable amino acid polymorphism that can be translated into a structurally defined epitope repertoire. We have analyzed post-allograft nephrectomy sera from 45 HLA-C mismatched cases submitted by 15 laboratories worldwide participating in the 15th International Histocompatibility Workshop. All of them had HLA class I antibodies detected by a Luminex-based solid phase method using single-allele beads. This study addressed the determination of antibodies against donor HLA-C mismatches. Analysis of antibody reactivity patterns was performed using HLAMatchmaker, a structurally based matching program that considers 56 HLA-C eplets to define antibody-reactive epitopes. Many eplets shared by groups of HLA-C antigens, whereas others are also shared with HLA-A and/or HLA-B antigens. Twenty-seven patients (60%) had donor-specific HLA-C antibodies, significantly less than the donor-specific antibodies induced by HLA-A and HLA-B mismatches. HLA-C antibody responses correlated with the eplet loads of the HLA-C mismatches. There were 352 instances whereby a donor HLA-C eplet was mismatched and for 84 (24%) of them there was antibody reactivity with a particular eplet (69 instances) or an eplet pair (15 instances). The latter generally consisted of mismatched eplets paired with self-eplets shared between the immunizing HLA-C alleles and HLA alleles of the patient. Several HLA-C eplets exhibited a relatively high immunogenicity as evidenced by their frequencies of specific antibodies. These findings demonstrate the importance of HLA-C mismatching in humoral sensitization and that HLA-C epitopes can induce specific antibodies. They

  16. Intestinal Transplant Inflammation: the Third Inflammatory Bowel Disease.

    PubMed

    Kroemer, Alexander; Cosentino, Christopher; Kaiser, Jason; Matsumoto, Cal S; Fishbein, Thomas M

    2016-11-01

    Intestinal transplantation is the most immunologically complex of all abdominal organ transplants. Understanding the role both humoral and innate and adaptive cellular immunity play in intestinal transplantation is critical to improving outcomes and increasing indications for patients suffering from intestinal failure. Recent findings highlighting the impact of donor-specific antibodies on intestinal allografts, the role of NOD2 as a key regulator of intestinal immunity, the protective effects of innate lymphoid cells, and the role of Th17 in acute cellular rejection are reviewed here.

  17. Transplantation of neuronal cells induced from human mesenchymal stem cells improves neurological functions after stroke without cell fusion.

    PubMed

    Xu, Haiyan; Miki, Kazunori; Ishibashi, Satoru; Inoue, Jun; Sun, Liyuan; Endo, Shu; Sekiya, Ichiro; Muneta, Takeshi; Inazawa, Joji; Dezawa, Mari; Mizusawa, Hidehiro

    2010-12-01

    The options for treating stroke are limited, but stem cells hold promise as a therapy because of their multipotency. Neuronal cells derived from mesenchymal stem cells (MSC) were reported to have more therapeutic effect than MSCs. For elucidating the therapeutic mechanism of neuronal cells, here we generated a model of focal cerebral infarction by performing left common carotid artery occlusion in adult gerbils. We transfected human trabecular bone-derived MSCs (hMSCs) with the Notch intracellular domain to induce their differentiation into neuronal cells (hN-MSCs). These cells were stereotaxically transplanted into the local ischemic hemisphere 4 days after the occlusion. Behavioral analyses were conducted 28 days after transplantation, and then fluorescence in situ hybridization (FISH) and a histological evaluation were performed. Histologically, transplanted cells were distributed around the periinfarct region, and approximately 8.5% and 4.2% of hN-MSCs and hMSCs survived, respectively; 53.2% ± 9.6% of hN-MSCs were microtubule-associated protein 2(+) (MAP-2(+) ) and extended neurites, whereas only 0.9% ± 0.3% of hMSCs were MAP-2(+) . In FISH, human nucleus-specific signals were detected in both hN-MSCs and hMSCs grafted brains, but no transplanted cell had a merged gerbil-specific nuclear signals. hN-MSC-transplanted animals showed significantly better recovery than animals given control vehicle in the T-maze, bilateral asymmetry, and open field tests. These findings suggested that hN-MSCs have greater therapeutic potential than hMSCs for stroke and that cell fusion does not primarily contribute to the therapeutic mechanism of MSC transplantation. Copyright © 2010 Wiley-Liss, Inc.

  18. Cord blood transplantation in Japan.

    PubMed

    Uchida, Naoyuki

    2016-05-01

    Cord blood transplantation (CBT) has increasingly been used in Japan and the annual number of CBT now exceeds 1,200. The cumulative number of CBT reached 12,853 in 2015, accounting for almost 1/3 of total CBT performed worldwide. It is true that smaller body size and lower costs, as compared to western countries, have been advantages for Japanese people in using CB as graft alternative. In addition, several novel findings regarding serious issues following CBT have been obtained, which further enhanced the use of CB. First, several mechanisms of engraftment failure following CBT other than cell dose have been reported, such as the presence of donor-specific anti-HLA antibodies or the development of hemophagocytic syndrome. Second, unique profiles of infectious complications following CBT have been reported, such as higher incidences of early bacterial infections and HHV-6 encephalitis, as compared to those following bone marrow (BM)/peripheral blood (PB) transplants. Third, the incidence of disease relapse was comparable to those following BM/PB transplants. Novel pre-transplant conditioning regimens using intravenous busulfan have been investigated with promising results being obtained to date. A recent analysis of Japanese transplant registry data revealed similar survival following CBT to HLA-matched unrelated BM/PB transplants.

  19. Alveolar recruitment prevents rapid-reperfusion-induced injury of lung transplants.

    PubMed

    DeCampos, K N; Keshavjee, S; Slutsky, A S; Liu, M

    1999-11-01

    Physical factors play an important role in ischemia-reperfusion-induced injury of lung transplants. For example, rapid restoration of reperfusion resulted in severe pulmonary edema and deterioration of pulmonary function of lung explants in an ex vivo reperfusion system. This type of injury can be prevented by a stepwise increase in the perfusion flow rate, or by adding prostaglandin E1 (PGE1) to the blood perfusate during the first 10 minutes. However, the mechanisms of these protective effects are unknown. We noted a dramatic decrease in airway pressure rather than pulmonary arterial pressure in these studies, suggesting that lung recruitment may be an important factor in minimizing injury. In the present study, we examined the importance of alveolar recruitment in preventing rapid-reperfusion-induced lung injury. Rat lungs were flushed preserved with low potassium dextran solution for 12 hours at 4 degrees C. Lung explants were randomly divided into three groups: 1) untreated control; 2) lungs inflated to total lung capacity for 2 minutes; and 3) lungs ventilated for 10 minutes prior to reperfusion. Postpreservation lung function was assessed in an isolated rat lung reperfusion model. Rapid initiation of reperfusion led to severe pulmonary edema and significant pulmonary dysfunction. In inflation or ventilation groups, the injury was significantly attenuated. The PaO2 and shunt fractions in these lungs were comparable to normal lungs. A significant drop in airway pressure was observed in these two groups and the lung compliance in the inflation group was significantly better than other two groups. These results suggest that overcoming alveolar collapse with inflation or ventilation, may protect the lung from mechanical-stress-induced injury during reperfusion.

  20. Luminex and antibody detection in kidney transplantation.

    PubMed

    Picascia, Antonietta; Infante, Teresa; Napoli, Claudio

    2012-06-01

    Preformed anti-human leukocyte antigen (HLA) antibodies have a negative effect on kidney transplantation outcome with an increased rejection rate and reduction in survival. Posttransplantation production of donor-specific anti-HLA antibodies is indicative of an active immune response and risk of transplantation rejection. For many years the primary technique for anti-HLA antibody detection was complement-dependent cytotoxicity (CDC), which has been integrated by solid-phase assays as HLA antigen-coated bead methods (Luminex). This new technological approach has allowed identification of anti-HLA antibodies, not detectable using conventional CDC method, in patients awaiting kidney transplantation. Moreover, use of Luminex technology has enabled better definition of acceptable or unacceptable antigens favoring transplantation in highly immunized patients. However, there are still many unresolved issues, including the clinical relevance of antibodies detected with this system.

  1. Parvovirus B 19 (PVB19) induced pure red cell aplasia (PRCA) in immunocompromised patient after liver transplantation.

    PubMed

    Mrzljak, Anna; Kardum-Skelin, Ika; Cvrlje, Vesna Colić; Kanizaj, Tajana Filipec; Sustercić, Dunja; Gustin, Denis; Kocman, Branislav

    2010-03-01

    Presented here is a case of human parvovirus B19 (PVB19) induced pure red-cell aplasia (PRCA) in immunocompromised patient after orthotopic liver transplantation (OLT). PVB19 is a small, single-stranded DNA whose target cell is the erythroid progenitor in bone marrow. Manifestations of PVB19 infection vary with the immunologic status of the patient, ranging from asymptomatic to severe infections and PRCA. Post-transplant PRCA is induced either by immunosuppressive agents or PVB19. In the presented case, bone marrow aspiration characterized by the absence of mature erythroid precursors and detection of PVB19 DNA in blood led to treatment with high-dose intravenous human immunoglobulins (IVIG) and subsequent recovery of erythropoiesis. Due to insufficient antibody response in immunocompromised patients, suppression of the PVB19 infection is delayed and repetitive treatments may be administrated in attempt of reversing PRCA.

  2. Transplantation of placenta-derived mesenchymal stem cell-induced neural stem cells to treat spinal cord injury

    PubMed Central

    Li, Zhi; Zhao, Wei; Liu, Wei; Zhou, Ye; Jia, Jingqiao; Yang, Lifeng

    2014-01-01

    Because of their strong proliferative capacity and multi-potency, placenta-derived mesenchymal stem cells have gained interest as a cell source in the field of nerve damage repair. In the present study, human placenta-derived mesenchymal stem cells were induced to differentiate into neural stem cells, which were then transplanted into the spinal cord after local spinal cord injury in rats. The motor functional recovery and pathological changes in the injured spinal cord were observed for 3 successive weeks. The results showed that human placenta-derived mesenchymal stem cells can differentiate into neuron-like cells and that induced neural stem cells contribute to the restoration of injured spinal cord without causing transplant rejection. Thus, these cells promote the recovery of motor and sensory functions in a rat model of spinal cord injury. Therefore, human placenta-derived mesenchymal stem cells may be useful as seed cells during the repair of spinal cord injury. PMID:25657742

  3. Unraveling the Role of Allo-Antibodies and Transplant Injury

    PubMed Central

    Matsuda, Yoshiko; Sarwal, Minnie M.

    2016-01-01

    Alloimmunity driving rejection in the context of solid organ transplantation can be grossly divided into mechanisms predominantly driven by either T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), though the co-existence of both types of rejections can be seen in a variable number of sampled grafts. Acute TCMR can generally be well controlled by the establishment of effective immunosuppression (1, 2). Acute ABMR is a low frequency finding in the current era of blood group and HLA donor/recipient matching and the avoidance of engraftment in the context of high-titer, preformed donor-specific antibodies. However, chronic ABMR remains a major complication resulting in the untimely loss of transplanted organs (3–10). The close relationship between donor-specific antibodies and ABMR has been revealed by the highly sensitive detection of human leukocyte antigen (HLA) antibodies (7, 11–15). Injury to transplanted organs by activation of humoral immune reaction in the context of HLA identical transplants and the absence of donor specific antibodies (17–24), strongly suggest the participation of non-HLA (nHLA) antibodies in ABMR (25). In this review, we discuss the genesis of ABMR in the context of HLA and nHLA antibodies and summarize strategies for ABMR management. PMID:27818660

  4. Transplantation of Embryonic and Induced Pluripotent Stem Cell-Derived 3D Retinal Sheets into Retinal Degenerative Mice

    PubMed Central

    Assawachananont, Juthaporn; Mandai, Michiko; Okamoto, Satoshi; Yamada, Chikako; Eiraku, Mototsugu; Yonemura, Shigenobu; Sasai, Yoshiki; Takahashi, Masayo

    2014-01-01

    Summary In this article, we show that mouse embryonic stem cell- or induced pluripotent stem cell-derived 3D retinal tissue developed a structured outer nuclear layer (ONL) with complete inner and outer segments even in an advanced retinal degeneration model (rd1) that lacked ONL. We also observed host-graft synaptic connections by immunohistochemistry. This study provides a “proof of concept” for retinal sheet transplantation therapy for advanced retinal degenerative diseases. PMID:24936453

  5. ELISA-Based Crossmatching Allowing the Detection of Emerging Donor-Specific Anti-HLA Antibodies through the Use of Stored Donors' Cell Lysates

    PubMed Central

    Schlaf, G.; Stöhr, K.; Rothhoff, A.; Altermann, W.

    2015-01-01

    About forty years ago the complement-dependent crossmatch assay (CDC-CM) was developed as standard procedure in order to select recipients without donor-specific antibodies directed against human leukocyte antigens of their given donors since the negative outcome of pretransplant crossmatching represents one of the most important requirements for a successful kidney graft survival. However, as a functional assay the CDC-CM strongly depends on the availability of donors' isolated lymphocytes and in particular on their vitality highly limiting its applicability for recipients treated with special drugs and therapeutic antibodies or suffering from underlying autoimmune diseases. In the great majority of these cases ELISA-based crossmatching has been demonstrated to be an adequate alternative procedure nevertheless leading to valid results. With these case reports we show for the first time that ELISA-based crossmatching is suitable to demonstrate the upcoming donor-specific anti-HLA antibodies as a consequence of allografting using deep-frozen deceased donor's material such as blood or spleen detergent lysate. Thus, this ELISA-based procedure first provides the option to routinely perform crossmatching using stored material of deceased donors in order to substitute or at least to complement virtual crossmatching, that is, the comparison of the recipients' anti-HLA antibody specificities with the donors' historically identified HLA types. PMID:26634169

  6. Zhichan decoction induces differentiation of dopaminergic neurons in Parkinson's disease rats after neural stem cell transplantation

    PubMed Central

    Shi, Huifen; Song, Jie; Yang, Xuming

    2014-01-01

    The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson's disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite (dihydroxyphenylacetic acid and homovanillic acid) content in the midbrain of Parkinson's disease rats was increased after neural stem cell transplantation + Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation + Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson's disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons. PMID:25206914

  7. Immune response to uv-induced tumors: transplantation immunity and lymphocyte populations exhibiting anti-tumor activity

    SciTech Connect

    Streeter, P.R.

    1985-01-01

    Ultraviolet light-induced murine skin tumors were analyzed for their ability to induce tumor-specific and cross-protective transplantation immunity in immunocompetent syngeneic mice. These studies revealed that progressor UV-tumors, like regressor UV-tumors, possess tumor-specific transplantation antigens. Cross-protective transplantation immunity to UV-tumors, however, was associated with sensitization to the serum used to culture the tumor lines rather than to cross-reactive or common determinants on UV-tumors. An analysis of the cytolytic activity of lymphocytes from the spleens of mice immunized with either regressor or progressor UV-tumors revealed a striking difference between the two immune splenocyte populations. From regressor tumor-immune animals, cytolytic T (Tc) lymphocytes with specificity for the immunizing tumor were found. However, the analysis of splenic lymphocytes from progressor tumor immune animals revealed no such effector cells. To more effectively examine those lymphocytes exhibiting cytolytic activity in vitro, T lymphocyte cloning technology was used as a means of isolating homogeneous lymphocyte populations with the effector activities described above. The mechanisms where NK cells and other nonspecific effector cells could be induced in tumor-immune animals are discussed in the context of class II restricted immune responses.

  8. Liver transplant

    MedlinePlus

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  9. Defining the optimal window for cranial transplantation of human induced pluripotent stem cell-derived cells to ameliorate radiation-induced cognitive impairment.

    PubMed

    Acharya, Munjal M; Martirosian, Vahan; Christie, Lori-Ann; Riparip, Lara; Strnadel, Jan; Parihar, Vipan K; Limoli, Charles L

    2015-01-01

    Past preclinical studies have demonstrated the capability of using human stem cell transplantation in the irradiated brain to ameliorate radiation-induced cognitive dysfunction. Intrahippocampal transplantation of human embryonic stem cells and human neural stem cells (hNSCs) was found to functionally restore cognition in rats 1 and 4 months after cranial irradiation. To optimize the potential therapeutic benefits of human stem cell transplantation, we have further defined optimal transplantation windows for maximizing cognitive benefits after irradiation and used induced pluripotent stem cell-derived hNSCs (iPSC-hNSCs) that may eventually help minimize graft rejection in the host brain. For these studies, animals given an acute head-only dose of 10 Gy were grafted with iPSC-hNSCs at 2 days, 2 weeks, or 4 weeks following irradiation. Animals receiving stem cell grafts showed improved hippocampal spatial memory and contextual fear-conditioning performance compared with irradiated sham-surgery controls when analyzed 1 month after transplantation surgery. Importantly, superior performance was evident when stem cell grafting was delayed by 4 weeks following irradiation compared with animals grafted at earlier times. Analysis of the 4-week cohort showed that the surviving grafted cells migrated throughout the CA1 and CA3 subfields of the host hippocampus and differentiated into neuronal (∼39%) and astroglial (∼14%) subtypes. Furthermore, radiation-induced inflammation was significantly attenuated across multiple hippocampal subfields in animals receiving iPSC-hNSCs at 4 weeks after irradiation. These studies expand our prior findings to demonstrate that protracted stem cell grafting provides improved cognitive benefits following irradiation that are associated with reduced neuroinflammation.

  10. Inhibition of inducible nitric oxide synthase prevents graft injury after transplantation of livers from rats after cardiac death.

    PubMed

    Shi, Yanjun; Rehman, Hasibur; Wright, Gary L; Zhong, Zhi

    2010-11-01

    This study investigated the roles of inducible nitric oxide synthase (iNOS) in the failure of rat liver grafts from cardiac death donors (GCDD). Livers were explanted after 30-minute aorta clamping and implanted after 4-hour storage in University of Wisconsin solution. The iNOS expression increased slightly in grafts from non-cardiac death donors (GNCDD) but markedly in GCDD. Serum nitrite and nitrate and hepatic 3-nitrotyrosine adducts, indicators of NO and peroxynitrite production, respectively, were substantially higher after transplantation of GCDD than GNCDD. Production of reactive nitrogen species (RNS) was largely blocked by 1400W (N-[1-naphthyl]ethylenediamine dihydrochloride; 5 μM), a specific iNOS inhibitor. Alanine aminotransferase release, bilirubin, necrosis, and apoptosis were 6.4-fold, 6.5-fold, 2.3-fold, and 2.7-fold higher, respectively, after transplantation of GCDD than GNCDD. The inhibitor 1400W effectively blocked these alterations and also increased survival of GCDD to 80% from 33%. Increased RNS production and failure of GCDD were associated with activation of c-Jun-N-terminal kinase (JNK), an effect that was blocked by inhibition of iNOS. Inhibition of JNK also improved the outcome after transplantation of GCDD. Together, the data indicate that iNOS increases substantially in GCDD, leading to RNS overproduction, JNK activation, and more severe graft injury. Inhibitors of iNOS are suggested as effective therapies to improve the outcome after transplantation of GCDD.

  11. Genetic disassociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice.

    PubMed

    Pearson, Todd; Markees, Thomas G; Serreze, David V; Pierce, Melissa A; Marron, Michele P; Wicker, Linda S; Peterson, Laurence B; Shultz, Leonard D; Mordes, John P; Rossini, Aldo A; Greiner, Dale L

    2003-07-01

    Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD x C57BL/6)F(1) mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F(1) mice shared the dendritic cell maturation defects and abnormal CD4(+) T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

  12. Neonatal testicular cell transplantation restores murine spermatogenesis damaged in the course of herpes simplex virus-induced orchitis.

    PubMed

    Malolina, Ekaterina A; Kulibin, Andrey Yu; Kushch, Alla A

    2016-04-01

    Genital tract infection and inflammation may affect male fertility, causing germ and Sertoli cell loss. We determined if testicular cell transplantation is effective at repairing testicular injury induced by herpes simplex virus (HSV) orchitis. ROSA26 mice were used as donors and the recipients were C57BL/6 mice after HSV testicular inoculation; some of the recipients were treated with the antiviral drug acyclovir (ACV). ACV reduced the amount of HSV antigen in testes on Day 3 after transplantation and enhanced the efficacy of transplantation at Day 30. In recipient testes, donor Sertoli cells formed new seminiferous tubules; significantly more new tubules were observed in the testes of ACV-treated mice compared with mice not treated with ACV (17.8% vs 3.6%). Over half (50.4%) of new tubules in ACV-treated testes contained germ cells and round spermatids were detected in 14.2% of new tubules compared with 15.9% and 5.3% in testes not treated with ACV, respectively. At Day 150 the seminiferous epithelium was completely recovered in some donor tubules and elongated spermatids were observed inside it. Thus, our findings reveal the effectiveness of the combination of antiviral therapy with neonatal testis-cell transplantation for the restoration of spermatogenesis damaged by viral infection.

  13. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model

    PubMed Central

    Jaramillo-Merchán, J; Jones, J; Ivorra, J L; Pastor, D; Viso-León, M C; Armengól, J A; Moltó, M D; Geijo-Barrientos, E; Martínez, S

    2013-01-01

    Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft. PMID:23990019

  14. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model.

    PubMed

    Jaramillo-Merchán, J; Jones, J; Ivorra, J L; Pastor, D; Viso-León, M C; Armengól, J A; Moltó, M D; Geijo-Barrientos, E; Martínez, S

    2013-08-29

    Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft.

  15. Polysaccharides from the peels of Citrus aurantifolia induce apoptosis in transplanted H22 cells in mice.

    PubMed

    Zhao, Yana; Sun, Hongyan; Ma, Ling; Liu, Anjun

    2017-08-01

    In this study, an acidic polysaccharide (CAs) was extracted and purified from the peels of Citrus aurantifolia by Sephadex G-150. HPGPC showed the molecular weight of CAs was about 7.94×10(6)Da. Ion chromatography (IC) analysis showed CAs was mainly composed of rhamnose (Rha), arabinose (Ara), galactose (Gal), glucose (Glu), mannose (Man) and galacturonic acid (GalA), with the molar ratio of 0.67: 7.67: 10.83: 3.83: 4.00: 1.00. (1)H and (13)C NMR spectra of CAs also identified the presence of five kinds of monosaccharides and galacturonic acid. Moreover, the antitumor activity of CAs was evaluated in mice transplanted H22 hepatoma cells. It was shown that CAs dose-dependently suppressed tumor cells growth with few toxic effects on host. Further investigations revealed that CAs increased the levels of tumor infiltrating CD8(+) T lymphocytes, blocked tumor cell cycle in S phase, down-regulated anti-apoptotic protein Bcl-xL and Mcl-1 expression, and led to the activation of caspase 3. These results suggested that CAs had capacity of inducing tumor cells apoptosis in vivo, and it supported considering CAs as an adjuvant reagent in hepatocellular carcinoma treatment. Copyright © 2017. Published by Elsevier B.V.

  16. Extent of pre-operative L-DOPA-induced dyskinesia predicts the severity of graft-induced dyskinesia after fetal dopamine cell transplantation.

    PubMed

    García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

    2011-12-01

    Graft-induced dyskinesia has emerged as a problematic side effect after transplantation of fetal dopamine cells into the striatum of patients with Parkinson's disease. These adverse effects of dystonic and choreatiform hyperkinesias that persisted even after withdrawal of L-DOPA medication are not yet fully understood, which poses a main obstacle for the re-initiation of neural transplantation in Parkinson's disease. The severity of pre-operative L-DOPA-induced dyskinesia has been proposed as one of several parameters influencing the development of graft-induced dyskinesia. We have therefore characterized graft-induced dyskinesia in the rat model of Parkinson's disease in animals with either mild or severe pre-operative L-DOPA-induced dyskinesia. We show that animals with intrastriatal grafts of fetal dopamine cells and severe pre-operative L-DOPA-induced dyskinesia will reduce their L-DOPA-induced dyskinesia scores by more than 75% but at the same time develop graft-induced dyskinesia of intermediate to strong severity. In contrast, animals with dopamine grafts of similar size but only mild pre-operative L-DOPA-induced dyskinesia also developed graft-induced dyskinesia but this was very mild and of intermediate severity only in a single animal. Severity of pre-operative L-DOPA-induced dyskinesia was correlated with the severity of graft-induced dyskinesia. Our data suggest that patients with no or only mild L-DOPA-induced dyskinesia may carry a lower risk for the development of graft-induced dyskinesia and therefore are better candidates to receive intracerebral grafts of fetal dopamine cells as compared to patients with more pronounced L-DOPA-induced dyskinesia.

  17. Photoreceptor transplantation in inherited and environmentally induced retinal degeneration: anatomy, immunohistochemistry and function.

    PubMed

    Silverman, M S; Hughes, S E

    1989-01-01

    In conclusion, we have shown that photoreceptors can be transplanted to retina in which the host's photoreceptors are lost by environmental (constant light) or inherited deficits. Furthermore transplanted photoreceptor cells maintain basic characteristics of normal photoreceptor cells by producing opsin and maintaining an intercellular organization and apposition to the host retina that is similar to that seen in the normal outer nuclear layer. To accomplish this we have devised a method to isolate the intact photoreceptor layer. This is significant because it will be necessary to maintain tight matrix organization if coherent vision is to be restored to the retina compromised by the loss of photoreceptors. We have further developed a surgical approach which minimizes trauma to the eye and allows controlled positioning of sheets of transplanted photoreceptors to their homotopic location within the eye. In addition these methods for transplantation and isolation of photoreceptors could be utilized to prepare and transplant other retinal layers so that selected populations of retinal cells can be used in other neurobiological investigations. Photoreceptors can be transplanted when developing or when mature. Not only can mature rat photoreceptors can be transplanted, but we have shown that mature photoreceptors from human donors can be transplanted as well. This is significantly different from neurons which must be immature in order to be transplanted. At present the reason for this difference is not known but has obvious importance for retinal and neural transplantation research in general. Finally, we have shown that transplanted photoreceptors activate the host's dystrophic retina in a light dependent manner that closely resembles the activation pattern seen in normal retina. This finding taken together with our results showing that human photoreceptors can be transplanted presents the possibility that some forms of human blindness might eventually be ameliorated

  18. Induction of antinuclear antibodies by de novo autoimmune hepatitis regulates alloimmune responses in rat liver transplantation.

    PubMed

    Nakano, Toshiaki; Goto, Shigeru; Lai, Chia-Yun; Hsu, Li-Wen; Tseng, Hui-Peng; Chen, Kuang-Den; Chiu, King-Wah; Wang, Chih-Chi; Cheng, Yu-Fan; Chen, Chao-Long

    2013-01-01

    Concanavalin A (Con A) is a lectin originating from the jack-bean and well known for its ability to stimulate T cells and induce autoimmune hepatitis. We previously demonstrated the induction of immunosuppressive antinuclear autoantibody in the course of Con A-induced transient autoimmune hepatitis. This study aimed to clarify the effects of Con A-induced hepatitis on liver allograft rejection and acceptance. In this study, we observed the unique phenomenon that the induction of transient de novo autoimmune hepatitis by Con A injection paradoxically overcomes the rejection without any immunosuppressive drug and exhibits significantly prolonged survival after orthotopic liver transplantation (OLT). Significantly increased titers of anti-nuclear Abs against histone H1 and high-mobility group box 1 (HMGB1) and reduced donor specific alloantibody response were observed in Con A-injected recipients. Induction of Foxp3 and IL-10 in OLT livers of Con A-injected recipients suggested the involvement of regulatory T cells in this unique phenomenon. Our present data suggest the significance of autoimmune responses against nuclear histone H1 and HMGB1 for competing allogeneic immune responses, resulting in the acceptance of liver allografts in experimental liver transplantation.

  19. Role of endothelial-to-mesenchymal transition induced by TGF-β1 in transplant kidney interstitial fibrosis.

    PubMed

    Wang, Zijie; Han, Zhijian; Tao, Jun; Wang, Jun; Liu, Xuzhong; Zhou, Wanli; Xu, Zhen; Zhao, Chunchun; Wang, Zengjun; Tan, Ruoyun; Gu, Min

    2017-10-01

    Chronic allograft dysfunction (CAD) induced by kidney interstitial fibrosis is the main cause of allograft failure in kidney transplantation. Endothelial-to-mesenchymal transition (EndMT) may play an important role in kidney fibrosis. We, therefore, undertook this study to characterize the functions and potential mechanism of EndMT in transplant kidney interstitial fibrosis. Proteins and mRNAs associated with EndMT were examined in human umbilical vein endothelial cells (HUVECs) treated with transforming growth factor-beta1 (TGF-β1) at different doses or at different intervals with western blotting, qRT-PCR and ELISA assays. Cell motility and migration were evaluated with motility and migration assays. The mechanism of EndMT induced by TGF-β1 was determined by western blotting analysis of factors involved in various canonical and non-canonical pathways. In addition, human kidney tissues from control and CAD group were also examined for these proteins by HE, Masson's trichrome, immunohistochemical, indirect immunofluorescence double staining and western blotting assays. TGF-β1 significantly promoted the development of EndMT in a time-dependent and dose-dependent manner and promoted the motility and migration ability of HUVECs. The TGF-β/Smad and Akt/mTOR/p70S6K signalling pathways were found to be associated with the pathogenesis of EndMT induced by TGF-β1, which was also proven in vivo by the analysis of specimens from the control and CAD groups. EndMT may promote transplant kidney interstitial fibrosis by targetting the TGF-β/Smad and Akt/mTOR/p70S6K signalling pathways, and hence, result in the development of CAD in kidney transplant recipients. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  20. Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant.

    PubMed

    Teachey, David T; Jubelirer, Tracey; Baluarte, H Jorge; Wade, Amanda; Manno, Catherine S

    2009-12-01

    The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft.

  1. Contrast-induced acute kidney injury in kidney transplant recipients: A systematic review and meta-analysis

    PubMed Central

    Cheungpasitporn, Wisit; Thongprayoon, Charat; Mao, Michael A; Mao, Shennen A; D'Costa, Matthew R; Kittanamongkolchai, Wonngarm; Kashani, Kianoush B

    2017-01-01

    AIM To evaluate the incidence of contrast-induced acute kidney injury (CIAKI) in kidney transplant recipients. METHODS A literature search was performed using MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from the inception of the databases through July 2016. Studies assessing the incidence of CIAKI in kidney transplant recipients were included. We applied a random-effects model to estimate the incidence of CIAKI. RESULTS Six studies of 431 kidney transplant recipients were included in the analyses to assess the incidence of CIAKI in kidney transplant recipients. The estimated incidence of CIAKI and CIAKI-requiring dialysis were 9.6% (95%CI: 4.5%-16.3%) and 0.4% (95%CI: 0.0%-1.2%), respectively. A sensitivity analysis limited only to the studies that used low-osmolar or iso-osmolar contrast showed the estimated incidence of CIAKI was 8.0% (95%CI: 3.5%-14.2%). The estimated incidences of CIAKI in recipients who received contrast media with cardiac catheterization, other types of angiogram, and CT scan were 16.1% (95%CI: 6.6%-28.4%), 10.1% (95%CI: 4.2%-18.0%), and 6.1% (95%CI: 1.8%-12.4%), respectively. No graft losses were reported within 30 d post-contrast media administration. However, data on the effects of CIAKI on long-term graft function were limited. CONCLUSION The estimated incidence of CIAKI in kidney transplant recipients is 9.6%. The risk stratification should be considered based on allograft function, indication, and type of procedure. PMID:28280699

  2. Osteogenic Effects of Dedifferentiated Fat Cell Transplantation in Rabbit Models of Bone Defect and Ovariectomy-Induced Osteoporosis

    PubMed Central

    Kikuta, Shinsuke; Tanaka, Nobuaki; Kazama, Tomohiko; Kazama, Minako; Kano, Koichiro; Ryu, Junnosuke; Tokuhashi, Yasuaki

    2013-01-01

    We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a β-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the β-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis. PMID:23566022

  3. Osteogenic effects of dedifferentiated fat cell transplantation in rabbit models of bone defect and ovariectomy-induced osteoporosis.

    PubMed

    Kikuta, Shinsuke; Tanaka, Nobuaki; Kazama, Tomohiko; Kazama, Minako; Kano, Koichiro; Ryu, Junnosuke; Tokuhashi, Yasuaki; Matsumoto, Taro

    2013-08-01

    We have previously reported that mature adipocyte-derived dedifferentiated fat (DFAT) cells have a high proliferative activity and the potential to differentiate into lineages of mesenchymal tissue similar to bone marrow mesenchymal stem cells (MSCs). In the present study, we examined the effects of autologous DFAT cell transplantation on bone regeneration in a rabbit bone defect model and an ovariectomy (OVX)-induced osteoporosis model. The formation of tissue-engineered bone (TEB) was observed when rabbit DFAT cells were loaded onto a β-tricalcium phosphate (TCP)/collagen sponge and cultured in an osteogenic differentiation medium for 3 weeks. Autologous implantation of DFAT cell-mediated TEB constructs promoted bone regeneration in a rabbit tibial defect model. Regenerated bone tissue induced by transplantation of DFAT cell-mediated TEB constructs was histologically well differentiated and exhibited higher bone strength in a three-point bending test compared to that induced by the β-TCP/collagen sponge alone. In OVX-induced osteoporosis model rabbits, DFAT cells were obtained with the osteogenic activity similar to cells from healthy rabbits. Intrabone marrow injection of autologous DFAT cells significantly increased the bone mineral density (BMD) at the injected site in the OVX rabbits. Transplanted DFAT cells remained mainly on the injection side of the bone marrow by at least 28 days after intrabone marrow injection and a part of them expressed osteocalcin. In conclusion, these results demonstrate that autologous implantation of DFAT cells contributed to bone regeneration in a rabbit bone defect model and an OVX-induced osteoporosis model. DFAT cells may be an attractive cell source for cell-based bone tissue engineering to treat nonunion fractures in all patients, including those with osteoporosis.

  4. Four-Way Kidney Exchange Transplant With Desensitization Increases Access to Living-Donor Kidney Transplant: First Report From India.

    PubMed

    Kute, Vivek B; Patel, Himanshu V; Shah, Pankaj R; Modi, Pranjal R; Shah, Veena R; Kasat, Govind S; Patil, Mayur V; Patel, Jaydeep C; Kumar, Deepak P; Trivedi, Hargovind L

    2017-09-26

    This study reports our experience of the first 4-way kidney exchange transplant combined with desensitization in India, which allows increased access to living-donor kidney transplant for sensitized patients. Four-way kidney exchange transplant procedures were approved by the ethics committee of our institution and the Organ Transplantation Authorization Committee of state governments of India (as per the Transplantation of Human Organs Act of India). The protocols conformed to Declaration of Istanbul principles and the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients, donors, and their guardians. In April 2016, our transplant team completed simultaneous 4-way kidney exchange transplant procedures without any medical (rejection and infections) or surgical complications. Reasons for being included for kidney exchange transplant were ABO incom-patible (2 recipients) and sensitization (2 recipients). All 4 recipients had stable graft function with no proteinuria and donor-specific antibody at 11-month follow-up on standard triple immunosup-pression. Patient and graft survival rates were both 100%. To the best of our knowledge, this is the first single-center report of 4-way kidney exchange transplant combined with desensitization from India. This procedure has the potential to expand living-donor kidney transplant in disadvantaged groups (eg, sensitized patients). Recipients who are hard to match due to high panel reactive antibody and difficult to desensitize due to strong donor-specific antibodies can receive a transplant with a combination of kidney exchange and desensitization. Our study suggests that 4-way kidney exchange transplant can be performed in developing countries (India) similar to that shown in programs in developed countries with team work, kidney exchange registry, and counseling.

  5. Bone marrow transplant

    MedlinePlus

    Transplant - bone marrow; Stem cell transplant; Hematopoietic stem cell transplant; Reduced intensity nonmyeloablative transplant; Mini transplant; Allogenic bone marrow transplant; Autologous bone marrow transplant; ...

  6. Evidence of induced non-tolerance in HLA-identical twins with hemoglobinopathy after in utero fetal transplantation.

    PubMed

    Orlandi, F; Giambona, A; Messana, F; Marino, M; Abate, I; Calzolari, R; Damiani, F; Jakil, C; Renda, M; Dieli, F; Buscemi, F; Westgren, M; Ringden, O; Maggio, A

    1996-09-01

    Fetus-to-fetus transplantation has been suggested for the treatment of hemoglobinopathies in utero. However, dissimilar results have to date been obtained by different groups. We describe a case in which fetus-to-fetus transplantation in HLA-identical twins was performed at the 19th week of gestation by infusion of 0.8 ml of fetal blood from normal to beta-thalassemia affected fetus with the main aim of inducing tolerance. No evidence of engraftment, determined by KM19 polymorphism, was present after 2 years of the procedure. Moreover, an alloreactive cytotoxic T lymphocyte precursor (CTLp) study of affected fetus vs donor and other different stimulators showed that immunization vs tolerance was the real effect of the procedure.

  7. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial.

    PubMed

    Moayyedi, Paul; Surette, Michael G; Kim, Peter T; Libertucci, Josie; Wolfe, Melanie; Onischi, Catherine; Armstrong, David; Marshall, John K; Kassam, Zain; Reinisch, Walter; Lee, Christine H

    2015-07-01

    Ulcerative colitis (UC) is difficult to treat, and standard therapy does not always induce remission. Fecal microbiota transplantation (FMT) is an alternative approach that induced remission in small series of patients with active UC. We investigated its safety and efficacy in a placebo-controlled randomized trial. We performed a parallel study of patients with active UC without infectious diarrhea. Participants were examined by flexible sigmoidoscopy when the study began and then were randomly assigned to groups that received FMT (50 mL, via enema, from healthy anonymous donors; n = 38) or placebo (50 mL water enema; n = 37) once weekly for 6 weeks. Patients, clinicians, and investigators were blinded to the groups. The primary outcome was remission of UC, defined as a Mayo score ≤2 with an endoscopic Mayo score of 0, at week 7. Patients provided stool samples when the study began and during each week of FMT for microbiome analysis. The trial was stopped early for futility by the Data Monitoring and Safety Committee, but all patients already enrolled in the trial were allowed to complete the study. Seventy patients completed the trial (3 dropped out from the placebo group and 2 from the FMT group). Nine patients who received FMT (24%) and 2 who received placebo (5%) were in remission at 7 weeks (a statistically significant difference in risk of 17%; 95% confidence interval, 2%-33%). There was no significant difference in adverse events between groups. Seven of the 9 patients in remission after FMT received fecal material from a single donor. Three of the 4 patients with UC ≤1 year entered remission, compared with 6 of 34 of those with UC >1 year (P = .04, Fisher's exact test). Stool from patients receiving FMT had greater microbial diversity, compared with baseline, than that of patients given the placebo (P = .02, Mann-Whitney U test). FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in

  8. Preclinical Studies of Induced Pluripotent Stem Cell-Derived Astrocyte Transplantation in ALS

    DTIC Science & Technology

    2014-12-01

    to the injection site, aswell as from a lumbar section of the spinal cord, a remote site from the area of transplant. Because we observed few...transplant-derived cells mi- grating even into the thoracic region of the spinal cord, we chose the lumbar region as an area in which no human RNAs are...present. The lumbar region was used to evaluate for any background cross- reactivity of the human-specific probeswith endogenous rat RNAs. Analysis of in

  9. Gastrointestinal infectious disease complications following transplantation and their differentiation from immunosuppressant-induced gastrointestinal toxicities.

    PubMed

    Rubin, R H

    2001-01-01

    It is often very difficult to distinguish between infection-related and immunosuppression-related gastrointestinal (GI) complications after transplantation. The risk of infection itself is determined by the patient's net state of immunosuppression as well as the presence of anatomic or technical abnormalities and the patient's epidemiological exposures. Of the anatomic abnormalities, diverticulitis is a particular problem in transplant patients, with a high rate of perforation and abscess formation. The causes of infectious disease syndromes are very different immediately after, early after, and late after transplantation. Infection during the first month may result from a pre-existing infection in the donor or recipient, or from the surgical wound, endotracheal tube, vascular access or drainage. During 1-6 months after transplantation, viruses attack and, with sustained immunosuppression, make opportunistic infections possible. Beyond 6 months after transplantation, the 80% of patients with good result from the transplant are at risk primarily for community-acquired microbes, including such enteric pathogens as Salmonella. Of the remaining patients, 10% have chronic viral infections and the 10% who have poor allograft function are at greatest risk for opportunistic infection. This time line is helpful in determining whether a GI complication is likely to be related to infection rather than a specific effect of an immunosuppressant drug. Fever, inflammatory cells in the stool, abnormalities on endoscopy or computed tomography and leukocytosis can be useful in the diagnosis but are inconsistent markers for an infectious cause.

  10. Cell Injury-Induced Release of Fibroblast Growth Factor 2: Relevance to Intracerebral Mesenchymal Stromal Cell Transplantations

    PubMed Central

    Vinodkumar, Deepti; McGrogan, Michael; Bates, Damien

    2015-01-01

    Beneficial effects of intracerebral transplantation of mesenchymal stromal cells (MSC) and their derivatives are believed to be mediated mostly by factors produced by engrafted cells. However, the mesenchymal cell engraftment rate is low, and the majority of grafted cells disappear within a short post-transplantation period. Here, we hypothesize that dying transplanted cells can affect surrounding tissues by releasing their active intracellular components. To elucidate the type, amounts, and potency of these putative intracellular factors, freeze/thaw extracts of MSC or their derivatives were tested in enzyme-linked immunosorbent assays and bioassays. We found that fibroblast growth factor (FGF)2 and FGF1, but not vascular endothelial growth factor and monocyte chemoattractant protein 1 levels were high in extracts despite being low in conditioned media. Extracts induced concentration-dependent proliferation of rat cortical neural progenitor cells and human umbilical vein endothelial cells; these proliferative responses were specifically blocked by FGF2-neutralizing antibody. In the neuropoiesis assay with rat cortical cells, both MSC extracts and killed cells induced expression of nestin, but not astrocyte differentiation. However, suspensions of killed cells strongly potentiated the astrogenic effects of live MSC. In transplantation-relevant MSC injury models (peripheral blood cell-mediated cytotoxicity and high cell density plating), MSC death coincided with the release of intracellular FGF2. The data showed that MSC contain a major depot of active FGF2 that is released upon cell injury and is capable of acutely stimulating neuropoiesis and angiogenesis. We therefore propose that both dying and surviving grafted MSC contribute to tissue regeneration. PMID:25873141

  11. Simultaneous Transplantation of Hematopoietic Stem Cells and a Vascularized Composite Allograft Leads to Tolerance

    PubMed Central

    Mathes, David W.; Chang, Jeff; Hwang, Billanna; Graves, Scott S.; Storer, Barry E.; Butts-Miwongtum, Tiffany; Sale, George E.; Storb, Rainer

    2014-01-01

    Background We have previously demonstrated that tolerance to a vascularized composite allograft (VCA) can be achieved after the establishment of mixed chimerism. Here, we test the hypothesis that tolerance to a VCA in our dog leukocyte antigen (DLA)-matched canine model is not dependent on the previous establishment of mixed chimerism and can be induced coincident with hematopoietic cell transplantation (HCT). Methods Eight DLA-matched, minor antigen mismatched dogs received 200 cGy of radiation and a VCA transplant. Four dogs received donor bone marrow at the time of VCA transplantation (group 1) while a second group of 4 dogs did not (group 2). All recipients received a limited course of post-grafting immunosuppression. All dogs that received HCT and VCA were given donor, third party and autologous skin grafts. Results All group 1 recipients were tolerant to their VCA (> 62 weeks). Three of the four dogs in group 2 rejected their VCA transplants after the cessation of immunosuppression. Biopsies obtained from muscle and skin of VCA from group 1 showed few infiltrating cells compared to extensive infiltrates in biopsies of VCA from group 2. Compared to autologous skin and muscle, elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle obtained from VCA of HCT recipients. All group 1 animals were tolerant to their donor skin graft and promptly rejected the third-part skin grafts. Conclusion These data demonstrated donor specific tolerance to all components of the VCA can be established through simultaneous nonmyeloablative allogeneic HCT and VCA transplant protocol. PMID:24918616

  12. Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation.

    PubMed

    Morozumi, Kunio; Takeda, Asami; Otsuka, Yasuhiro; Horike, Keiji; Gotoh, Norihiko; Narumi, Shunji; Watarai, Yoshihiko; Kobayashi, Takaaki

    2016-07-01

    The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure.

  13. Microassay for glucose-induced preproinsulin mRNA expression to assess islet functional potency for islet transplantation

    PubMed Central

    Omori, Keiko; Mitsuhashi, Masato; Todorov, Ivan; Rawson, Jeffrey; Shiang, Keh-Dong; Kandeel, Fouad; Mullen, Yoko

    2009-01-01

    Background The capacity for insulin synthesis in islets is important for islet transplantation to succeed. We developed a micro assay that evaluates the potency of human islets by measuring changes in glucose induced insulin gene (INS) expression using a single islet in octuplicate samples. Methods Poly (A)+ mRNA was purified from a set of single handpicked human islets. Glucose induced mature (post-spliced) and premature (pre-spliced) insulin mRNA were quantified by RT-PCR using several insulin mRNA primers designed at different locations including, intron, exon, and an exon-intron junction. Results The synthesis of premature INS mRNA was significantly increased in islets exposed to high glucose for 16 hours (vs. 4-hour, p<0.01), whereas mature INS mRNA showed no difference. Glucose-induced premature INS mRNA synthesis was attenuated in heat-damaged islets. Stimulation index (SI) calculated by normalizing premature by mature INS mRNA (SI_INS mRNA) positively correlated with SI of insulin release (SI_16h-insulin) from the same set of islets during 16-hour incubation in high or low glucose media, as well as SI of glucose-mediated insulin release obtained from the same islet lot in a perifusion system (N=12). Furthermore, linear multiple regression analysis using SI_INS mRNA and SI_16h-insulin predicted islet transplantation outcome in NODscid mice (N=8). Conclusion The measurement of glucose induced premature INS mRNA normalized by mature INS mRNA can be used to assess the functional quality of human islets and may predict islet function after transplantation in type 1 diabetic patients. PMID:20098276

  14. Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients.

    PubMed

    de Andrade, Luis Gustavo M; Rodrigues, Maria Aparecida M; Romeiro, Fernando G; Garcia, Paula D; Contti, Mariana M; de Carvalho, Maria Fernanda C

    2014-11-01

    Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000 and 2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. Cytomegalovirus (CMV) immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), inflammatory bowel disease (IBD)-like colitis (25%), normal/near normal (18.8%), graft-versus-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18.75%). No graft loss occurred. Four patients died during the study period. Late-onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

  15. Autologous fat transplantation for depressed linear scleroderma-induced facial atrophic scars.

    PubMed

    Roh, Mi Ryung; Jung, Jin Young; Chung, Kee Yang

    2008-12-01

    Facial linear scleroderma results in depressed atrophic scars. Autologous fat transplantation has been widely used, and fat appears to be an ideal material for filling depressed atrophic scars and contour deformities, but long-term results for autologous fat transplantation are controversial. To review the short- and long-term results of 20 patients who underwent multiple autologous fat transplantations for depressed atrophic scar correction. Twenty patients with clinically inactive facial linear scleroderma were included. They received at least two transplantations and had a 12-month follow-up evaluation. On the forehead, 51% to 75% improvement (average grading scale: 2.4) was achieved when observed at least 12 months after the last treatment. For the chin, correction was poor (average grading scale: 0.7) with less than 25% improvement. The infraorbital area showed fair correction, but the nose showed poor correction. Two of three patients with scalp reduction surgery showed excellent results, showing only slight scar widening. Autologous fat transplantation is an effective method for long-term correction of depressed atrophic scars left by linear scleroderma on the forehead but is less effective for corrections on the nose, infraorbital area, and chin.

  16. Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in β amyloid-induced neurodegeneration

    PubMed Central

    Esposito, Giuseppe; Sarnelli, Giovanni; Capoccia, Elena; Cirillo, Carla; Pesce, Marcella; Lu, Jie; Calì, Gaetano; Cuomo, Rosario; Steardo, Luca

    2016-01-01

    Alzheimer’s disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD. PMID:26940982

  17. Impact of dopamine versus serotonin cell transplantation for the development of graft-induced dyskinesia in a rat Parkinson model.

    PubMed

    García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

    2012-08-27

    Graft-induced dyskinesia (GID), covering a range of dystonic and choreiform involuntary movements, has been observed in some patients with Parkinson's disease (PD) after intracerebral cell transplantation. These dyskinesias have been severe in a number of patients and represent one of the main obstacles for further development of the cell therapy in PD. Serotonin neurons, included into the dopaminergic cell suspension due to the nature of the dissection process, have been suggested as a key factor for the development of GID, since the administration of the serotonin (5-HT)(1A)-receptor agonist buspirone reduced dyskinesia in transplanted PD patients. In the present study, we characterized GID in the rat PD model after transplantation of dopaminergic grafts containing different amounts of serotonin neurons. The severity of GID was significantly correlated with the amount of grafted dopamine and serotonin neurons, but the r-values were low. However, neither the innervation density of dopamine and serotonin fibers in the grafted striatum nor the dopamine-to-serotonin cell ratio correlated significantly with the severity of GID. The results extend prior knowledge of the role of dopaminergic grafts in the development of GID and show that, in the animal model, serotonin neurons within the graft suspension might be involved, but given sufficient dopamine cells, their impact on GID may be minor.

  18. Vaccination against Streptococcus pneumoniae does not induce antibodies against HLA or MICA in clinically stable kidney transplant recipients.

    PubMed

    Lindemann, Monika; Heinemann, Falko M; Horn, Peter A; Witzke, Oliver

    2013-10-01

    There are concerns in the community that immune activation after vaccination could lead to (subclinical) rejection. Our aim was to define if pneumococcal vaccination induced HLA antibodies using highly sensitive methods. Forty-nine kidney transplant recipients were immunized with Pneumovax 23. The median interval between transplantation and vaccination was 6.5 years, the median serum creatinine concentration 1.3, 1.3 and 1.4 mg/dL pre-vaccination, at month 1 and 15 post-vaccination, respectively. In none of the patients biopsy-proven acute rejection was diagnosed within three years post-vaccination. Pneumococcal, HLA class I and II and major histocompatibility class I-related chain A (MICA) antibodies were determined by Luminex™ technology (xMAP™ Pneumococcal Immunity Panel and LABScreen™ Mixed beads, respectively) and HLA antibodies also by ELISA (Lambda Antigen Tray™). While pneumococcal antibodies were significantly higher at month 1 and 15 post- vs. pre-vaccination (p<0.0001 each), HLA/MICA antibodies remained unchanged as determined by Luminex™ and ELISA. Positive Luminex™ reactions were present in 63%, 67% and 63% (HLA class I), 47%, 47% and 55% (HLA class II) and 29%, 29% and 29% (MICA) pre-vaccination, at month 1 and 15, respectively. In clinically stable kidney transplant recipients there is no evidence for an increase in HLA antibodies after pneumococcal vaccination. Copyright © 2013 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  19. Building A New Treatment For Heart Failure-Transplantation of Induced Pluripotent Stem Cell-derived Cells into the Heart

    PubMed Central

    Miyagawa, Shigeru; Fukushima, Satsuki; Imanishi, Yukiko; Kawamura, Takuji; Mochizuki-Oda, Noriko; Masuda, Shigeo; Sawa, Yoshiki

    2016-01-01

    Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing “proof-of-concept” of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.

  20. Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

    PubMed

    Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-10-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

  1. Clinical Significance of Pre- and Post-Transplant BAFF Levels in Kidney Transplant Recipients

    PubMed Central

    Min, Ji Won; Kim, Kyoung Woon; Kim, Bo-Mi; Doh, Kyoung Chan; Choi, Min Seok; Choi, Bum Soon; Park, Cheol Whee; Yang, Chul Woo; Kim, Yong-Soo

    2016-01-01

    It is well known that pre-transplant B cell activating factor (BAFF) levels are associated with the development of de novo anti-HLA antibodies and antibody mediated rejection post-transplant. However, the clinical significance of BAFF values at allograft rejection has not been determined. In this study, we investigated the clinical significance of pre-transplant BAFF level as well as post-transplant BAFF levels measured when indication biopsy was done. We checked for anti-HLA antibodies in 115 kidney transplant recipients who required allograft biopsy due to an increase in serum creatinine. With the same serum specimen, we measured BAFF levels, and in 78 of these patients, pre-transplant BAFF and anti-HLA antibody levels were detected as well. Patients in each group were divided into tertiles according to BAFF levels. We investigated the relationship between BAFF levels and the occurrence of anti-HLA antibodies. Pre-transplant BAFF levels showed significant association with pre-transplant sensitization, and also with early rejection (Tertile 3, 26.9% vs. Tertile 1, 11.5%; P<0.05). Post-transplant BAFF levels showed significant association with pre-transplant sensitization, but did not show association with anti-HLA antibodies and positive donor-specific antibodies at the time of biopsy. We did not find any association between post-transplant BAFF levels and allograft biopsy results, Banff scores and microvascular inflammation scores. In conclusion, pre-transplant BAFF levels are associated with pre-transplant sensitization and are useful in predicting allograft rejection. But post-transplant BAFF levels measured at the time of indication biopsy are not associated with the appearance of de novo HLA-DSA, allograft rejection, biopsy findings and other allograft outcomes. PMID:27631619

  2. Abate Cytochrome C induced apoptosome to protect donor liver against ischemia reperfusion injury on rat liver transplantation model

    PubMed Central

    Zhuang, Zhuonan; Lian, Peilong; Wu, Xiaojuan; Shi, Baoxu; Zhuang, Maoyou; Zhou, Ruiling; Zhao, Rui; Zhao, Zhen; Guo, Sen; Ji, Zhipeng; Xu, Kesen

    2016-01-01

    Objective: Aim of this study is to protect donor liver against ischemia-reperfusion injury by abating Cytochrome C induced apoptosome on rat model. Methods: A total of 25 clean SD inbred male rats were used in this research. The rats in ischemia-reperfusion injury group (I/R group, n=5) were under liver transplantation operation; rats in dichloroacetate diisopropylamine group (DADA group, n=5) were treated DADA before liver transplantation; control group (Ctrl group, n=5); other 10 rats were used to offer donor livers. Results: In DADA therapy group, Cytochrome C expression in donor hepatocellular cytoplasm was detected lower than that in I/R group. And the Cytochrome C induced apoptosome was also decreased in according to the lower expressions of Apaf-1 and Caspase3. Low level of cleaved PARP expression revealed less apoptosis in liver tissue. The morphology of donor liver mitochondria in DADA group was observed to be slightly edema but less than I/R group after operation 12 h. The liver function indexes of ALT and AST in serum were tested, and the results in DADA group showed it is significantly lower than I/R group after operation 12 h. The inflammation indexes of IL-6 and TNF-α expressions in DADA group were significantly lower than that in I/R group after operation 24 h. Conclusion: The dichloroacetate diisopropylamine treatment could protect the hepatocellular mitochondria in case of the spillage of Cytochrome C induced apoptosome, and protect the liver against ischemia-reperfusion injury. Thus, it may be a method to promote the recovery of donor liver function after transplantation. PMID:27186297

  3. REGRESSION OF TRANSPLANTED LYMPHOMAS INDUCED IN VIVO BY MEANS OF NORMAL GUINEA PIG SERUM

    PubMed Central

    Kidd, John G.

    1953-01-01

    In the experiments here described transplanted lymphomas of two kinds regularly regressed following repeated injections of normal guinea pig serum intraperitoneally into mice carrying them, the animals meanwhile remaining lively and devoid of signs of illness or wasting. The lymphomas of untreated control mice, by contrast, usually grew progressively and killed their hosts within 20 to 30 days, and the same was true of the growth of other mice given repeated injections of horse serum or rabbit serum. In similar experiments, the cells of a transplanted lymphosarcoma of rats were temporarily kept from proliferating by repeated intraperitoneal injections of guinea pig serum, though the cells of two transplanted mammary carcinomas of mice, and those of fibrosarcoma, grew unimpeded in hosts likewise treated. Additional experiments related to the phenomenon here described, and a discussion of the findings as a whole, are given in an associated paper. PMID:13109110

  4. Trichophyton rubrum-induced Majocchi's Granuloma in a heart transplant recipient. A therapeutic challenge.

    PubMed

    Steiner, Urs C; Trüeb, Ralph M; Schad, Karin; Kamarashev, Jivko; Koch, Simon; French, Lars E; Hofbauer, Günther F L

    2012-09-28

    Solid organ transplant recipients are at an increased risk for infections because of long-term immunosuppression to prevent graft rejection. Fungal infections with dermatophytes are a common cause of cutaneous infections seen in organ transplant recipients and cutaneous dermatophyte infections may progress to Majocchi's granuloma. Itraconazole is an anti-fungal compound used for the treatment of infections of the skin, nails and mucous membranes. We report on a heart transplant recipient who developed widespread Trichophyton rubrum infection presenting as Majocchi's granuloma. Itraconazole treatment was complicated by drug interactions. Tricho-phyton rubrum infection progressed, while itraconazole treatment was varied in dose and delivery form. In patients with Trichophyton rubrum infections, refractory to itraconazole treatment, altered drug absorption or drug interactions has to be considered. Careful monitoring and adjustment of itraconazole is of vital importance.

  5. Multiple carcinomas in the hemodialysis access induced ischemic hand of a renal transplant patient.

    PubMed

    Van Hoek, Frank; Van Tits, Herm W; Van Lijnschoten, Ineke; De Haas, Boudewijn D; Scheltinga, Marc R

    2010-01-01

    Long term immunosuppression following organ transplantation promotes the onset of skin cancers. A renal transplant patient developed multiple hyperkeratotic nodi in the left hand and digital pain following prolonged immunosuppression. Several skin abnormalities were observed in an ischemic and atrophic left hand in the presence of a patent Cimino-Brescia arteriovenous fistula previously used for hemodialysis. Severe hand ischemia was confirmed by digital plethysmography. Pathological examination of all 7 excised skin lesions indicated manifestations of well differentiated squamous cell carcinomas (SCC). Severe loco-regional ischemia due to an intact hemodialysis access may enhance the toxic effects of chronic immunosuppressive medication. Oxidative stress may act as a co-carcinogenic factor for the development of SCC in renal transplant patients receiving immunosuppressive agents.

  6. Memory CD4 T Cells Induce Antibody-Mediated Rejection of Renal Allografts.

    PubMed

    Gorbacheva, Victoria; Fan, Ran; Fairchild, Robert L; Baldwin, William M; Valujskikh, Anna

    2016-11-01

    Despite advances in immunosuppression, antibody-mediated rejection is a serious threat to allograft survival. Alloreactive memory helper T cells can induce potent alloantibody responses and often associate with poor graft outcome. Nevertheless, the ability of memory T cells to elicit well characterized manifestations of antibody-mediated rejection has not been tested. We investigated helper functions of memory CD4 T cells in a mouse model of renal transplantation. Whereas the majority of unsensitized C57Bl/6 recipients spontaneously accepted fully MHC-mismatched A/J renal allografts, recipients containing donor-reactive memory CD4 T cells rapidly lost allograft function. Increased serum creatinine levels, high serum titers of donor-specific alloantibody, minimal T cell infiltration, and intense C4d deposition in the grafts of sensitized recipients fulfilled all diagnostic criteria for acute renal antibody-mediated rejection in humans. IFNγ neutralization did not prevent the renal allograft rejection induced by memory helper T cells, and CD8 T cell depletion at the time of transplantation or depletion of both CD4 and CD8 T cells also did not prevent the renal allograft rejection induced by memory helper T cells starting at day 4 after transplantation. However, B cell depletion inhibited alloantibody generation and significantly extended allograft survival, indicating that donor-specific alloantibodies (not T cells) were the critical effector mechanism of renal allograft rejection induced by memory CD4 T cells. Our studies provide direct evidence that recipient T cell sensitization may result in antibody-mediated rejection of renal allografts and introduce a physiologically relevant animal model with which to investigate mechanisms of antibody-mediated rejection and novel therapeutic approaches for its prevention and treatment. Copyright © 2016 by the American Society of Nephrology.

  7. Severe hyperkalaemia induced by trimethoprim in combination with an angiotensin-converting enzyme inhibitor in a patient with transplanted lungs.

    PubMed

    Bugge, J F

    1996-10-01

    A 40-year-old woman with transplanted lungs developed life threatening hyperkalaemia (6.8 mmol L-1) during high dose treatment with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia. Trimethoprim has an amiloride-like effect on the distal nephron and may thus induce hyperkalaemia, particularly if other contributing factors coexist. The present patient was also treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril, and the combination of ACE-inhibition and potassium-sparing diuretics is known to induce hyperkalaemia. Hyperkalaemia was probably induced by the combination of ACE-inhibitor and trimethoprim, and this combination may be as dangerous as the combination of ACE-inhibitors with other potassium-sparing diuretics.

  8. Mechanisms of Alloimmunization and Subsequent Bone Marrow Transplantation Rejection Induced by Platelet Transfusion in a Murine Model

    PubMed Central

    Patel, Seema R; Smith, Nicole H; Kapp, Linda; Zimring, James C

    2015-01-01

    For many non-malignant hematological disorders, HLA-matched bone marrow transplantation (BMT) is curative. However, due to lack of neoplasia, the toxicity of stringent conditioning regimens is difficult to justify, and reduced-intensity conditioning is used. Unfortunately, current reduced-intensity regimens have high rates of BMT rejection. We have recently reported in a murine model that mHAs on transfused platelet products induce subsequent BMT rejection. Most non-malignant hematological disorders require transfusion support prior to BMT and the rate of BMT rejection in humans correlates to the number of transfusions given. Herein, we perform a mechanistic analysis of platelet transfusion induced BMT rejection and report that unlike exposure to alloantigens during transplantation, platelet transfusion primes alloimmunity but does not stimulate full effector function. Subsequent BMT is itself an additional and distinct immunizing event, which does not induce rejection without antecedent priming from transfusion. Both CD4+ and CD8+ T cells are required for priming during platelet transfusion, but only CD8+ T cells are required for BMT rejection. In neither case are antibodies required for rejection to occur. PMID:22300526

  9. Endothelial Cell Apoptosis Induces TGF-β Signaling-Dependent Host Endothelial-Mesenchymal Transition to Promote Transplant Arteriosclerosis.

    PubMed

    Li, J; Xiong, J; Yang, B; Zhou, Q; Wu, Y; Luo, H; Zhou, H; Liu, N; Li, Y; Song, Z; Zheng, Q

    2015-12-01

    Endothelial cells (ECs) apoptosis is an initial event in transplant arteriosclerosis (TA), resulting in allograft function loss. To elucidate the precise mechanisms of ECs apoptosis leading to neointimal smooth muscle cells (SMCs) accumulation during TA. We induced apoptosis in cultured ECs by overexpressing p53 through lentivirus-mediated transfection. ECs apoptosis induced the production of transforming growth factor (TGF)-β1 in both apoptotic and neighboring viable cells, leading to increased TGF-β1 in the culture media. Conditioned media from Ltv-p53-transfected ECs further promoted transition of cultured ECs to SM-like cells by activating TGF-β/Smad3, PI3K/Akt/mTOR, and MAPK/ERK signaling in a TGF-β-dependent manner. In transgenic rat aorta transplantation models, inhibition of ECs apoptosis in Bcl-xL(+/+) knock-in rat aortic allografts significantly reduced TGF-β1 production both in allograft endothelia and in blood plasma, which in turn decreased accumulation of SM22α+ cells from transgenic recipient ECs originally marked with EGFP knock-in in neointima and alleviated TA. Systemic treatment with SIS3, AP23573, or PD98059 also prevented recipient ECs-originated SM-like cells accumulation and intima hyperplasia in aortic allografts. These data suggest that allograft EC apoptosis induced recipient endothelial-mesenchymal (smooth muscle) transition via TGF-β signaling, resulting in recipient EC-derived SMC accumulation as a major mechanism of vascular remodeling during TA.

  10. Fecal microbiota transplantation inducing remission in Crohn's colitis and the associated changes in fecal microbial profile.

    PubMed

    Kao, Dina; Hotte, Naomi; Gillevet, Patrick; Madsen, Karen

    2014-08-01

    Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the intestine of unclear etiology. Increasing evidence has pointed to intestinal dysbiosis as a potential factor in a genetically susceptible individual. Fecal microbiota transplantation (FMT) has been used to treat inflammatory bowel disease with variable degrees of success. Herein, we report a patient with Crohn's colitis, previously failing an immunosuppressant, who achieved clinical, endoscopic, and histologic remission after a single fecal microbiota transplantation infusion. We have further characterized the changes in the fecal microbiota associated with this observation.

  11. Single-centre experience with nonmyeloablative allogeneic stem cell transplantation in patients with multiple myeloma: prolonged remissions induced.

    PubMed

    van Dorp, S; Meijer, E; van de Donk, N W C J; Dekker, A W; Nieuwenhuis, K; Minnema, M C; Petersen, E; Schutgens, R; Verdonck, L F; Lokhorst, H M

    2007-05-01

    The role of allogeneic stem cell transplantation in multiple myeloma is not yet established. We retrospectively evaluated the outcome of nonmyeloablative allogeneic stem cell transplantation (NMA) in patients with multiple myeloma treated at the Department of Haematology of the University Medical Centre Utrecht. Thirty-six patients received NMA as part of the first-line treatment; 23 patients as part of salvage therapy. Conditioning regimen was low-dose total body irradiation (TBI, 2 Grays) only; fludarabine was added in patients without previous autologous stem cell transplantation and patients with matched unrelated donors received antithymocyte globulin in addition to fludarabine and TBI. Following NMA overall response increased from 84 to 90%, complete remission rate from 15 to 32%. As part of first-line treatment NMA induced complete remission in 50% of patients vs one patient (4%) treated for relapsed multiple myeloma. Median progression-free survival was 26 months (13 months for the salvage group, 38 months for the 'upfront' patients). Median overall survival has not been reached yet. The achievement of complete remission following NMA as part of first-line treatment was associated with prolonged progression-free and overall survival. Major toxicities were acute and chronic graft-vs-host disease occurring in 64% (23% grade 3-4) and in 54% (49% extensive) patients, respectively. Seven patients (12%) died from nonrelapse mortality, five patients (9%) directly related to toxicity of NMA. NMA in multiple myeloma is feasible, is associated with acceptable nonrelapse mortality and may induce prolonged complete remission. In pretreated patients the result of NMA is disappointing which urges new strategies.

  12. Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome

    PubMed Central

    Ding, Ying; Xu, Yuemei; Shuai, Xuanyu; Shi, Xuhui; Chen, Xiang; Huang, Wenbin; Liu, Yun; Liang, Xiubin; Zhang, Zhihong; Su, Dongming

    2014-01-01

    The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure. This may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3α (Reg3α) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/L versus 13.48 ± 0.35 mmol/L, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/mL versus 1.16 ± 0.16 ng/mL, P < 0.05) compared with the control group. The decline of apoptotic events (0.57% ± 0.15% versus 1.06% ± 0.07%, P < 0.05) and increased β-cell proliferation (0.70% ± 0.10% versus 0.36% ± 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic β cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic β cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation. PMID:25826674

  13. Bioluminescent Imaging of Genetically Selected Induced Pluripotent Stem Cell-Derived Cardiomyocytes after Transplantation into Infarcted Heart of Syngeneic Recipients

    PubMed Central

    Lepperhof, Vera; Polchynski, Olga; Kruttwig, Klaus; Brüggemann, Chantal; Neef, Klaus; Drey, Florian; Zheng, Yunjie; Ackermann, Justus P.; Choi, Yeong-Hoon; Wunderlich, Thomas F.; Hoehn, Mathias; Hescheler, Jürgen; Šarić, Tomo

    2014-01-01

    Cell loss after transplantation is a major limitation for cell replacement approaches in regenerative medicine. To assess the survival kinetics of induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) we generated transgenic murine iPSC lines which, in addition to CM-specific expression of puromycin N-acetyl-transferase and enhanced green fluorescent protein (EGFP), also constitutively express firefly luciferase (FLuc) for bioluminescence (BL) in vivo imaging. While undifferentiated iPSC lines generated by random integration of the transgene into the genome retained stable FLuc activity over many passages, the BL signal intensity was strongly decreased in purified iPS-CM compared to undifferentiated iPSC. Targeted integration of FLuc-expression cassette into the ROSA26 genomic locus using zinc finger nuclease (ZFN) technology strongly reduced transgene silencing in iPS-CM, leading to a several-fold higher BL compared to iPS-CM expressing FLuc from random genomic loci. To investigate the survival kinetics of iPS-CM in vivo, purified CM obtained from iPSC lines expressing FLuc from a random or the ROSA26 locus were transplanted into cryoinfarcted hearts of syngeneic mice. Engraftment of viable cells was monitored by BL imaging over 4 weeks. Transplanted iPS-CM were poorly retained in the myocardium independently of the cell line used. However, up to 8% of cells survived for 28 days at the site of injection, which was confirmed by immunohistological detection of EGFP-positive iPS-CM in the host tissue. Transplantation of iPS-CM did not affect the scar formation or capillary density in the periinfarct region of host myocardium. This report is the first to determine the survival kinetics of drug-selected iPS-CM in the infarcted heart using BL imaging and demonstrates that transgene silencing in the course of iPSC differentiation can be greatly reduced by employing genome editing technology. FLuc-expressing iPS-CM generated in this study will enable further

  14. Autologous subcutaneous adipose tissue transplants improve adipose tissue metabolism and reduce insulin resistance and fatty liver in diet-induced obesity rats.

    PubMed

    Torres-Villalobos, Gonzalo; Hamdan-Pérez, Nashla; Díaz-Villaseñor, Andrea; Tovar, Armando R; Torre-Villalvazo, Ivan; Ordaz-Nava, Guillermo; Morán-Ramos, Sofía; Noriega, Lilia G; Martínez-Benítez, Braulio; López-Garibay, Alejandro; Torres-Landa, Samuel; Ceballos-Cantú, Juan C; Tovar-Palacio, Claudia; Figueroa-Juárez, Elizabeth; Hiriart, Marcia; Medina-Santillán, Roberto; Castillo-Hernández, Carmen; Torres, Nimbe

    2016-09-01

    Long-term dietary and pharmacological treatments for obesity have been questioned, particularly in individuals with severe obesity, so a new approach may involve adipose tissue transplants, particularly autologous transplants. Thus, the aim of this study was to evaluate the metabolic effects of autologous subcutaneous adipose tissue (SAT) transplants into two specific intraabdominal cavity sites (omental and retroperitoneal) after 90 days. The study was performed using two different diet-induced obesity (DIO) rat models: one using a high-fat diet (HFD) and the other using a high-carbohydrate diet (HCHD). Autologous SAT transplant reduced hypertrophic adipocytes, improved insulin sensitivity, reduced hepatic lipid content, and fasting serum-free fatty acids (FFAs) concentrations in the two DIO models. In addition, the reductions in FFAs and glycerol were accompanied by a greater reduction in lipolysis, assessed via the phosphorylation status of HSL, in the transplanted adipose tissue localized in the omentum compared with that localized in the retroperitoneal compartment. Therefore, the improvement in hepatic lipid content after autologous SAT transplant may be partially attributed to a reduction in lipolysis in the transplanted adipose tissue in the omentum due to the direct drainage of FFAs into the liver. The HCHD resulted in elevated fasting and postprandial serum insulin levels, which were dramatically reduced by the autologous SAT transplant. In conclusion, the specific intraabdominal localization of the autologous SAT transplant improved the carbohydrate and lipid metabolism of adipose tissue in obese rats and selectively corrected the metabolic parameters that are dependent on the type of diet used to generate the DIO model. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  15. Bone marrow transplant - discharge

    MedlinePlus

    Transplant - bone marrow - discharge; Stem cell transplant - discharge; Hematopoietic stem cell transplant - discharge; Reduced intensity; Non-myeloablative transplant - discharge; Mini transplant - discharge; Allogenic bone marrow transplant - ...

  16. Improvement of neurological deficits in 6-hydroxydopamine-lesioned rats after transplantation with allogeneic simian virus 40 large tumor antigen gene-induced immortalized dopamine cells

    PubMed Central

    Clarkson, Edward D.; Rosa, Francisco G. La; Edwards-Prasad, Judith; Weiland, David A.; Witta, Samir E.; Freed, Curt R.; Prasad, Kedar N.

    1998-01-01

    The replacement of dopamine (DA) by DA neuron transplants in the treatment of advanced Parkinson disease (PD) is a rational approach. Because of limitations associated with fetal tissue transplants, a clone (1RB3AN27) of simian virus 40 large tumor antigen (LTa) gene-induced immortalized DA neurons were used in this study. These allogeneic immortalized dopamine neurons, when grafted into striata of normal rats, did not divide, did not form tumors, did not produce LTa, did not extend neurites to host neurons, and were not rejected, for as long as 13 months after transplantation. Grafted cells when recultured in vitro resumed cell proliferation and LTa production, suggesting the presence of a LTa gene-inhibiting factor in the brain. The grafting of undifferentiated and differentiated 1RB3AN27 cells or differentiated murine neuroblastoma (NBP2) cells into striata of 6-hydroxydopamine-lesioned rats (an animal model of PD) caused a time-dependent improvement in neurological deficits (reduction in the methamphetamine-induced turning rate). At 3 months after transplantation, 100% of the animals receiving differentiated 1RB3AN27 cells, 63% of the animals receiving undifferentiated 1RB3AN27 cells, 56% of the animals receiving differentiated NBP2 cells, and 0% of the sham-transplanted animals showed improvements in neurological deficits. At 6 months after transplantation, there was a progressive increase in spontaneous recovery in sham-transplanted animals. These results suggest that immortalized DA neurons should be further studied for their potential use in transplant therapy in advanced PD patients. PMID:9448320

  17. The reversal of hyperglycemia after transplantation of mouse embryonic stem cells induced into early hepatocyte-like cells in streptozotocin-induced diabetic mice.

    PubMed

    Boroujeni, Nasim Beigi; Hashemi, Seyed Mahmoud; Khaki, Zohreh; Soleimani, Masoud

    2011-04-01

    Cellular replacement therapy is a potential therapeutic strategy for diabetes. In this study, we investigated the effect of transplantation of induced mouse embryonic stem cells (mESCs) into endoderm and early hepatocyte-like cells in streptozotocin (STZ)-diabetic mice. After embryoid body (EB) formation from mESC, the EBs were cultured in the presence of dexamethasone (DEX) and insulin for 4 days then was added acidic fibroblast growth factor (aFGF), hepatocyte growth factor (HGF) and oncostatin M (OSM) for 10 days, respectively. Blood glucose levels, intraperitoneal glucose tolerance (IGT) test and islet histology were assessed. The result revealed that transplantation of induced mESCs into early hepatocyte-like cells could repair pancreatic islets of control group. Blood glucose levels and intraperitoneal glucose tolerance test were significantly improved in test group compared to control group. Furthermore, there was significant increase in the number of islets in test group compared to control group. The findings declare that induced mESCs into endoderm and early hepatocyte-like cells, are appropriate candidate for regenerative therapy of pancreatic islets in type I diabetes.

  18. Impact of Antibodies That React With Liver Tissue and Donor-Specific Anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis.

    PubMed

    Hirata, Yoshihiro; Yoshizawa, Atsushi; Egawa, Hiroto; Ueda, Daisuke; Okamoto, Shinya; Okajima, Hideaki; Yurugi, Kimiko; Hishida, Rie; Hirai, Hideyo; Miyagawa-Hayashino, Aya; Maekawa, Taira; Haga, Hironori; Uemoto, Sinji

    2017-05-01

    The cause of late graft dysfunction has not been elucidated. Although an antibody-mediated reaction is suspected as a potential mechanism, the target antigens have not been clarified. To clarify the etiology of idiopathic posttransplantation hepatitis (IPTH), we simultaneously examined the presence of antibodies that react with liver tissue (ARLT) by means of indirect immunofluorescence staining, as well as the presence of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA). A subanalysis of the IPTH group was also performed. Within the IPTH group, the correlation between ARLT titer and clinical data were analyzed. In the sera of patients with IPTH (30 patients), ARLT were found at a significantly higher frequency than in patients without IPTH (42 patients; P < 0.001). Moreover, the ARLT titer appeared to be correlated with the severity of hepatitis or hepatic injury. In contrast, the frequency of HLA-DSA was significantly lower in patients with IPTH than in patients without IPTH (P = 0.001). Our findings indicate that ARLT, and not HLA-DSA, profoundly influence the etiology of IPTH.

  19. Pomelo-induced increase in the blood level of tacrolimus in a renal transplant patient.

    PubMed

    Egashira, Kanoko; Fukuda, Etsuko; Onga, Takayuki; Yogi, Yasuo; Matsuya, Fukuzou; Koyabu, Noriko; Ohtani, Hisakazu; Sawada, Yasufumi

    2003-04-15

    Tacrolimus, an immunosuppressive agent, is widely used in patients after transplantation to prevent allograft rejection. Because tacrolimus has a narrow therapeutic range, it is essential to carefully control the blood level. It has been demonstrated that tacrolimus is metabolized mainly by cytochrome P-450 (CYP) 3A4, and that tacrolimus is a substrate of P-glycoprotein. This article reports a case of considerable increase in the blood level of tacrolimus after the intake of pomelo in a renal transplant recipient. Pomelo may increase the blood concentration of tacrolimus by inhibiting CYP 3A4, P-glycoprotein, or both. Patients taking drugs such as tacrolimus or cyclosporine, which have their kinetics affected by grapefruit juice, should avoid pomelo and other grapefruit-related citrus fruits.

  20. Mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis.

    PubMed

    Enns, Winnie; von Rossum, Anna; Choy, Jonathan

    2015-05-17

    Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

  1. Autologous CLL cell vaccination early after transplant induces leukemia-specific T cells.

    PubMed

    Burkhardt, Ute E; Hainz, Ursula; Stevenson, Kristen; Goldstein, Natalie R; Pasek, Mildred; Naito, Masayasu; Wu, Di; Ho, Vincent T; Alonso, Anselmo; Hammond, Naa Norkor; Wong, Jessica; Sievers, Quinlan L; Brusic, Ana; McDonough, Sean M; Zeng, Wanyong; Perrin, Ann; Brown, Jennifer R; Canning, Christine M; Koreth, John; Cutler, Corey; Armand, Philippe; Neuberg, Donna; Lee, Jeng-Shin; Antin, Joseph H; Mulligan, Richard C; Sasada, Tetsuro; Ritz, Jerome; Soiffer, Robert J; Dranoff, Glenn; Alyea, Edwin P; Wu, Catherine J

    2013-09-01

    Patients with advanced hematologic malignancies remain at risk for relapse following reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We conducted a prospective clinical trial to test whether vaccination with whole leukemia cells early after transplantation facilitates the expansion of leukemia-reactive T cells and thereby enhances antitumor immunity. We enrolled 22 patients with advanced chronic lymphocytic leukemia (CLL), 18 of whom received up to 6 vaccines initiated between days 30 and 45 after transplantation. Each vaccine consisted of irradiated autologous tumor cells admixed with GM-CSF-secreting bystander cells. Serial patient PBMC samples following transplantation were collected, and the impact of vaccination on T cell activity was evaluated. At a median follow-up of 2.9 (range, 1-4) years, the estimated 2-year progression-free and overall survival rates of vaccinated subjects were 82% (95% CI, 54%-94%) and 88% (95% CI, 59%-97%), respectively. Although vaccination only had a modest impact on recovering T cell numbers, CD8+ T cells from vaccinated patients consistently reacted against autologous tumor, but not alloantigen-bearing recipient cells with increased secretion of the effector cytokine IFN-γ, unlike T cells from nonvaccinated CLL patients undergoing allo-HSCT. Further analysis confirmed that 17% (range, 13%-33%) of CD8+ T cell clones isolated from 4 vaccinated patients by limiting dilution of bulk tumor-reactive T cells solely reacted against CLL-associated antigens. Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control following allo-HSCT. Clinicaltrials.gov NCT00442130. NCI (5R21CA115043-2), NHLBI (5R01HL103532-03), and Leukemia and Lymphoma Society Translational Research Program.

  2. Role of MDR1 gene polymorphisms in gingival overgrowth induced by cyclosporine in transplant patients.

    PubMed

    De Iudicibus, S; Castronovo, G; Gigante, A; Stocco, G; Decorti, G; Di Lenarda, R; Bartoli, F

    2008-12-01

    The aim of the present study was to determine the association between genotypes of the MDR1 gene, encoding P-glycoprotein, and gingival overgrowth in transplant patients treated with cyclosporine, and to evaluate the effect of periodontal treatment in these patients. Fifty transplant patients receiving therapy with cyclosporine and suffering from gingival overgrowth were subjected to nonsurgical periodontal treatment and received oral hygiene instructions. Hyperplastic index, periodontal probing depths, bleeding and plaque scores were recorded at baseline and after 3 and 6 mo. Patients were dichotomized into two groups: those with a hyperplastic index of < 30% (minimal gingival overgrowth) and those with a hyperplastic index of > or = 30% (clinically significant gingival overgrowth). MDR1 C3435T and G2677T polymorphisms were evaluated in all patients and in 100 controls. At baseline, 32 patients (64%) had minimal gingival overgrowth and 18 patients (36%) had clinically significant gingival overgrowth. The mutated C3435T genotype was significantly more frequent in the second group (p < 0.019). The significant association between gingival overgrowth and the 3435TT genotype was confirmed by logistic regression analysis (p < 0.031). The differences in hyperplastic index, observed at baseline between patients with the TT genotype and those with the CC/CT genotype disappeared in the second and third evaluation. The mean monthly change of the square root of the gingival overgrowth scores for all patients, assessed using linear models, was significantly different from baseline (-0.17 points per month, p < 0.00001); and this was particularly evident in subjects with renal transplant (-1.62, p < 0.01). Aetiological periodontal and self-performed maintenance therapy is effective in reducing gingival overgrowth, particularly in subjects with the 3435TT genotype and in patients with renal transplant.

  3. Intracranial hemorrhage induced uncontrolled seizure in a deceased donor liver transplant patient: a case report

    PubMed Central

    Oh, Seung-Young; Lee, Hannah; Park, Yang-Hyo

    2016-01-01

    Seizure is the second most common neurologic complication after liver transplantation and may be caused by metabolic abnormalities, electrolyte imbalance, infection, and immunosuppressant toxicity. A 61-year-old male patient underwent liver transplantation due to hepatitis B virus-related liver cirrhosis with portal systemic encephalopathy. The immediate postoperative course of the patient was uncomplicated. However, on postoperative day (POD) 6, weakness developed in both lower extremities. No abnormal findings were detected on a brain computed tomography (CT) scan on POD 8, but a generalized tonic clonic seizure developed which was difficult to control even with multiple antiepileptic drugs. A follow-up brain CT scan on POD 15 showed a 2.7 cm sized acute intracranial hemorrhage (ICH) in the left parietal lobe. The patient's mental status improved after 2 months and he was able to communicate through eye blinking or head shaking. Our case reports an acute ICH that manifested into a refractory seizure in a patient who underwent a liver transplant. PMID:27703637

  4. Transplantation models to characterize the mechanisms of stem cell-induced islet regeneration.

    PubMed

    Bell, Gillian I; Seneviratne, Ayesh K; Nasri, Grace N; Hess, David A

    2013-09-20

    This unit describes our current knowledge regarding the isolation human bone marrow-derived progenitor cells for the paracrine stimulation of islet regeneration after transplantation into immunodeficient mouse models of diabetes. By using high aldehyde dehydrogenase (ALDH(hi) ) activity, a conserved function in multiple stem cell lineages, a mixed population of hematopoietic, endothelial, and mesenchymal progenitor cells can be efficiently purified using flow cytometry. We describe in vitro approaches to characterize and expand these distinct cell types. Importantly, these cell types can be transplanted into immunodeficient mice rendered beta-cell deficient by streptozotocin (STZ) treatment, in order monitor functional recovery from hyperglycemia and to characterize endogenous islet regeneration via paracrine mechanisms. Herein, we provide detailed protocols for: (1) isolation and characterization of ALDH(hi) cells for the establishment of hematopoietic and multipotent-stromal progenitor lineages; (2) intravenous and intrapancreatic transplantation of human stem cell subtypes for the quantification of glycemic recovery in STZ-treated immunodeficient mice; and (3) immunohistochemical characterization of islet recovery via the stimulation of islet neogenic, beta-cell proliferative, and islet revascularization programs. Collectively, these systems can be used to support the pre-clinical development of human progenitor cell-based therapies to treat diabetes via islet regeneration.

  5. The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants

    PubMed Central

    Pankhurst, Laura; Hudson, Alex; Mumford, Lisa; Willicombe, Michelle; Galliford, Jack; Shaw, Olivia; Thuraisingham, Raj; Puliatti, Carmelo; Talbot, David; Griffin, Sian; Torpey, Nicholas; Ball, Simon; Clark, Brendan; Briggs, David; Fuggle, Susan V.; Higgins, Robert M.

    2017-01-01

    Background ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. Methods The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. Results For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. Conclusions Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy. PMID:28706984

  6. The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants.

    PubMed

    Pankhurst, Laura; Hudson, Alex; Mumford, Lisa; Willicombe, Michelle; Galliford, Jack; Shaw, Olivia; Thuraisingham, Raj; Puliatti, Carmelo; Talbot, David; Griffin, Sian; Torpey, Nicholas; Ball, Simon; Clark, Brendan; Briggs, David; Fuggle, Susan V; Higgins, Robert M

    2017-07-01

    ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

  7. Hematopoietic cell transplantation for tolerance induction: animal models to clinical trials.

    PubMed

    Sykes, Megan

    2009-02-15

    The induction of donor-specific immune tolerance is the "holy grail" of transplantation, as it would avoid the toxicities of chronic immunosuppressive therapies while preventing acute and chronic graft rejection. A large number of approaches to tolerance induction have been described in the experimental literature, but only hematopoietic cell transplantation has shown preliminary success for intentional tolerance induction in pilot clinical trials. This review summarizes the conditions that allow progress to be made in moving strategies for tolerance induction from the bench to the bedside and discuss the mechanisms by which tolerance may be achieved through hematopoietic cell transplantation.

  8. On-chip monitoring of skeletal myoblast transplantation for the treatment of hypoxia-induced myocardial injury.

    PubMed

    He, Juan; Ma, Chao; Liu, Wenming; Wang, Jinyi

    2014-09-21

    A comprehensive elucidation of the unexpected adverse events that occur in skeletal myoblast transplantation is fundamental for the optimization of myocardial therapeutic effects. However, a well-defined method to study the interactions between skeletal myoblasts and cardiomyocytes during the healing process is out of reach. Here, we describe a microfluidic method for monitoring the interactions between skeletal myoblasts and hypoxia-injured cardiomyocytes in a spatiotemporally-controlled manner, mimicking the in vivo cell transplantation process. A myocardial hypoxia environment was created using an oxygen consumption blocking reagent, carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone. Meanwhile, the interactions between the skeletal L6 myoblasts and hypoxia-injured myocardium H9c2 cells were investigated, and the effects of a L6 conditional medium on H9c2 cells were comparatively analyzed by quantitatively measuring the morphological and pathophysiological dynamics of H9c2 cells. The results showed that skeletal myoblasts could repair hypoxia-injured H9c2 cells mainly through direct cell-to-cell interactions. This simple on-chip assay for investigating myocardial repair processes may provide avenues for the in vitro screening of drug-induced cardiotoxicity.

  9. Study of mouse induced pluripotent stem cell transplantation intoWistar albino rat cochleae after hair cell damage.

    PubMed

    Gökcan, Mustafa Kürşat; Mülazimoğlu, Selçuk; Ocak, Emre; Can, Pınar; Çalışkan, Murat; Beşaltı, Ömer; Dizbay Sak, Serpil; Kaygusuz, Gülşah

    2016-11-17

    As the regeneration capacity of hair cells is limited, inner ear stem cell therapies hold promise. Effects of mouse induced pluripotent stem cells (IPSCs) on Wistar albino rats (WARs) with hearing impairment were investigated. Thirty-five adult WARs with normal hearing were divided into 4 groups. Excluding the study group (n = 15), the other three groups served as control groups for ototoxicity and IPSC injection models. IPSC injections were performed via cochleostomy after a retroauricular approach. Auditory functions were evaluated with auditory brainstem responses (ABRs) before and after the injections. After a final hearing assessment the WARs were sacrificed and cochleae were extracted to see the biologic behavior of IPSCs in the inner ear by light microscopy and immunohistochemistry. There were no significant differences in the click-ABR thresholds in the study group after IPSC transplantation. The mean hearing threshold in the study group after ototoxic agent injection was 53.2 dB (10-90 dB). There was no significant difference between groups (P > 0.05) and no differentiated stem cells were observed immunohistochemically. Transplanted IPSCs did not show a therapeutic effect in this trial. We discuss potential pitfalls and factors affecting the therapeutic effect.

  10. Heparin-induced thrombocytopenia (HIT II) in liver transplant recipients: a retrospective multivariate analysis of prognostic factors.

    PubMed

    Hüser, Norbert; Aßfalg, Volker; Reim, Daniel; Novotny, Alexander; Thorban, Stefan; Cheng, Zhangjun; Kornberg, Arno; Friess, Helmut; Büchler, Peter; Matevossian, Edouard

    2012-07-01

    We investigated the prevalence of HIT II in liver transplant recipients and analysed associated factors. In recipients with clinically suspected HIT II in the 4Ts pretest clinical scoring system HIPA-assay was performed. Next, 37 clinical variables were analysed retrospectively for their association with HIT II. Factors significantly correlated to our findings in univariate analysis were included in a multivariate model and binary logistic regression analysis. Among 46 recipients 21 patients were suspicious in the 4Ts pretest and 14 of them (30.4%) were diagnosed HIT-antibody positive. Patient's age (P = 0.001), postoperative dialysis (P = 0.028), and postoperative hospital stay (P = 0.035) were significantly associated with development of HIT-antibodies in univariate analysis. Postoperative dialysis and postoperative hospital stay turned out as epiphenomena of patient's age, the only independent predictor (P = 0.021). Using multiple χ(2) -testing, a cut-off could be calculated, assigning patients younger than 59 years to a low risk group and patients of 59 years and older to a high risk group. High incidence of peri-operative HIT II seroconversion in liver transplant recipients is not associated with factors known to induce thrombocyte activation, like blood products or cell-saver. Only patients' age was identified as independent predictor.

  11. Essential role for B cells in transplantation tolerance

    PubMed Central

    Redfield, Robert R; Rodriguez, Eduardo; Parsons, Ronald; Vivek, Kumar; Mustafa, Moiz M; Noorchashm, Hooman; Naji, Ali

    2017-01-01

    T lymphocytes are the primary targets of immunotherapy in clinical transplantation. However, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Therefore, the achievement of transplantation tolerance will likely require induction of both T and B cell tolerance to alloantigens. Moreover, human and animal investigations have shown that subsets of B cells, Transitional and Regulatory, are inherently tolerogenic. Developing therapeutic strategies that exploit these populations may be key to achieving transplantation tolerance. In this review we describe the current evidence for the essential role of B cells in transplant tolerance and discuss emerging B cell directed strategies to achieve allograft tolerance. PMID:21982511

  12. Total lymphatic irradiation and bone marrow in human heart transplantation

    SciTech Connect

    Kahn, D.R.; Hong, R.; Greenberg, A.J.; Gilbert, E.F.; Dacumos, G.C.; Dufek, J.H.

    1984-08-01

    Six patients, aged 36 to 59 years, had heart transplants for terminal myocardial disease using total lymphatic irradiation (TLI) and donor bone marrow in addition to conventional therapy. All patients were poor candidates for transplantation because of marked pulmonary hypertension, unacceptable tissue matching, or age. Two patients are living and well more than four years after the transplants. Two patients died of infection at six and seven weeks with normal hearts. One patient, whose preoperative pulmonary hypertension was too great for an orthotopic heart transplant, died at 10 days after such a procedure. The other patient died of chronic rejection seven months postoperatively. Donor-specific tolerance developed in 2 patients. TLI and donor bone marrow can produce specific tolerance to donor antigens and allow easy control of rejection, but infection is still a major problem. We describe a new technique of administering TLI with early reduction of prednisone that may help this problem.

  13. In vivo expansion of the endogenous B-cell compartment stimulated by radiation and serial bone marrow transplantation induces B-cell leukaemia in mice.

    PubMed

    Holyoake, T L; Freshney, M G; Samuel, K; Ansell, J; Watson, G E; Wright, E G; Graham, G J; Pragnell, I B

    2001-07-01

    Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells. This B-cell lineage is established during ontogeny and replenished by the process of self-renewal. Spontaneous and induced leukaemias that frequently affect this lineage are thought to arise as a result of the frequent cell division required to maintain the population throughout adulthood and in response to repeated exposure to environmental antigens. In a series of bone marrow transplant (BMT) experiments performed in B6D2F1 mice, B-cell leukaemia occurred in recipients of serially transplanted syngeneic bone marrow. This study was therefore designed to determine the frequency and phenotype of the observed leukaemia. Male donor cells were initially transplanted into lethally irradiated female hosts and secondary (2 degrees ) BMT was performed at 3 months. At 1, 2, 3 and 16 months following primary (1 degrees ) BMT, and when 2 degrees BMT recipients developed leukaemia, animals were sacrificed and their tissues extensively examined. These analyses confirmed a host-derived CD5(+) transplantable B-cell leukaemia that was initiated in 50% of 1 degrees BMT recipients. With serial passage, the leukaemia became more aggressive and lost CD5 expression, suggesting transformation to a high-grade leukaemia/lymphoma. This previously unreported observation suggests that the combination of radiation and subsequent serial transplantation induces a proliferative stress to the host B-cell compartment that is causative in leukaemic transformation.

  14. Kidney Transplant

    MedlinePlus

    Kidney transplant Overview By Mayo Clinic Staff A kidney transplant is a surgical procedure to place a healthy kidney ... bloodstream via a machine (dialysis) or a kidney transplant to stay alive. Mayo Clinic's approach . Mayo Clinic ...

  15. Lung Transplant

    MedlinePlus

    Lung transplant Overview By Mayo Clinic Staff A lung transplant is a surgical procedure to replace a diseased or ... lung, usually from a deceased donor. A lung transplant is reserved for people who have tried other ...

  16. Kidney transplant

    MedlinePlus

    Renal transplant; Transplant - kidney ... Barry JM, Conlin MJ. In: Renal transplantation. Wein AJ, ed. Campbell-Walsh Urology . 10th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 44. Kidney Disease: Improving Global Outcomes ( ...

  17. Efficacy of induction therapy with ATG and intravenous immunoglobulins in patients with low-level donor-specific HLA-antibodies.

    PubMed

    Bächler, K; Amico, P; Hönger, G; Bielmann, D; Hopfer, H; Mihatsch, M J; Steiger, J; Schaub, S

    2010-05-01

    Low-level donor-specific HLA-antibodies (HLA-DSA) (i.e. detectable by single-antigen flow beads, but negative by complement-dependent cytotoxicity crossmatch) represent a risk factor for early allograft rejection. The short-term efficacy of an induction regimen consisting of polyclonal anti-T-lymphocyte globulin (ATG) and intravenous immunoglobulins (IvIg) in patients with low-level HLA-DSA is unknown. In this study, we compared 67 patients with low-level HLA-DSA not having received ATG/IvIg induction (historic control) with 37 patients, who received ATG/IvIg induction. The two groups were equal regarding retransplants, HLA-matches, number and class of HLA-DSA. The overall incidence of clinical/subclinical antibody-mediated rejection (AMR) was lower in the ATG/IvIg than in the historic control group (38% vs. 55%; p = 0.03). This was driven by a significantly lower rate of clinical AMR (11% vs. 46%; p = 0.0002). Clinical T-cell-mediated rejection (TCR) was significantly lower in the ATG/IvIg than in the historic control group (0% vs. 50%; p < 0.0001). Within the first year, allograft loss due to AMR occurred in 7.5% in the historic control and in 0% in the ATG/IvIg group. We conclude that in patients with low-level HLA-DSA, ATG/IvIg induction significantly reduces TCR and the severity of AMR, but the high rate of subclinical AMR suggests an insufficient control of the humoral immune response.

  18. Treatment of surgically induced acute liver failure with transplantation of highly differentiated immortalized human hepatocytes.

    PubMed

    Kobayashi, N; Miyazaki, M; Fukaya, K; Inoue, Y; Sakaguchi, M; Noguchi, H; Matsumura, T; Watanabe, T; Totsugawa, T; Tanaka, N; Namba, M

    2000-01-01

    Primary human hepatocytes are an ideal source of hepatic function in bioartficial liver (BAL), but the shortage of human livers available for hepatocyte isolation limits this modality. To resolve this issue, primary human fetal hepatocytes were immortalized using simian virus 40 large T antigen. One of the immortal cell lines, OUMS-29, showed highly differentiated liver functions. Intrasplenic transplantation of OUMS-29 cells protected 90% hepatectomized rats from hyperammonemia and significantly prolonged their survival. Essentially unlimited availability of OUMS-29 cells supports their clinical use for BAL treatment.

  19. Persistence of Yellow Fever vaccine-induced antibodies after cord blood stem cell transplant

    PubMed Central

    Avelino-Silva, Vivian Iida; Freire, Marcos da Silva; Rocha, Vanderson; Rodrigues, Celso Arrais; Novis, Yana Sarkis; Sabino, Ester C.; Kallas, Esper Georges

    2016-01-01

    ABSTRACT We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments. PMID:26618995

  20. Hepatic Sinusoidal Obstruction Syndrome Induced by Non-transplant Chemotherapy for Non-Hodgkin Lymphoma

    PubMed Central

    Sakumura, Miho; Tajiri, Kazuto; Miwa, Shigeharu; Nagata, Kohei; Kawai, Kengo; Miyazono, Takayoshi; Arita, Kotaro; Wada, Akinori; Murakami, Jun; Sugiyama, Toshiro

    2017-01-01

    Hepatic sinusoidal obstruction syndrome (SOS), a serious complication that mainly occurs after hematopoietic-stem cell transplantation (HSCT), is caused by damage to the sinusoidal endothelial cells after the obstruction of the sinusoid. Recently, hepatic SOS was reported to occur after non-HSCT chemotherapies. This report describes a patient who experienced hepatic SOS after non-HSCT chemotherapy for non-Hodgkin lymphoma. A liver biopsy showed the slight dilatation of the hepatic sinusoid, which may be indicative of hepatic SOS. Hepatic SOS should be included in the differential diagnosis of patients with severe liver injury following the administration of chemotherapy regimens that are toxic to the vascular endothelial cells. PMID:28202860

  1. Tolerance induction in rats, using a combination of anti-CD154 and donor splenocytes, given once on the day of transplantation.

    PubMed

    Sebille, Fabien; Brouard, Sophie; Petzold, Thomas; Degauque, Nicolas; Guillet, Marina; Moreau, Anne; Benjamin, Christopher D; Soulillou, Jean-Paul

    2003-01-27

    Donor-specific tolerance induction remains an attractive objective that generates much research in the field of transplantation. Unfortunately, most of the protocols available involve pregraft conditioning, making these treatments incompatible with clinical applications. LEW.1A rats were grafted with histoincompatible LEW.1W hearts. On the day of transplantation, recipients were treated with anti-CD40L combined with donor splenocytes. The hearts were evaluated for graft survival; cellular infiltrate and intragraft cytokines were determined using real-time reverse transcriptase-polymerase chain reaction. Tolerance induction was assessed by skin grafting and adoptive transfers. The combination of a single injection of anti-CD40L and donor splenocytes, given on the day of surgery, allowed 40% of cardiac allografts to survive long-term (mean survival time=66.3 day). The cellular composition or the extent of graft infiltrate was not modified but was associated with a massive decrease of proinflammatory cytokines expression within the graft. Long-term survivors accepted donor-matched skin grafts, and leukocytes harvested from these animals transferred tolerance into irradiated freshly grafted recipients. A combination of costimulation blockade and donor cells, given once at the time of transplantation, is sufficient to induce allograft tolerance in rats.

  2. Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

    PubMed

    Hui, John

    2016-02-01

    This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole. © The Author(s) 2014.

  3. Dimethyl sulfoxide-induced toxicity in cord blood stem cell transplantation: report of three cases and review of the literature.

    PubMed

    Ruiz-Delgado, Guillermo J; Mancías-Guerra, Consuelo; Tamez-Gómez, Edna L; Rodríguez-Romo, Laura N; López-Otero, Avril; Hernández-Arizpe, Ana; Gómez-Almaguer, David; Ruiz-Argüelles, Guillermo J

    2009-01-01

    Umbilical cord blood transplantation using nonmyeloablative conditioning is currently considered by many as a valid potential alternative for any patient who requires an unrelated donor allograft and who is without a suitably matched and readily available volunteer. Dimethyl sulfoxide (DMSO) has been used for years as a cryoprotectant agent; it acts by penetrating the cell and binding water molecules and it has been described as harmless for the individual who receives it in limited amounts. In this paper, we describe 3 cases of DMSO-induced toxicities and briefly review the most common adverse reactions of the DMSO when used as a cryopreservation agent for the long-term storage of cord blood cells. Two of the 3 cases had a dismal prognosis. A brief review of the literature is presented. 2009 S. Karger AG, Basel

  4. Antibody-Mediated Lung Transplant Rejection

    PubMed Central

    Hachem, Ramsey

    2012-01-01

    Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428

  5. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation.

    PubMed

    Rodrigo, L; de Francisco, R; Pérez-Pariente, J M; Cadahia, V; Tojo, R; Rodriguez, M; Lucena, Ma I; Andrade, R J

    2002-11-01

    We present the case of a 63-year-old woman who had undergone 7 months of treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The patient was admitted to our unit with a clinical picture of progressive jaundice over 3 weeks. Clinical and analytical studies revealed acute liver failure, this being confirmed by liver biopsy, which showed submassive necrosis. Serological tests for different viral agents causing hepatitis were all negative. In addition, she presented a picture of severe haemolytic anaemia resistant to several treatments and needed multiple transfusions. Twenty-three days after admission, the patient presented hepatic encephalopathy and received an orthotopic liver transplant on day 25. The evolution after transplantation was good and the patient continues in good health with no evidence of haemolysis almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our knowledge the occurrence of haemolytic anaemia has not been related to this drug previously. For these reasons, Nimesulide has been restricted or removed from the market in several countries in recent months.

  6. Detection of Donor-Derived Microparticles in the Peripheral Blood of a Hand Transplant Recipient During Rejection

    PubMed Central

    Kim, Joseph Y.; Kelesidis, Theodoros; Yang, Otto O.

    2017-01-01

    Background Microparticles (MPs) are released from the plasma membrane of activated or dying cells and bear surface molecules from those cells. We examined whether donor-derived MPs in the peripheral blood of the recipient could serve as a marker of tissue damage due to rejection of a transplanted hand. Methods Platelet-free plasma from the recipient of the transplanted hand was analyzed for MPs bearing the donor-specific HLA molecule A*02 using flow cytometry. Rejection status of the transplanted hand was monitored by histopathology of skin punch biopsies. Results Donor-specific MPs expressing HLA A*02 were quantifiable in the peripheral blood of the recipient. Levels of these MPs increased with worsening rejection of the transplanted hand. Conclusions These findings demonstrate the ability to detect donor specific MPs through staining of graft cell-specific HLA and promote further investigation into the potential utility of flow cytometry for donor-derived MPs as a noninvasive tool to assess rejection in solid organ transplantation patients.

  7. Sensitivity to myc-induced apoptosis is retained in spontaneous and transplanted lymphomas of CD2-mycER mice.

    PubMed

    Blyth, K; Stewart, M; Bell, M; James, C; Evan, G; Neil, J C; Cameron, E R

    2000-02-10

    To study the effects of the Myc oncoprotein in a regulatable in vivo system, we generated lines of transgenic mice in which a tamoxifen inducible Myc fusion protein (c-mycER) is expressed under the control of the CD2 locus control region. Activation of the Myc oncoprotein resulted in both proliferation and apoptosis in vivo. Lines with a high transgene copy number developed spontaneous lymphomas at low frequency, but the tumour incidence was significantly increased with tamoxifen treatment. Surprisingly, we found that cellular sensitivity to Myc-induced apoptosis was retained in tumours from these mice and in most lymphoma cell lines, even when null for p53. Resistance to Myc-induced apoptosis could be conferred on these cells by co-expression of Bcl-2. However, acquired resistance is clearly not an obligatory progression event as sensitivity to apoptosis was retained in transplanted tumours in athymic mice. In conclusion, lymphomas arising in CD2-mycER mice retain the capacity to undergo apoptosis in response to Myc activation and show no phenotypic evidence of the presence of an active dominant inhibitor.

  8. Prolonging survival in vascularized bone allograft transplantation: developing specific immune unresponsiveness

    SciTech Connect

    Paskert, J.P.; Yaremchuk, M.J.; Randolph, M.A.; Weiland, A.J.

    1987-04-01

    Vascularized bone allografts (VBAs) could be useful adjuncts to the clinical reconstructive surgeon's arsenal. These grafts are known experimentally to be subject to host rejection. One way to control the rejection problem would be to develop specific immune unresponsiveness via host conditioning. Using a proven reliable model in inbred rats for studying heterotopic VBA transplantation, recipient animals were conditioned preoperatively with third-party unrelated blood, donor-specific blood (DSB) alone and with cyclosporine, and ultraviolet irradiated donor-specific blood. The combination of DSB plus cyclosporine delayed rejection of grafts across a strong histocompatibility barrier for three to four weeks. However, rejection was delayed across a weak histocompatibility barrier for five to six weeks using this same host pretreatment. The implications are that specific immunosuppression, although possible, is difficult to achieve in VBA transplantation, and that such techniques will rely on tissue-matching to minimize the genetic disparity between graft and host.

  9. Anti-thymocyte globulin induced non-cardiogenic pulmonary edema during renal transplantation.

    PubMed

    Parikh, Beena K; Bhosale, Guruprasad P; Shah, Veena R

    2011-10-01

    Non-cardiogenic pulmonary edema (NCPE) is a clinical syndrome characterized by simultaneous presence of severe hypoxemia, bilateral alveolar infiltrates on chest radiograph, without evidence of left atrial hypertension/congestive heart failure/fluid overload. The diagnosis of drugrelated NCPE relies upon documented exclusion of other causes of NCPE like gastric aspiration, sepsis, trauma, negative pressure pulmonary edema. We describe a 28year-old, 50 kg male with ASA risk III posted for laparoscopic renal transplantation, who developed NCPE after 4 hours of administration of rabbit anti-human thymocyte immunoglobulin (ATG). He was successfully treated with mechanical ventilatory support and adjuvant therapy. This report emphasizes that this fatal complication may occur with use of ATG.

  10. Association of Campylobacter pylori with induced expression of class II transplantation antigens on gastric epithelial cells.

    PubMed Central

    Engstrand, L; Scheynius, A; Påhlson, C; Grimelius, L; Schwan, A; Gustavsson, S

    1989-01-01

    Campylobacter pylori was identified with immunoperoxidase staining and a mouse monoclonal antibody directed against C. pylori in gastric biopsy specimens from 24 patients with gastritis. C. pylori was not found in gastric biopsy specimens from six subjects with histologically normal mucosa. The monoclonal antibody, which was reactive with a surface protein of approximately 20 kilodaltons, was found to be specific for C. pylori, and the immunoperoxidase staining proved to be more sensitive and rapid than culture in detecting the organism. In the tissue specimens where C. pylori was detected with the monoclonal antibody, there was a strong expression of class II transplantation antigens on the epithelial cells and an increased number of T lymphocytes. These findings indicate that C. pylori may initiate local immune responses. Images PMID:2645211

  11. Effects of bone marrow cell transplant on thyroid function in an I131-induced low T4 and elevated TSH rat model

    PubMed Central

    Guajardo-Salinas, Gustavo E; Carvajal, Juan A; Gaytan-Ramos, Ángel A; Arroyo, Luis; López-Reyes, Alberto G; Islas, José F; Cano, Beiman G; Arroyo-Currás, Netzahualcoyótl; Dávalos, Alfredo; Madrid, Gloria; Moreno-Cuevas, Jorge E

    2007-01-01

    Background We developed a study using low dose radioactive iodine creating an animal model of transient elevation of thyroid stimulating hormone (TSH). Male derived bone marrow cells were transplanted to asses their effect on thyroid function and their capability to repair the thyroid parenchyma. Results At 40 an 80 days after I131 treatment, the study groups TSH and T4 serum values both increased and decreased significantly respectively compared to the negative control group. Eight weeks after cell transplantation, neither TSH nor T4 showed a significant difference in any group. The mean number of SRY gene copies found in group I (Left Intracardiac Transplant) was 523.3 and those in group II (Intrathyroid Transplant) were only 73. Group III (No Transplant) and IV had no copies. Group I presented a partial restore of the histological pattern of rat thyroid with approximately 20% – 30% of normal-sized follicles. Group II did not show any histological differences compared to group III (Positive control). Conclusion Both a significant increase of TSH and decrease of T4 can be induced as early as day 40 after a low dose of I131 in rats. Restore of normal thyroid function can be spontaneously achieved after using a low dose RAI in a rat model. The use of BM derived cells did not affect the re-establishment of thyroid function and might help restore the normal architecture after treatment with RAI. PMID:17233913

  12. Tumour-Associated Transplantation Antigens of Neoplasms Induced by a Naturally Occurring Murine Sarcoma Virus (FBJ-MSV)

    PubMed Central

    Jones, David B.; Moore, Michael

    1973-01-01

    FBJ osteosarcoma virus (FBJ-MSV) isolated originally from a spontaneously arising osteosarcoma in a CF1 mouse is the only known naturally occurring murine sarcoma virus (MSV). It is unique among strains of MSV in producing primarily sarcomata in mice. The capacity of tumour cells transformed in vivo by this agent to elicit specific transplantation immunity in syngeneic hosts was investigated. A low level of resistance (104-105 cells) was consistently induced by implantation of x-irradiated (15,000 rad) tumours or surgical excision of developing subcutaneous grafts. By contrast intraperitoneal inoculation of virus containing cellfree extracts of FBJ-MSV sarcomata was a far less effective immunization procedure. Confirmatory evidence for the antigenicity of these neoplasms was obtained in tests in which preincubation of tumour cells with lymphoid cells from specifically immune donors inhibited in vivo outgrowth of the FBJ-MSV cells in untreated syngeneic recipients. The induction of host resistance to FBJ-MSV cells by immunization with identical and independently-induced FBJ-MSV tumours established that FBJ-MSV cells possess common cell surface antigenic specificities in a manner analogous to those of experimental neoplasms induced by other oncogenic DNA and RNA viruses. Since FBJ-MSV cells release infectious virus it was not possible in this system to establish whether the tumour-rejection antigen was cellular or virion in nature. The antigenic weakness of FBJ-MSV cells in syngeneic hosts is comparable with that of virus-induced murine leukaemias of the Gross (G) or “wild” type subgroup to which category FBJ-MSV also belongs. These features suggest that FBJ-MSV exemplifies naturally occurring sarcomagenic viruses more closely than those of the Friend-Moloney-Rauscher-Graffi (FMRGr) subgroup which in general induce highly antigenic neoplasms. PMID:4516007

  13. Characterization of transfusion-elicited acute antibody-mediated rejection in a rat model of kidney transplantation.

    PubMed

    Huang, G; Wilson, N A; Reese, S R; Jacobson, L M; Zhong, W; Djamali, A

    2014-05-01

    Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients.

  14. Hypoxia Induces Mesenchymal Gene Expression in Renal Tubular Epithelial Cells: An in vitro Model of Kidney Transplant Fibrosis.

    PubMed

    Zell, Stephanie; Schmitt, Roland; Witting, Sandra; Kreipe, Hans H; Hussein, Kais; Becker, Jan U

    2013-01-01

    The development of interstitial fibrosis and tubular atrophy is a common complication after kidney transplantation and is associated with reduced long-term outcome. The hallmark of tubulointerstitial fibrosis is an increase in extracellular matrix resulting from exaggerated activation of fibroblasts/myofibroblasts, and tubular atrophy is characterized by a decrease in tubular diameter and loss of function. Atrophic epithelial cells may undergo epithelial-to-mesenchymal transition (EMT) with potential differentiation into interstitial fibroblasts. One potential driver of EMT in developing interstitial fibrosis and tubular atrophy is chronic hypoxia. The expression of 46 EMT-related genes was analyzed in an in vitro hypoxia model in renal proximal tubular epithelial cells (RPTEC). Furthermore, the expression of 342 microRNAs (miR) was evaluated in hypoxic culture conditions. Hypoxic RPTEC expressed markers of a more mesenchymal phenotype and showed an increased expression of matrix metalloproteinase-2 (MMP2). MMP2 expression in RPTEC correlated inversely with a decreased expression of miR-124, which was found to have a putative binding site for the MMP2 transcript. Overexpression of miR-124 inhibited MMP2 protein translation. Hypoxia was associated with increased migration/proliferation of RPTEC which was reversed by miR-124. These results indicate that hypoxia promotes a mesenchymal and migratory phenotype in renal epithelial cells, which is associated with increased MMP2 expression. Hypoxia-dependent MMP2 expression is regulated via a reduced transcription of miR-124. Overexpression of miR-124 antagonizes hypoxia-induced cell migration. Further research is needed to elucidate the functional role of miR-124 and MMP2 in the development of fibrosis in renal transplant degeneration.

  15. Hypoxia Induces Mesenchymal Gene Expression in Renal Tubular Epithelial Cells: An in vitro Model of Kidney Transplant Fibrosis

    PubMed Central

    Zell, Stephanie; Schmitt, Roland; Witting, Sandra; Kreipe, Hans H.; Hussein, Kais; Becker, Jan U.

    2013-01-01

    Background The development of interstitial fibrosis and tubular atrophy is a common complication after kidney transplantation and is associated with reduced long-term outcome. The hallmark of tubulointerstitial fibrosis is an increase in extracellular matrix resulting from exaggerated activation of fibroblasts/myofibroblasts, and tubular atrophy is characterized by a decrease in tubular diameter and loss of function. Atrophic epithelial cells may undergo epithelial-to-mesenchymal transition (EMT) with potential differentiation into interstitial fibroblasts. One potential driver of EMT in developing interstitial fibrosis and tubular atrophy is chronic hypoxia. Methods The expression of 46 EMT-related genes was analyzed in an in vitro hypoxia model in renal proximal tubular epithelial cells (RPTEC). Furthermore, the expression of 342 microRNAs (miR) was evaluated in hypoxic culture conditions. Results Hypoxic RPTEC expressed markers of a more mesenchymal phenotype and showed an increased expression of matrix metalloproteinase-2 (MMP2). MMP2 expression in RPTEC correlated inversely with a decreased expression of miR-124, which was found to have a putative binding site for the MMP2 transcript. Overexpression of miR-124 inhibited MMP2 protein translation. Hypoxia was associated with increased migration/proliferation of RPTEC which was reversed by miR-124. Conclusions These results indicate that hypoxia promotes a mesenchymal and migratory phenotype in renal epithelial cells, which is associated with increased MMP2 expression. Hypoxia-dependent MMP2 expression is regulated via a reduced transcription of miR-124. Overexpression of miR-124 antagonizes hypoxia-induced cell migration. Further research is needed to elucidate the functional role of miR-124 and MMP2 in the development of fibrosis in renal transplant degeneration. PMID:23898346

  16. Point mutation in activated c-Ha-ras gene of a chemically induced transplantable human pancreas carcinoma

    SciTech Connect

    Maheshwari, K.K.; Parsa, I.

    1986-03-05

    The authors have reported a model of human pancreas carcinogenesis where repeated treatment with MNU of explants results in the development of transplantable carcinoma. This report compares the endonuclease digests of DNAs from normal human pancreas (HP) and MNU-induced transplantable tumor (HP-T1) analyzed with /sup 32/P-labelled Ha-ras probe prepared from clone BS-9. The hybridization patterns of BamHI, BglII, EcoRI and HindIII digests of HP were significantly different from those of HP-T1. In EcoRI digests a 3.0 kb fragments of HP-T1 DNA hybridized with Ha-ras probe instead of a 4.3 kb fragments seen in HP DNA. The pattern for HindIII digests was similar to those of EcoRI. The BgIII digests of HP DNA revealed two hybridizing fragments of 8.0 and 4.3 kb whereas those of HP-T1 DNA fragments measured 8.5 and 4.0 kb. BamHI treated HP DNA showed only hybridizing fragments of 6.6 kb while the HP-T1 DNA showed to hybridizing fragments of 6.8 and 7.2 kb. The digested DNAs by HhaI, HinfI, KpnI, pstI, PvuII, SaII, SstI, TaqI and XbaI showed similar hybridization profiles. The point mutation in c-Ha-ras was examined in the HpaII and MspI double digests of both DNAs by 0.6 Kb SmaI fragments of pEJ. The hybridized fragments measured 412 and 355 bp in DNA digests from tumor and normal pancreas respectively.

  17. Post-translational modification of manganese superoxide dismutase in acutely rejecting cardiac transplants: role of inducible nitric oxide synthase.

    PubMed

    Nilakantan, Vani; Halligan, Nadine L N; Nguyen, Thanh K; Hilton, Gail; Khanna, Ashwani K; Roza, Allan M; Johnson, Christopher P; Adams, Mark B; Griffith, Owen W; Pieper, Galen M

    2005-10-01

    Nitration of a critical tyrosine residue in the active site of manganese superoxide dismutase (MnSOD) can lead to enzyme inactivation. In this study, we examined the effect of inducible nitric oxide synthase (iNOS) on MnSOD expression, activity and nitration in acutely rejecting cardiac transplants. Lewis (isograft) or Wistar-Furth (allograft) donor hearts were transplanted into Lewis recipient rats. Some rats received L-N6-(1-iminoethyl) lysine (l-NIL), a specific iNOS inhibitor. Protein nitration was determined by immunohistochemical, Western blot and slot-blot analyses. MnSOD enzyme activity and gene expression were determined using Western, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoprecipitation techniques. MnSOD protein levels were decreased 50% by post-operative day 6 (POD 6), which was prevented by L-NIL. RT-PCR analysis indicated that this decrease could not be explained by any changes in MnSOD mRNA. MnSOD enzyme activity but not protein was decreased at POD 5 in untreated allografts. The loss of MnSOD activity at POD 5 was also prevented by L-NIL. Immunoreactive nitrotyrosine was apparent in untreated allografts at POD 6. Slot-blot analysis indicated that nitrotyrosine formation in allografts could be blocked by L-NIL. Nitration of MnSOD was evident upon immunoprecipitation of MnSOD followed by Western blotting for nitrotyrosine. These results suggest that the decreased MnSOD enzyme activity in acutely rejecting cardiac allografts can be attributed to a post-translational modification related to nitration arising via an iNOS-dependent pathway. This could be a potential major source of amplified oxidative stress in acute graft rejection.

  18. Hand transplantation.

    PubMed

    Amer, Hatem; Carlsen, Brian T; Dusso, Jennifer L; Edwards, Brooks S; Moran, Steven L

    2011-05-01

    The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010.

  19. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation.

    PubMed

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway.

  20. Microarray expression profiles of genes in lung tissues of rats subjected to focal cerebral ischemia-induced lung injury following bone marrow-derived mesenchymal stem cell transplantation

    PubMed Central

    Hu, Yue; Xiong, Liu-Lin; Zhang, Piao; Wang, Ting-Hua

    2017-01-01

    Ischemia-induced stroke is the most common disease of the nervous system and is associated with a high mortality rate worldwide. Cerebral ischemia may lead to remote organ dysfunction, particular in the lungs, resulting in lung injury. Nowadays, bone marrow-derived mesenchymal stem cells (BMSCs) are widely studied in clinical trials as they may provide an effective solution to the treatment of neurological and cardiac diseases; however, the underlying molecular mechanisms remain unknown. In this study, a model of permanent focal cerebral ischemia-induced lung injury was successfully established and confirmed by neurological evaluation and lung injury scores. We demonstrated that the transplantation of BMSCs (passage 3) via the tail vein into the lung tissues attenuated lung injury. In order to elucidate the underlying molecular mechanisms, we analyzed the gene expression profiles in lung tissues from the rats with focal cerebral ischemia and transplanted with BMSCs using a Gene microarray. Moreover, the Gene Ontology database was employed to determine gene function. We found that the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) were downregulated in the BMSC transplantation groups, compared with the control group. These results suggested that BMSC transplantation may attenuate lung injury following focal cerebral ischemia and that this effect is associated with the downregulation of TGF-β, PDGF and the PI3K-AKT pathway. PMID:27922691

  1. Miconazole mucoadhesive buccal tablet in high-dose therapy with autologous stem cell transplantation (HDT/ASCT)-induced mucositis.

    PubMed

    Orvain, C; Moles-Moreau, M P; François, S; Mercier, M; Moal, F; Hamel, J F; Parot-Schinkel, E; Ifrah, N; Hunault-Berger, M; Tanguy-Schmidt, A

    2015-02-01

    Oral mucositis is a major cause of morbidity in high-dose therapy/autologous stem cell transplantation (HDT/ASCT), where microbial colonization has an important pathological implication. In this study, we evaluated the impact of miconazole mucoadhesive buccal tablet (MBT) on mucositis-related complications. During two consecutive 34-month periods, patients treated with HDT/ASCT in our hematology department received either miconazole MBT (60 patients) or conventional oral amphotericin B suspensions three times a day (44 patients) in order to prevent or decrease chemotherapy-induced mucositis. The use of miconazole MBT is associated with less infectious complications as indicated by shorter antibiotic use (7.8 vs. 12.3 days; p < 0.0001), shorter intravenous antifungal use (1.4 vs. 3.6 days; p = 0.02), and a trend towards less yeast contamination in stool samples. Less patients required any analgesic drugs during hospitalization in the miconazole MBT group (18 vs. 7 %; p = 0.09). Indirect indicators of chemotherapy-induced mucositis (duration of hospitalization, morphine use) were in favor of miconazole MBT in patients with multiple myeloma (MM) but not for those with lymphoma. This study suggests that miconazole MBT provides a valid alternative to oral amphotericin B suspensions in regards to mucositis-related complications. A prospective and randomized study is warranted to establish the definite role of miconazole MBT.

  2. Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation

    PubMed Central

    Doi, Daisuke; Samata, Bumpei; Katsukawa, Mitsuko; Kikuchi, Tetsuhiro; Morizane, Asuka; Ono, Yuichi; Sekiguchi, Kiyotoshi; Nakagawa, Masato; Parmar, Malin; Takahashi, Jun

    2014-01-01

    Summary Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. Here, we show that human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, CORIN. We induced DA neurons using scalable culture conditions on human laminin fragment, and the sorted CORIN+ cells expressed the midbrain DA progenitor markers, FOXA2 and LMX1A. When transplanted into 6-OHDA-lesioned rats, the CORIN+ cells survived and differentiated into midbrain DA neurons in vivo, resulting in significant improvement of the motor behavior, without tumor formation. In particular, the CORIN+ cells in a NURR1+ cell-dominant stage exhibited the best survival and function as DA neurons. Our method is a favorable strategy in terms of scalability, safety, and efficiency and may be advantageous for clinical application. PMID:24672756

  3. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis.

    PubMed

    Kump, Patrizia K; Gröchenig, Hans-Peter; Lackner, Stefan; Trajanoski, Slave; Reicht, Gerhard; Hoffmann, K Martin; Deutschmann, Andrea; Wenzl, Heimo H; Petritsch, Wolfgang; Krejs, Guenter J; Gorkiewicz, Gregor; Högenauer, Christoph

    2013-09-01

    In patients with ulcerative colitis (UC), alterations of the intestinal microbiota, termed dysbiosis, have been postulated to contribute to intestinal inflammation. Fecal microbiota transplantation (FMT) has been used as effective therapy for recurrent Clostridium difficile colitis also caused by dysbiosis. The aims of the present study were to investigate if patients with UC benefit from FMT and if dysbiosis can be reversed. Six patients with chronic active UC nonresponsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA-based microbial community profiling using high-throughput pyrosequencing from mucosal and stool samples. All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of Proteobacteria and an increase in Bacteroidetes after FMT. FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy-refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. The results suggest that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.

  4. Outcomes of pediatric identical living-donor liver and hematopoietic stem cell transplantation.

    PubMed

    Hartleif, Steffen; Lang, Peter; Handgretinger, Rupert; Feuchtinger, Tobias; Fuchs, Jörg; Königsrainer, Alfred; Nadalin, Silvio; Sturm, Ekkehard

    2016-11-01

    Chronic IS is associated with significant morbidity in transplant recipients. Moreover, IS does not prevent chronic graft failure frequently. Allograft immune tolerance in LT can be induced by complete donor chimerism through allogenic HSCT combined with identical LDLT. This approach may exempt patients from chronic lifelong IS. However, it is unclear whether its benefits justify its risks. Here, we present three cases from our institution and analyze seven additional reports of children treated with HSCT/LDLT, all receiving HSCT due to hemato-oncological indications. In eight of 10 cases, donor macrochimerism resulted in allograft tolerance. Nine patients survived. One patient died due to fulminant ADV infection. Further complications were GvHD (n = 3) and bone marrow failure (n = 2). In conclusion, donor-specific allograft tolerance can be achieved by identical-donor HSCT/LDLT. However, at present, this approach should generally be limited to selected indications due to a potentially unfavorable risk-benefit ratio. Novel toxicity-reduced conditioning protocols for HSCT/LDLT in the absence of malignant or non-hepatic disease may prove to be a sufficiently safe approach for inducing graft tolerance in children receiving a LDLT in the future. This concept may reduce the burden of lifelong IS. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. The long-term outcome of treated sensitized patients who undergo heart transplantation.

    PubMed

    Kobashigawa, Jon A; Patel, Jignesh K; Kittleson, Michelle M; Kawano, Matt A; Kiyosaki, Krista K; Davis, Stephanie N; Moriguchi, Jaime D; Reed, Elaine F; Ardehali, Abbas A

    2011-01-01

    Sensitized patients prior to heart transplantation are reportedly at risk for hyperacute rejection and for poor outcome after heart transplantation. It is not known whether the reduction of circulating antibodies pre-transplant alters post-transplant outcome. Between July 1993 and July 2003, we reviewed 523 heart transplant patients of which 95 had pre-transplant panel reactive antibody (PRAs) >10%; 21/95 were treated pre-transplant for circulating antibodies. These 21 patients had PRAs > 10% (majority 50-100%) and were treated with combination therapy including plasmapheresis, intravenous gamma globulin and rituximab to reduce antibody counts. The 74 untreated patients with PRAs > 10% (untreated sensitized group) and those patients with PRAs < 10% (control group) were used for comparison. Routine post-transplant immunosuppression included triple-drug therapy. After desensitization therapy, circulating antibody levels pre-transplant decreased from a mean of 70.5 to 30.2%, which resulted in a negative prospective donor-specific crossmatch and successful heart transplantation. Compared to the untreated sensitized group and the control group, the treated sensitized group had similar five-yr survival (81.1% and 75.7% vs. 71.4%, respectively, p = 0.523) and freedom from cardiac allograft vasculopathy (74.3% and 72.7% vs. 76.2%, respectively, p = 0.850). Treatment of sensitized patients pre-transplant appears to result in acceptable long-term outcome after heart transplantation. © 2010 John Wiley & Sons A/S.

  6. The long-term outcome of treated sensitized patients who undergo heart transplantation

    PubMed Central

    Kobashigawa, Jon A.; Patel, Jignesh K.; Kittleson, Michelle M.; Kawano, Matt A.; Kiyosaki, Krista K.; Davis, Stephanie N.; Moriguchi, Jaime D.; Reed, Elaine F.; Ardehali, Abbas A.

    2013-01-01

    Background Sensitized patients prior to heart transplantation are reportedly at risk for hyperacute rejection and for poor outcome after heart transplantation. It is not known whether the reduction of circulating antibodies pre-transplant alters post-transplant outcome. Methods and Results Between July 1993 and July 2003, we reviewed 523 heart transplant patients of which 95 had pre-transplant panel reactive antibody (PRAs) >10%; 21/95 were treated pre-transplant for circulating antibodies. These 21 patients had PRAs > 10% (majority 50–100%) and were treated with combination therapy including plasmapheresis, intravenous gamma globulin and rituximab to reduce antibody counts. The 74 untreated patients with PRAs > 10% (untreated sensitized group) and those patients with PRAs < 10% (control group) were used for comparison. Routine post-transplant immunosuppression included triple-drug therapy. After desensitization therapy, circulating antibody levels pre-transplant decreased from a mean of 70.5 to 30.2%, which resulted in a negative prospective donor-specific crossmatch and successful heart transplantation. Compared to the untreated sensitized group and the control group, the treated sensitized group had similar five-yr survival (81.1% and 75.7% vs. 71.4%, respectively, p = 0.523) and freedom from cardiac allograft vasculopathy (74.3% and 72.7% vs. 76.2%, respectively, p = 0.850). Conclusion Treatment of sensitized patients pre-transplant appears to result in acceptable long-term outcome after heart transplantation. PMID:20973825

  7. N-acetylcysteine induces shedding of selectins from liver and intestine during orthotopic liver transplantation

    PubMed Central

    Taut, F J H; Schmidt, H; Zapletal, C M; Thies, J C; Grube, C; Motsch, J; Klar, E; Martin, E

    2001-01-01

    In orthotopic liver transplantation (OLT), N-acetylcysteine (NAC) reduces ischaemia/reperfusion (I/R) injury, improves liver synthesis function and prevents primary nonfunction of the graft. To further elucidate the mechanisms of these beneficial effects of NAC, we investigated influence of high-dose NAC therapy on the pattern of adhesion molecule release from liver and intestine during OLT. Nine patients receiving allograft OLT were treated with 150 mg NAC/kg during the first hour after reperfusion; 10 patients received the carrier only. One hour after reperfusion, samples of arterial, portal venous and hepatic venous plasma were taken and blood flow in the hepatic artery and the portal vein was measured. Absolute concentrations of sICAM-1, sVCAM-1, sP-selectin and sE-selectin were not markedly different. However, balance calculations showed release of selectins from NAC-treated livers as opposed to net uptake in controls (P ≤ 0·02 for sP-selectin). This shedding of selectins might be a contributing factor to the decrease in leucocyte adherence and improved haemodynamics found experimentally with NAC-treatment. PMID:11422213

  8. Physiological relaxation induced by horticultural activity: transplanting work using flowering plants

    PubMed Central

    2013-01-01

    Background Despite increasing attention and a growing volume of research data, little physiological evidence is available on the benefits of horticultural activity and the different effects on individuals. Therefore, the aim of the present study was to investigate the physiological effects of horticultural activity and to examine how differences in personality alter these effects. Results The effects of transplanting real flowers (horticultural activity) and handling artificial flowers (control activity) on human physiological activity were compared. On the first day, eight participants engaged in horticultural activity and another eight in the control activity. On the second day, participants switched roles. Participants’ physiological conditions during each activity were assessed by measuring the heart rate and heart rate variability (HRV). Psychological responses, which were measured using a semantic differential rating scale, showed that the horticultural activity promoted comfortable, soothed, and natural feelings, compared to the control activity. Analysis of physiological responses using two-way repeated measures analysis of variance (ANOVA) revealed that sympathetic nervous activity significantly decreased in the late time period (11 to 15 minutes) of horticultural activity only in the type A group. Conclusions This study supports the fact that the horticultural activity can enhance psychological and physiological relaxation effects, although these physiological effects can differ among individuals with different personalities. PMID:24112302

  9. Physiological relaxation induced by horticultural activity: transplanting work using flowering plants.

    PubMed

    Lee, Min-sun; Park, Bum-jin; Lee, Juyoung; Park, Kun-tae; Ku, Ja-hyeong; Lee, Jun-woo; Oh, Kyung-ok; Miyazaki, Yoshifumi

    2013-10-10

    Despite increasing attention and a growing volume of research data, little physiological evidence is available on the benefits of horticultural activity and the different effects on individuals. Therefore, the aim of the present study was to investigate the physiological effects of horticultural activity and to examine how differences in personality alter these effects. The effects of transplanting real flowers (horticultural activity) and handling artificial flowers (control activity) on human physiological activity were compared. On the first day, eight participants engaged in horticultural activity and another eight in the control activity. On the second day, participants switched roles. Participants' physiological conditions during each activity were assessed by measuring the heart rate and heart rate variability (HRV). Psychological responses, which were measured using a semantic differential rating scale, showed that the horticultural activity promoted comfortable, soothed, and natural feelings, compared to the control activity. Analysis of physiological responses using two-way repeated measures analysis of variance (ANOVA) revealed that sympathetic nervous activity significantly decreased in the late time period (11 to 15 minutes) of horticultural activity only in the type A group. This study supports the fact that the horticultural activity can enhance psychological and physiological relaxation effects, although these physiological effects can differ among individuals with different personalities.

  10. Transplantation of bone marrow-derived mesenchymal stem cells rescues partially rachitic phenotypes induced by 1,25-Dihydroxyvitamin D deficiency in mice

    PubMed Central

    Zhang, Zengli; Yin, Shaomeng; Xue, Xian; Ji, Ji; Tong, Jian; Goltzman, David; Miao, Dengshun

    2016-01-01

    To determine whether the transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) can improve the 1,25(OH)2D deficiency-induced rachitic phenotype, 2×106 BM-MSCs from wild-type mice or vehicle were transplanted by tail vein injection into mice deficient in 1,25(OH)2D due to targeted deletion of 1α(OH)ase (1α(OH)ase-/-). Our results show that 1α(OH)ase mRNA was expressed in the BM-MSCs derived from wild-type mice, and was detected in long bone, kidney and intestine from BM-MSC-transplanted 1α(OH)ase-/- recipients. Serum calcium, 1,25(OH)2D3 levels and body weight were significantly increased in BM-MSC-transplanted 1α(OH)ase-/- recipients compared to vehicle-treated 1α(OH)ase-/- mice. Skeletal mineralization improved in 1α(OH)ase-/- recipients as demonstrated by BMD measurement, micro-CT analysis and von Kossa staining of undecalcified sections. Expression levels of type I collagen, osteocalcin, bone sialoprotein and vitronectin and the size of calcified nodules were decreased in BM-MSC cultures from 1α(OH)ase-/- mice compared with those from wild-type mice, however, these parameters were increased in those from BM-MSCs-transplanted 1α(OH)ase-/- recipients compared with those from vehicle-treated 1α(OH)ase-/- mice. This study indicates that donor BM-MSCs cells can relocate to multiple tissues where they synthesize 1α(OH)ase and produce 1,25(OH)2D that contributes to the improvement of serum calcium and skeletal mineralization. Results from this study suggest that BM-MSC transplantation may provide a therapeutic approach to treatment of pseudovitamin D-deficiency rickets. PMID:27830022

  11. Therapeutic Efficacy of Human Hepatocyte Transplantation in a SCID/uPA Mouse Model with Inducible Liver Disease

    PubMed Central

    Douglas, Donna N.; Kawahara, Toshiyasu; Sis, Banu; Bond, David; Fischer, Karl P.; Tyrrell, D. Lorne J.; Lewis, Jamie T.; Kneteman, Norman M.

    2010-01-01

    Background Severe Combined Immune Deficient (SCID)/Urokinase-type Plasminogen Activator (uPA) mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH) which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk)/ganciclovir (GCV) system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK)/GCV system of hepatic failure in SCID/uPA mice. Methodology/Principal Findings In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32–87%). Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH. Conclusions/Significance Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced

  12. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression

    PubMed Central

    Kawai, Tatsuo; Cosimi, A. Benedict; Spitzer, Thomas R.; Tolkoff-Rubin, Nina; Suthanthiran, Manikkam; Saidman, Susan L.; Shaffer, Juanita; Preffer, Frederic I.; Ding, Ruchuang; Sharma, Vijay; Fishman, Jay A.; Dey, Bimalangshu; Ko, Dicken S.C.; Hertl, Martin; Goes, Nelson B.; Wong, Waichi; Williams, Winfred W.; Colvin, Robert B.; Sykes, Megan; Sachs, David H.

    2010-01-01

    Summary Five patients with end-stage renal disease received combined bone marrow and kidney transplants from HLA single-haplotype mismatched living related donors, with the use of a nonmyeloablative preparative regimen. Transient chimerism and reversible capillary leak syndrome developed in all recipients. Irreversible humoral rejection occurred in one patient. In the other four recipients, it was possible to discontinue all immunosuppressive therapy 9 to 14 months after the transplantation, and renal function has remained stable for 2.0 to 5.3 years since transplantation. The T cells from these four recipients, tested in vitro, showed donor-specific unresponsiveness and in specimens from allograft biopsies, obtained after withdrawal of immunosuppressive therapy, there were high levels of P3 (FOXP3) messenger RNA (mRNA) but not granzyme B mRNA. PMID:18216355

  13. Lung rejection occurs in lung transplant recipients with blood chimerism.

    PubMed

    Knoop, C; Andrien, M; Defleur, V; Antoine, M; de Francquen, P; Goldman, M; Estenne, M

    1997-07-15

    It has been postulated that chimerism after transplantation might promote graft acceptance. In the present study, we prospectively assessed blood chimerism in 10 lung transplant recipients during the first posttransplant year and investigated whether chimerism was associated with an immunologically stable situation of the graft. The recipients' peripheral blood mononuclear cells were obtained before transplantation and at various time points during the first postoperative year. Donor cells were detected using nested polymerase chain reaction amplification of a donor-specific HLA-DRB1 allele. Clinical graft acceptance was determined by the number of rejection episodes. The incidence of blood chimerism was high during the first 3 postoperative months and then decreased over time. All patients experienced at least one acute rejection episode, and three patients developed chronic rejection. We, thus, conclude that rejection of the lung allograft may occur in the presence of blood chimerism.

  14. Amifostine Induces Antioxidant Enzymatic Activities in Normal Tissues and a Transplantable Tumor That Can Affect Radiation Response

    SciTech Connect

    Grdina, David J. Murley, Jeffrey S.; Kataoka, Yasushi; Baker, Kenneth L.; Kunnavakkam, Rangesh; Coleman, Mitchell C.; Spitz, Douglas R.

    2009-03-01

    Purpose: To determine whether amifostine can induce elevated manganese superoxide dismutase (SOD2) in murine tissues and a transplantable SA-NH tumor, resulting in a delayed tumor cell radioprotective effect. Methods and Materials: SA-NH tumor-bearing C3H mice were treated with a single 400 mg/kg or three daily 50 mg/kg doses of amifostine administered intraperitoneally. At selected time intervals after the last injection, the heart, liver, lung, pancreas, small intestine, spleen, and SA-NH tumor were removed and analyzed for SOD2, catalase, and glutathione peroxidase (GPx) enzymatic activity. The effect of elevated SOD2 enzymatic activity on the radiation response of SA-NH cells was determined. Results: SOD2 activity was significantly elevated in selected tissues and a tumor 24 h after amifostine treatment. Catalase and GPx activities remained unchanged except for significant elevations in the spleen. GPx was also elevated in the pancreas. SA-NH tumor cells exhibited a twofold elevation in SOD2 activity and a 27% elevation in radiation resistance. Amifostine administered in three daily fractions of 50 mg/kg each also resulted in significant elevations of these antioxidant enzymes. Conclusions: Amifostine can induce a delayed radioprotective effect that correlates with elevated levels of SOD2 activity in SA-NH tumor. If limited to normal tissues, this delayed radioprotective effect offers an additional potential for overall radiation protection. However, amifostine-induced elevation of SOD2 activity in tumors could have an unanticipated deleterious effect on tumor responses to fractionated radiation therapy, given that the radioprotector is administered daily just before each 2-Gy fractionated dose.

  15. How deceased donor transplantation is impacting a decline in commercial transplantation-the Tamil Nadu experience.

    PubMed

    Abraham, Georgi; Reddy, Yuvaram N V; Amalorpavanathan, Joseph; Daniel, Dolly; Roy-Chaudhury, Prabir; Shroff, Sunil; Reddy, Yogesh

    2012-04-27

    India with a population of 1.2 billion has a renal transplantation rate of 3.25 per million population. The major cause of chronic kidney disease is hypertension and diabetes. The crude and age-adjusted incidence rates of end-stage renal disease are estimated to be 151 and 232 per million population, respectively, in India. There was a remarkable lack of knowledge in the public about deceased organ donation until a decade ago. However, the role played by the media and nongovernmental organizations in partnership with the government has emphasized and implemented deceased donor transplantation in certain states in India-to mention particularly, the Tamil Nadu model. In the last 2 years, deceased organ donation has reached 1.3 per million population in Tamil Nadu, thereby effectively eliminating commercial transplantation. There is no religious bar for organ donation. A central transplant coordinator appointed by the government oversees legitimate and transparent allocation of deceased organs both in the public and private facilities as per the transplant waiting list. This model also takes care of the poor sections of society by conducting donation and transplantation through government-run public facilities free of cost. In the last 2 years, deceased donor transplantation has been performed through this network procuring organs such as the heart, heart valves, lung, liver, kidneys, cornea, and skin. The infrastructural lack of immunological surveillance-including donor-specific antibody monitoring, human leukocyte antigen typing, and panel reactive antibody except in a few tertiary care centers-prevents allocation according to the immunological status of the recipient. This private-public partnership promoting deceased donor transplantation has effectively eliminated commercialization in transplantation in the state of Tamil Nadu with a population of 72 million which is a model for other regions of South Asia and developing countries.

  16. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice

    PubMed Central

    Govey, Peter M.; Zhang, Yue; Donahue, Henry J.

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone’s capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure. PMID:27936104

  17. Mechanical Loading Attenuates Radiation-Induced Bone Loss in Bone Marrow Transplanted Mice.

    PubMed

    Govey, Peter M; Zhang, Yue; Donahue, Henry J

    2016-01-01

    Exposure of bone to ionizing radiation, as occurs during radiotherapy for some localized malignancies and blood or bone marrow cancers, as well as during space travel, incites dose-dependent bone morbidity and increased fracture risk. Rapid trabecular and endosteal bone loss reflects acutely increased osteoclastic resorption as well as decreased bone formation due to depletion of osteoprogenitors. Because of this dysregulation of bone turnover, bone's capacity to respond to a mechanical loading stimulus in the aftermath of irradiation is unknown. We employed a mouse model of total body irradiation and bone marrow transplantation simulating treatment of hematologic cancers, hypothesizing that compression loading would attenuate bone loss. Furthermore, we hypothesized that loading would upregulate donor cell presence in loaded tibias due to increased engraftment and proliferation. We lethally irradiated 16 female C57Bl/6J mice at age 16 wks with 10.75 Gy, then IV-injected 20 million GFP(+) total bone marrow cells. That same day, we initiated 3 wks compression loading (1200 cycles 5x/wk, 10 N) in the right tibia of 10 of these mice while 6 mice were irradiated, non-mechanically-loaded controls. As anticipated, before-and-after microCT scans demonstrated loss of trabecular bone (-48.2% Tb.BV/TV) and cortical thickness (-8.3%) at 3 wks following irradiation. However, loaded bones lost 31% less Tb.BV/TV and 8% less cortical thickness (both p<0.001). Loaded bones also had significant increases in trabecular thickness and tissue mineral densities from baseline. Mechanical loading did not affect donor cell engraftment. Importantly, these results demonstrate that both cortical and trabecular bone exposed to high-dose therapeutic radiation remain capable of an anabolic response to mechanical loading. These findings inform our management of bone health in cases of radiation exposure.

  18. Autologous bone marrow stromal cell transplantation as a treatment for acute radiation enteritis induced by a moderate dose of radiation in dogs.

    PubMed

    Xu, Wenda; Chen, Jiang; Liu, Xu; Li, Hongyu; Qi, Xingshun; Guo, Xiaozhong

    2016-05-01

    Radiation enteritis is one of the most common complications of cancer radiotherapy, and the development of new and effective measures for its prevention and treatment is of great importance. Adult bone marrow stromal stem cells (ABMSCs) are capable of self-renewal and exhibit low immunogenicity. In this study, we investigated ABMSC transplantation as a treatment for acute radiation enteritis. We developed a dog model of acute radiation enteritis using abdominal intensity-modulated radiation therapy in a single X-ray dose of 14 Gy. ABMSCs were cultured in vitro, identified via immunofluorescence and flow cytometry, and double labeled with CM-Dil and superparamagnetic iron oxide (SPIO) before transplantation, which took place 48 hours after abdominal irradiation in a single fraction. The dog model of acute radiation enteritis was transplanted with cultured ABMSCs labeled with CM-Dil and SPIO into the mesenteric artery through the femoral artery. Compared with untreated control groups, dogs treated with ABMSCs exhibited substantially longer survival time and improved relief of clinical symptoms. ABMSC transplantation induced the regeneration of the intestinal epithelium and the recovery of intestinal function. Furthermore, ABMSC transplantation resulted in elevated serum levels of the anti-inflammatory cytokine interleukin-11 (IL10) and intestinal radioprotective factors, such as keratinocyte growth factor, basic fibroblast growth factor-2, and platelet-derived growth factor-B while reducing the serum level of the inflammatory cytokine IL17. ABMSCs induced the regeneration of the intestinal epithelium and regulated the secretion of serum cytokines and the expression of radioprotective proteins and thus could be beneficial in the development of novel and effective mitigators of and protectors against acute radiation enteritis.

  19. Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells.

    PubMed

    Zhen, Guohua; Xue, Zheng; Zhao, Jianping; Gu, Naibing; Tang, Zhouping; Xu, Yongjian; Zhang, Zhenxiang

    2010-09-01

    Pulmonary emphysema is characterized by loss of alveolar structures. We have found that bone marrow (BM) mesenchymal stem cell (MSC) transplantation ameliorates papain-induced pulmonary emphysema. However, the underlying mechanism is not completely understood. It has been shown that blocking the vascular endothelial growth factor (VEGF) signaling pathway leads to apoptosis of lung cells and pulmonary emphysema, and MSC are capable of secreting VEGF. We hypothesized that MSC transplantation may have a protective effect on pulmonary emphysema by increasing VEGF-A expression and inhibiting apoptosis of lung cells. We examined the morphology and expression of VEGF-A in rat lung after papain treatment and MSC transplantation. We also used a co-culture system in which MSC and cells prepared from papain-treated lungs or control lungs were cultured together. The levels of VEGF-A in cells and culture medium were determined, and apoptosis of cultured lung cells was evaluated. VEGF-A expression in rat lungs was decreased after papain treatment, which was partly rescued by MSC transplantation. MSC production of VEGF-A was increased when MSC were co-cultured with cells prepared from papain-treated lungs. Furthermore, the apoptosis of papain-treated lung cells was inhibited when co-cultured with MSC. The induction of MSC production of VEGF-A by papain-treated lung cells was inhibited by adding anti-tumor necrosis factor (TNF)-alpha antibody to the medium. The protective effect of MSC transplantation on pulmonary emphysema may be partly mediated by increasing VEGF-A expression and inhibiting the apoptosis of lung cells. TNF-alpha released from papain-treated lung cells induces MSC to secret VEGF-A.

  20. Transplantation of Adipose-Derived Mesenchymal Stem Cells Efficiently Rescues Thioacetamide-Induced Acute Liver Failure in Mice.

    PubMed

    Deng, L; Kong, X; Liu, G; Li, C; Chen, H; Hong, Z; Liu, J; Xia, J

    2016-01-01

    We aimed to investigate the efficacy of adipose-derived mesenchymal stem cell (ADMSC) transplantation in acute liver failure caused by thioacetamide in mice as well as its underlying mechanism by comparing transplantation routes. ADMSCs were isolated from inguinal fat pads of enhanced green fluorescent protein (EGFP) transgenic mice and analyzed regarding their surface markers and differentiation potential. Acute liver failure models were established by infusion of thioacetamide, and then we injected EGFP-ADMSCs or phosphate-buffered saline solution by intrasplenic or intravenous route. The restoration of biologic functions of the livers receiving transplantation was assessed by means of a variety of approaches, such as survival rates, live function parameters, histology, localization of EGFP-ADMSCs, and immunofluorescence analysis. ADMSCs were positive for CD90 and CD44 and negative for CD34 and had adipogenic and osteogenic differentiation potential. And they prevented the release of liver injury biomarkers. Transplantation via tail vein provided a significant survival benefit, but no significant differences were observed in the intrasplenic pathway and between the 2 pathways in our animal experiments. Furthermore, the transplanted cells were well integrated into injured livers and produced albumin and cytokeratin-8. Direct transplantation of ADMSCs is an effective treatment for acute liver failure rather than intrasplenic transplantation. The transplanted ADMSCs exhibit the potential to differentiate into hepatocyte-like cells in the injured livers. Thus, ADCMSCs would be a potential option for treatment of acute liver failure. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Platelets in Early Antibody-Mediated Rejection of Renal Transplants

    PubMed Central

    Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina; Chiesa-Vottero, Andres

    2015-01-01

    Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. PMID:25145937

  2. The clinical impact of humoral immunity in pediatric renal transplantation.

    PubMed

    Chaudhuri, Abanti; Ozawa, Mikki; Everly, Matthew J; Ettenger, Robert; Dharnidharka, Vikas; Benfield, Mark; Mathias, Robert; Portale, Anthony; McDonald, Ruth; Harmon, William; Kershaw, David; Vehaskari, V Matti; Kamil, Elaine; Baluarte, H Jorge; Warady, Bradley; Li, Li; Sigdel, Tara K; Hsieh, Szu-chuan; Dai, Hong; Naesens, Maarten; Waskerwitz, Janie; Salvatierra, Oscar; Terasaki, Paul I; Sarwal, Minnie M

    2013-03-01

    The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.

  3. The Clinical Impact of Humoral Immunity in Pediatric Renal Transplantation

    PubMed Central

    Chaudhuri, Abanti; Ozawa, Mikki; Everly, Matthew J.; Ettenger, Robert; Dharnidharka, Vikas; Benfield, Mark; Mathias, Robert; Portale, Anthony; McDonald, Ruth; Harmon, William; Kershaw, David; Vehaskari, V. Matti; Kamil, Elaine; Baluarte, H. Jorge; Warady, Bradley; Li, Li; Sigdel, Tara K.; Hsieh, Szu-chuan; Dai, Hong; Naesens, Maarten; Waskerwitz, Janie; Salvatierra, Oscar; Terasaki, Paul I.

    2013-01-01

    The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study. PMID:23449533

  4. Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

    PubMed

    Kennedy, M J; Vogelsang, G B; Jones, R J; Farmer, E R; Hess, A D; Altomonte, V; Huelskamp, A M; Davidson, N E

    1994-02-01

    We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

  5. Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

    PubMed Central

    Jin, Fengyan; Lin, Hai; Gao, Sujun; Wang, Hengxiang; Yan, Hongmin; Guo, Jinglong; Hu, Zheng; Jin, Chunhui; Wang, Yongqi; Wang, Zhidong; Zhao, Yangzhi; Liu, Yu; Zheng, Xiaoli; Tan, Yehui; Li, Wei; Dai, Yun; Yang, Yanping

    2017-01-01

    During human cytomegalovirus (CMV) infection after umbilical cord blood or HLA-matched hematopoietic stem cell transplantation (HSCT), a population of NKG2C-expressing natural killer (NK) cells expand and persist. The expanded NK cells express high levels of inhibitory killer immunoglobulin-like receptors (KIR) specific for self-HLA and potently produce IFNγ. However, it remains unknown whether similar events would occur after haploidentical HSCT (haplo-HSCT). Here, we demonstrated that IFNγ-producing NK cells were expanded in haplo-HSCT patients with CMV reactivation. We then identified these expanded cells as a subset of CD56dim NK cells that expressed higher levels of both NKG2C and KIR, but lower level of NKG2A. Functionally, the subset of NK cells expressing NKG2C and self-KIR in patients with CMV reactivation accounted for IFNγ production in response to K562 cells. However, these phenomena were not observed in patients without CMV reactivation. We therefore characterized a subset of NK cells with the CD56dim, NKG2C+, and self-KIR+ phenotype that expanded and were responsible for IFNγ production during CMV infection after haplo-HSCT. Together, these findings support a notion that CMV reactivation induces expansion of more mature NK cells with memory-like features, which contributes to long-term control of both CMV infection and leukemia relapse after haplo-HSCT. PMID:27980216

  6. ST Elevation Infarction after Heart Transplantation Induced by Coronary Spasms and Mural Thrombus Detected by Optical Coherence Tomography

    PubMed Central

    Holm, Niels Ramsing; Eiskjær, Hans; Poulsen, Steen Hvitfeldt; Maeng, Michael; Terkelsen, Christian Juhl; Christiansen, Evald Høj

    2016-01-01

    The case illustrates the possible link between coronary spasms, intraluminal thrombus formation, and widespread organized and layered thrombi in HTx patients. Furthermore, the case underlines the clinical value of OCT as a novel method for high-resolution vessel imaging in heart-transplanted (HTx) patients with coronary spasms and suspected coronary artery disease. Coronary spasms and sudden death are frequent complications after HTx. The underlying mechanisms leading to these complications are unknown. The present case displays the clinical course of a 19-year-old HTx patient who was hospitalized due to acute myocardial infarction induced by severe coronary spasms. The patients remained unstable on conservative therapy. Therefore, an optical coherence tomography (OCT) was performed and revealed massive, organized thrombi in the left main coronary artery, the circumflex coronary artery, and the left anterior descending coronary artery. The patient was stabilized after percutaneous coronary intervention. As a mural thrombus often goes undetected by coronary angiography, OCT may prove benefit in HTx patients with myocardial infarction or suspected coronary spasms. PMID:27980873

  7. Differentiation-inducing liposoluble vitamin deficiency may explain frequent secondary solid tumors after hematopoietic stem cell transplantation: minireview.

    PubMed

    Gedikoglu, G; Altinoz, M A

    2008-01-01

    Secondary cancers are among the most threatening long-term health problems of hematopoetic stem cell- transplant (HSCT) patients. There are several lines of evidence indicating the possibility of a prolonged Vitamin A deficiency for solid tumor-type secondary cancers: I- Solid tumors such as oral cavity, head/neck region squamous carcinomas, skin cancers and melanomas, where lowered Vitamin A concentrations and chemo-preventing activity of its derivatives (retinoids) are most explicitly proven, arise much more frequently than others. II- Early monitorings: A significant retinol deficiency in HSCT patients is detectable along with a severity of mucositis and the vulnerability to infection. III- Monitoring of other liposoluble vitamins: Vitamin D, a differentiation-inducing vitamin like Vitamin A, showed a sustained decrease. Another similarity of these two vitamins is that they also depend on intestinal absorption and are decreased due to bowel injury by conditioning agents and chronic graft-versus-host disease. IV- Peroxidative reactions and inflammation can directly exhaust retinol levels despite sufficient intake. Considering the similar inhibitory role of Vitamin D analogs (deltanoids) on squamous carcinomas, skin tumors and melanomas, we propose that animal studies and extended vitamin surveillance studies in HSCT patients may unfold a preventive strategy against long-term complications.

  8. Delayed epidural transplantation of human induced pluripotent stem cell-derived neural progenitors enhances functional recovery after stroke.

    PubMed

    Lee, I-Hui; Huang, Shiang-Suo; Chuang, Ching-Yu; Liao, Ko-Hsun; Chang, Li-Hsin; Chuang, Chia-Chi; Su, Yu-Shih; Lin, Hung-Jui; Hsieh, Jui-Yu; Su, Shu-Han; Lee, Oscar Kuang-Sheng; Kuo, Hung-Chih

    2017-05-16

    Induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs) are a promising source of tailor-made cell therapy for neurological diseases. However, major obstacles to clinical use still exist. To circumvent complications related to intracerebral administration, we implanted human iPSC-NPCs epidurally over the peri-infarct cortex 7 days after permanent middle cerebral artery occlusion in adult rats. Compared to controls, cell-treated rats showed significant improvements in paretic forelimb usage and grip strength from 10 days post-transplantation (dpt) onwards, as well as reductions in lesion volumes, inflammatory infiltration and astrogliosis at 21 dpt. Few iPSC-NPCs migrated into rat peri-infarct cortices and exhibited poor survival in tissue. To examine the paracrine therapeutic mechanisms of epidural iPSC-NPC grafts, we used transmembrane co-cultures of human iPSC-NPCs with rat cortical cells subjected to oxygen-glucose deprivation. Compared to other human stem cells, iPSC-NPCs were superior at promoting neuronal survival and outgrowth, and mitigating astrogliosis. Using comparative whole-genome microarrays and cytokine neutralization, we identified a neurorestorative secretome from iPSC-NPCs, and neutralizing enriched cytokines abolished neuroprotective effects in co-cultures. This proof-of-concept study demonstrates a relatively safe, yet effective epidural route for delivering human iPSC-NPCs, which acts predominately through discrete paracrine effects to promote functional recovery after stroke.

  9. Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia.

    PubMed

    Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur; Yuan, Han; Ho, Tzu-Chieh; Wang, Tiansu; Vora, Shailee; Solovyov, Alexander; Husser, Chrystel; Olszewska, Malgorzata; Teruya-Feldstein, Julie; Perumal, Deepak; Klimek, Virginia M; Spyridonidis, Alexandros; Rampal, Raajit K; Silverman, Lewis; Reddy, E Premkumar; Papaemmanuil, Elli; Parekh, Samir; Greenbaum, Benjamin D; Leslie, Christina S; Kharas, Michael G; Papapetrou, Eirini P

    2017-03-02

    Myeloid malignancy is increasingly viewed as a disease spectrum, comprising hematopoietic disorders that extend across a phenotypic continuum ranging from clonal hematopoiesis to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this study, we derived a collection of induced pluripotent stem cell (iPSC) lines capturing a range of disease stages encompassing preleukemia, low-risk MDS, high-risk MDS, and secondary AML. Upon their differentiation, we found hematopoietic phenotypes of graded severity and/or stage specificity that together delineate a phenotypic roadmap of disease progression culminating in serially transplantable leukemia. We also show that disease stage transitions, both reversal and progression, can be modeled in this system using genetic correction or introduction of mutations via CRISPR/Cas9 and that this iPSC-based approach can be used to uncover disease-stage-specific responses to drugs. Our study therefore provides insight into the cellular events demarcating the initiation and progression of myeloid transformation and a new platform for testing genetic and pharmacological interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Attenuation of radiation-induced gastrointestinal damage by epidermal growth factor and bone marrow transplantation in mice.

    PubMed

    Pejchal, Jaroslav; Šinkorová, Zuzana; Tichý, Aleš; Kmochová, Adéla; Ďurišová, Kamila; Kubelková, Klára; Pohanka, Miroslav; Bureš, Jan; Tachecí, Ilja; Kuča, Kamil; Vávrová, Jiřina

    2015-01-01

    We examined the effect of epidermal growth factor (EGF) and bone marrow transplantation (BMT) on gastrointestinal damage after high-dose irradiation of mice. C57Black/6 mice were used. Two survival experiments were performed (12 and 13 Gy; (60)Co, 0.59-0.57 Gy/min). To evaluate BMT and EGF action, five groups were established - 0 Gy, 13 Gy, 13 Gy + EGF (at 2 mg/kg, first dose 24 h after irradiation and then every 48 h), 13 Gy + BMT (5 × 10(6) cells from green fluorescent protein [GFP] syngenic mice, 4 h after irradiation), and 13 Gy + BMT + EGF. Survival data, blood cell counts, gastrointestine and liver parameters and GFP positive cell migration were measured. BMT and EGF (three doses, at 2 mg/kg, administered 1, 3 and 5 days after irradiation) significantly increased survival (13 Gy). In blood, progressive cytopenia was observed with BMT, EGF or their combination having no improving effect early after irradiation. In gastrointestinal system, BMT, EGF and their combination attenuated radiation-induced atrophy and increased regeneration during first week after irradiation with the combination being most effective. Signs of systemic inflammatory reaction were observed 30 days after irradiation. Our data indicate that BMT together with EGF is a promising strategy in the treatment of high-dose whole-body irradiation damage.

  11. Future of liver transplantation: non-human primates for patient-specific organs from induced pluripotent stem cells.

    PubMed

    Sanal, Madhusudana Girija

    2011-08-28

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient's genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly.

  12. Cytokine induced killer cells as adoptive immunotherapy strategy to augment graft versus tumor after hematopoietic cell transplantation.

    PubMed

    Sangiolo, D; Mesiano, G; Carnevale-Schianca, F; Piacibello, W; Aglietta, M; Cignetti, A

    2009-07-01

    Donor lymphocyte infusion (DLI) is used to increase the graft versus tumor (GVT) effect after allogeneic hematopoietic cell transplant (HCT). The limited spectrum of activity and high risk of graft versus host disease (GVHD) remain major limitations of this approach. The finding of new cell populations for adoptive immunotherapy, with the ability to separate GVT from GVHD, would be useful. Here we review the main basic, preclinical and clinical research on cytokine-induced killer (CIK) cells, highlighting the aspects of their antitumor and alloreactive potentials that might favourably affect the balance between GVT and GVHD. CIK cells are ex vivo-expanded T lymphocytes sharing NK markers and endowed with a potent MHC-unrestricted antitumor activity against haematological and solid malignancies. Studies in preclinical animal models have demonstrated their low GVHD potential when infused across MHC-barriers, and recent clinical studies seem to confirm these findings in patients with hematological malignancies relapsing after HCT. If consolidated with larger clinical trials, adoptive immunotherapy with CIK cells might represent an effective alternative to classic DLI, helping HCT to succesfully meet current challenges like the extension across major HLA-barriers and application to solid tumors.

  13. STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model

    PubMed Central

    Couronné, Lucile; Scourzic, Laurianne; Pilati, Camilla; Valle, Véronique Della; Duffourd, Yannis; Solary, Eric; Vainchenker, William; Merlio, Jean-Philippe; Beylot-Barry, Marie; Damm, Frederik; Stern, Marc-Henri; Gaulard, Philippe; Lamant, Laurence; Delabesse, Eric; Merle-Beral, Hélène; Nguyen-Khac, Florence; Fontenay, Michaëla; Tilly, Hervé; Bastard, Christian; Zucman-Rossi, Jessica; Bernard, Olivier A.; Mercher, Thomas

    2013-01-01

    STAT3 protein phosphorylation is a frequent event in various hematologic malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T-cell large granular lymphocytic leukemia, a rare T-cell disorder. In this study, we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4 of 258) of patients with T-cell neoplasms, in 2.5% (2 of 79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0 of 104) or patients with myeloid malignancies (0 of 96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo, and may represent a novel therapeutic target in some lymphoid malignancies. PMID:23872306

  14. Future of liver transplantation: Non-human primates for patient-specific organs from induced pluripotent stem cells

    PubMed Central

    Sanal, Madhusudana Girija

    2011-01-01

    Strategies to fill the huge gap in supply versus demand of human organs include bioartificial organs, growing humanized organs in animals, cell therapy, and implantable bioengineered constructs. Reproducing the complex relations between different cell types, generation of adequate vasculature, and immunological complications are road blocks in generation of bioengineered organs, while immunological complications limit the use of humanized organs produced in animals. Recent developments in induced pluripotent stem cell (iPSC) biology offer a possibility of generating human, patient-specific organs in non-human primates (NHP) using patient-derived iPSC and NHP-derived iPSC lacking the critical developmental genes for the organ of interest complementing a NHP tetraploid embryo. The organ derived in this way will have the same human leukocyte antigen (HLA) profile as the patient. This approach can be curative in genetic disorders as this offers the possibility of gene manipulation and correction of the patient’s genome at the iPSC stage before tetraploid complementation. The process of generation of patient-specific organs such as the liver in this way has the great advantage of making use of the natural signaling cascades in the natural milieu probably resulting in organs of great quality for transplantation. However, the inexorable scientific developments in this direction involve several social issues and hence we need to educate and prepare society in advance to accept the revolutionary consequences, good, bad and ugly. PMID:21990949

  15. Reversible metronidazole-induced cerebellar toxicity in a multiple transplant recipient.

    PubMed

    Graves, Tracey D; Condon, Marie; Loucaidou, Marina; Perry, Richard J

    2009-10-15

    Metronidazole-induced central nervous system (CNS) toxicity causes a spectrum of neurological symptoms including ataxia, encephalopathy and peripheral neuropathy. It is associated with characteristic MRI changes of high signal intensity in the dentate nuclei. Given the increasing use of metronidazole, it is import to recognise this drug as a cause of ataxia, as it is entirely reversible on drug withdrawal.

  16. Lung Transplantation

    MedlinePlus

    ... who have severe COPD Cystic fibrosis Idiopathic pulmonary fibrosis Alpha-1 antitrypsin deficiency Pulmonary hypertension Complications of lung transplantation include rejection of the transplanted lung and infection. NIH: National Heart, Lung, and Blood Institute

  17. Liver Transplant

    MedlinePlus

    ... Home > Your Liver > Liver Disease Information > Liver Transplant Liver Transplant Explore this section to learn more about ... resource. www.paulcox.com.au Why is the liver important? The liver is the second largest organ ...

  18. Cornea Transplant

    MedlinePlus

    ... who had several conditions, such as certain central nervous system conditions, infections, and prior eye surgery or eye conditions, or from people who died from an unknown cause. During your cornea transplant On the day of your cornea transplant, you' ...

  19. Intestine Transplant

    MedlinePlus

    ... Heart/Lung Kidney Pancreas Kidney/Pancreas Liver Intestine Intestine Transplant Although it is possible for a living donor to donate an intestine segment, most intestine transplants involve a whole organ ...

  20. Hair transplant

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/007205.htm Hair transplant To use the sharing features on this page, please enable JavaScript. A hair transplant is a surgical procedure to improve baldness. Description ...

  1. Pancreas transplant

    MedlinePlus

    ... In: Cameron JL, Cameron AM, eds. Current Surgical Therapy . 11th ed. Philadelphia, PA: Elsevier Saunders; 2014:511-5. Gruessner AC, Gruessner RWG. Pancreas and kidney transplantation for diabetic nephropathy. In: Morris PJ, Knechtle SJ, eds. Kidney Transplantation: ...

  2. Interleukin-10 gene promoter polymorphisms are associated with cyclosporin A-induced gingival overgrowth in renal transplant patients.

    PubMed

    Luo, Yixi; Gong, Yiming; Yu, Youcheng

    2013-09-01

    Interleukin-10 (IL-10) is an anti-inflammatory cytokine whose genetic polymorphisms are associated with the production of IL-10 and the susceptibility to periodontal diseases. The aim of this study was to investigate the possible association of IL-10 single nucleotide polymorphisms (SNPs) and cyclosporin A (CsA)-induced gingival overgrowth (GO) in renal transplant patients in a Chinese population, taking into account subgingival microbiota as additional variables. A total of 202 patients were dichotomized into two groups: 122 with GO and 80 without GO. The IL-10-1082 SNP, -819 SNP and -592 SNP were measured using an allele-specific PCR method. The levels of subgingival bacteria were measured by real-time PCR. Genotype and allele frequencies were analyzed using the Chi-square test and logistic regression analysis. The frequency of IL-10-819TT (-592AA) genotype was statistically higher in patients with GO than that in patients without GO (P<0.05). Multiple logistic regression analysis demonstrated that the prevalence of GO is not dependent on age, gender, and pharmacological variables, being significantly associated with the carriers of ATA haplotype (OR=2.425, 95%CI=1.214-4.845, P=0.012). Moreover, ATA positive carriers in the GO group presented significantly higher levels of Porphyromonas gingivalis and Treponema denticola than those negative carriers. Our results show that IL-10-819TT (-592AA) genotype and ATA halpotype are associated with susceptibility to CsA-induced GO. Meanwhile, ATA haplotype is associated with a higher detection of P. gingivalis and T. denticola in GO patients, and may increase the risk of developing GO. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Desensitization for solid organ and hematopoietic stem cell transplantation

    PubMed Central

    Zachary, Andrea A; Leffell, Mary S

    2014-01-01

    Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. PMID:24517434

  4. Simultaneous pancreas and kidney transplantation: current trends and future directions

    PubMed Central

    Redfield, Robert R.; Scalea, Joseph R.; Odorico, Jon S.

    2015-01-01

    Purpose of review Important trends are being observed in pancreas transplantation in the USA. We will describe recent trends in simultaneous pancreas kidney (SPK) transplantation related to immunosuppression, treatment of rejection, and transplantation for patients of advanced age and C-peptide positive diabetes. Recent findings Rates of pancreas transplantation have declined, despite improved pancreatic graft outcomes. Regarding immunosuppression, trends in SPK transplantation include T-cell depletion induction therapy, waning mammalian target of rapamycin inhibitor use and steroid use in greater than 50% of pancreas transplant recipients with few patients undergoing late steroid weaning. Rejection of the pancreas may be discordant with the kidney after SPK and there is a greater appreciation of antibody-mediated rejection of the pancreas allograft. De-novo donor-specific antibody without graft dysfunction remains an active area of study, and the treatment for this condition is unclear. SPKs are being performed with greater frequency in type 2 diabetes mellitus patients and in patients of advanced age, with exemplary results. Summary The current state of the art in SPK transplantation is yielding superb and improving results. PMID:25565444

  5. Desensitization for solid organ and hematopoietic stem cell transplantation.

    PubMed

    Zachary, Andrea A; Leffell, Mary S

    2014-03-01

    Desensitization protocols are being used worldwide to enable kidney transplantation across immunologic barriers, i.e. antibody to donor HLA or ABO antigens, which were once thought to be absolute contraindications to transplantation. Desensitization protocols are also being applied to permit transplantation of HLA mismatched hematopoietic stem cells to patients with antibody to donor HLA, to enhance the opportunity for transplantation of non-renal organs, and to treat antibody-mediated rejection. Although desensitization for organ transplantation carries an increased risk of antibody-mediated rejection, ultimately these transplants extend and enhance the quality of life for solid organ recipients, and desensitization that permits transplantation of hematopoietic stem cells is life saving for patients with limited donor options. Complex patient factors and variability in treatment protocols have made it difficult to identify, precisely, the mechanisms underlying the downregulation of donor-specific antibodies. The mechanisms underlying desensitization may differ among the various protocols in use, although there are likely to be some common features. However, it is likely that desensitization achieves a sort of immune detente by first reducing the immunologic barrier and then by creating an environment in which an autoregulatory process restricts the immune response to the allograft. © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

  6. Intestinal and multivisceral transplantation

    PubMed Central

    Meira, Sérgio Paiva; Guardia, Bianca Della; Evangelista, Andréia Silva; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Epstein, Marina Gabrielle; Pedroso, Pamella Tung; Salvalaggio, Paolo; Meirelles, Roberto Ferreira; Rocco, Rodrigo Andrey; de Almeida, Samira Scalso; de Rezende, Marcelo Bruno

    2015-01-01

    Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run. PMID:25993080

  7. Derivation of transplantable 7,12-dimethylbenz(a)anthracene-induced chicken fibrosarcoma lines: differences in metastasizing properties and organ specificity

    SciTech Connect

    Galton, J.E.; Xue, B.; Hochwald, G.M.; Thorbecke, G.J.

    1982-08-01

    Transplantable 7,12-dimethylbenz(a)anthracene-induced SC chicken fibrosarcoma (CHCT-NYU) lines were studied for their ability to grow in internal organs after iv injection (artificial metastases) into 1- to 3-week-old chickens. Some tumor lines were recently derived, whereas others were studied after many serial subcutaneous transplantations. Artificial metastases were seen in the stomach, pancreas, lungs, heart, and muscle, and occasionally in the kidneys and liver. Agammaglobulinemic recipients showed more extensive organ involvement than normal recipients of the same age. Whole-body ..gamma..-irradiation enhanced the incidence of artificial metastases, particularly in lungs. Antibody from the serum of a primary tumor-bearing host reduced the growth of the corresponding tumor in many organs. The metastatic pattern of line CHCT-NYU4 was a relatively stable property. However, intravenous transplantation of tumor cells from line CHCT-NYU4 taken from the liver, lungs, and pancreas of a single recipient established sublines with changes in organ specificity. After a few such serial transplants of liver-derived tumor, a line was derived that grew virtually in the liver alone. A subline with preference for growth in lungs was also obtained, but its ability to grow in the pancreas persisted. A pancreas-derived tumor line also grew in the liver and lungs. Subcutaneous transplants of tissue fragments of the lung-derived tumor line caused the appearance of spontaneous metastases in lungs. The incidence of spontaneous metastases with the lung-derived line was much greater than that with the liver-derived line or with the original CHCT-NYU4 line.

  8. Simultaneous Occurrence of Varicella Zoster Virus-Induced Pancreatitis and Hepatitis in a Renal Transplant Recipient: A Case Report and Review of Literature

    PubMed Central

    Chhabra, Puneet; Ranjan, Priyadarshi; Bhasin, Deepak K

    2017-01-01

    Introduction: Gastrointestinal complications are common after renal transplantation, including oral lesions, esophagitis, gastritis, diarrhea, and colon carcinoma. The differential diagnosis is difficult in this scenario because multiple factors such as drugs, infections, and preexisting gastrointestinal disease come into play. Case Presentation: We report a case of varicella zoster virus-induced pancreatitis and hepatitis in a renal transplant recipient. The patient underwent renal transplantation 3 years earlier and now presented with severe pain in the epigastrium radiating to his back and had raised serum lipase levels and skin lesions characteristic of varicella. Liver enzyme levels were also elevated. He was started on a regimen of acyclovir. His pain improved in 24 hours, and liver enzyme levels returned to normal in 48 hours. Discussion: There is a paucity of literature on the simultaneous occurrence of varicella zoster virus-induced hepatitis and pancreatitis in both immunocompetent and immunocompromised patients. Our case highlights the gastrointestinal complications of varicella infection in immunocompromised patients that may precede the characteristic dermatologic manifestations, and the fact that rarely both hepatitis and pancreatitis may be seen. PMID:28333601

  9. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation

    PubMed Central

    He, Hongzhen; Stone, James R; Perkins, David L

    2003-01-01

    The roles of innate and adaptive immunity in allograft rejection remain incompletely understood. Previous studies analysing lymphocyte deficient or syngeneic graft recipients have identified subsets of inflammatory chemokines and cytokines induced by antigen independent mechanisms. In the current study, we analysed a panel of 60 inflammatory parameters including serum cytokines, intragraft chemokines and cytokines, receptors, and cellular markers. Our results confirmed the up-regulation of a subset of markers by innate mechanisms and also identified a subset of parameters up-regulated only in the context of an adaptive response. Thus, we successfully differentiated markers of the innate and adaptive phases of rejection. Current paradigms emphasize that innate signals can promote a subsequent adaptive response. Interestingly, in our studies, expression of the markers induced by innate mechanisms was markedly amplified in the allogeneic, but not syngeneic or lymphocyte deficient, recipients. These results suggest that inflammatory mediators can have functional overlap between the innate and adaptive responses, and that the adaptive component of the rejection process amplifies the innate response by positive feedback regulation. PMID:12757613

  10. Protein a Immunoadsorption May Hamper the Decision to Transplant Due to Interference With CDC Crossmatch Results.

    PubMed

    Koefoed-Nielsen, Pernille; Bistrup, Claus; Christiansen, Mette

    2016-06-03

    Transplanting immunized patients requires immunological monitoring in the pretransplant phase to follow reduction of donor specific HLA antibodies (DSA) after Staphylococcus aureus protein A (SPA) immunoadsorption (IA) or therapeutic plasma exchange followed by IVIG and Rituximab administration. Pretreatment aims to significantly reduce DSA strength. The Tissue Typing Lab at Aarhus University Hospital performs immunological monitoring of approximately 150 kidney transplantation patients per year from two transplant centers. From 2012 to 2013, we experienced seven patients desensitized using SPA IA, initially presenting negative cytotoxic complement dependent (CDC) T-cell crossmatches but positive B and T cell flowcytometric crossmatch, who despite significant DSA reduction developed weakly positive CDC T-cell crossmatch shortly prior to transplantation. We hypothesised that leached SPA during IA could be the cause, as the complication was not observed in patients who received plasma exchanges. We found that the positive CDC was not donor specific and SPA column material incubated with control serum reproduced a positive CDC T-cell crossmatch. Finally, we detected leached SPA in one of the patient samples using a highly sensitive time-resolved fluorescent assay. In conclusion, the results emphasize the importance of carefully considering CDC crossmatch results subsequent to IA, before a planned transplantation is either postponed or cancelled. J. Clin. Apheresis 00:000-000, 2016. © 2016 Wiley Periodicals, Inc.

  11. Uterus transplantation.

    PubMed

    Altchek, Albert

    2003-05-01

    Until recently, only life and death situations warranted organ transplantation. Nonvital transplantation, to further a patient s wishes and goals, was not considered justified. It can be argued, however, that this distinction is not morally significant. Patients with kidney failure, for example, can be kept alive by dialysis. But their quality of life would be greatly enhanced by kidney transplant, which is thus considered a justified procedure. So a spectrum of rationales may justify transplantation. Transplantation of the uterus would relieve the anguish of women who greatly desire to conceive a child. Some women do not have a uterus. In some cases this is due to a congenital absence (Rokitansky s syndrome). In other cases, surgical removal of the uterus was required to repair an obstetrical rupture. With a transplanted uterus, many of these women could have the opportunity to become pregnant as a result of nonvital organ transplant. While other organ transplant donations most often come from cadavers and less often from living donors (kidney or partial liver), the donor source for a uterus may be an otherwise healthy living patient who requires uterus removal as a standard care procedure. Furthermore, it should be possible to remove the transplanted uterus from the recipient after successful pregnancies, so the patient would not be subjected to lifelong antirejection medications. Since animal uterus transplantation has been done successfully, human uterus transplantation might be considered for select cases. One such case has been reported.

  12. Pancreas Transplantation

    PubMed Central

    Sutherland, David ER

    2010-01-01

    Diabetes mellitus is generally treated with oral diabetic drugs and/or insulin. However, the morbidity and mortality associated with this condition increases over time, even in patients receiving intensive insulin treatment, and this is largely attributable to diabetic complications or the insulin therapy itself. Pancreas transplantation in humans was first conducted in 1966, since when there has been much debate regarding the legitimacy of this procedure. Technical refinements and the development of better immunosuppressants and better postoperative care have brought about marked improvements in patient and graft survival and a reduction in postoperative morbidity. Consequently, pancreas transplantation has become the curative treatment modality for diabetes, particularly for type I diabetes. An overview of pancreas transplantation is provided herein, covering the history of pancreas transplantation, indications for transplantation, cadaveric and living donors, surgical techniques, immunosuppressants, and outcome following pancreas transplantation. The impact of successful pancreas transplantation on the complications of diabetes will also be reviewed briefly. PMID:21253293

  13. Magnetic fluid hyperthermia induced by radiofrequency capacitive field for the treatment of transplanted subcutaneous tumors in rats.

    PubMed

    Li, Xu-Hong; Rong, Peng-Fei; Jin, He-Kun; Wang, Wei; Tang, Jin-Tian

    2012-02-01

    Magnetic fluid hyperthermia (MFH) induced by a magnetic field has become a new heating technology for the treatment of malignant tumors due to its ability to heat the tumor tissue precisely and properly, and due to its significant therapeutic effects. In this study, MFH induced by radiofrequency capacitive field (RCF) for the treatment of transplanted subcutaneous tumors in rats, was investigated. A total of 50 rats bearing subcutaneous tumors were randomly divided into five groups, including i) a pseudo-treatment (PT) control group, ii) magnetic fluid (MF) group, iii) pure hyperthermia (PH) group, iv) magnetic fluid hyperthermia 1 (MFH1) group, and v) magnetic fluid hyperthermia 2 (MFH2) group. Tumors were irradiated for 30 min in the MFH1 group 24 h following injection of MF. Tumors were irradiated for 30 min in the MFH2 group 24 h following injection of MF, and irradiation was repeated for 30 min 72 h following injection of MF. Tumor volumes, tumor volume inhibition ratios and survival times in the rat model were examined. Temperatures of tumor cores and rims both rapidly reached the desired temperature (∼50°C) for tumor treatment within 5 to 10 min in the MFH1 and MFH2 groups, and we maintained this temperature level by manually adjusting the output power (70-130 W). Tumor volumes of the MFH1 and MFH2 groups were reduced compared to those of the PT, MF and PH groups. The inhibitory effect on tumor growth in the MFH2 group (91.57%) was higher compared to that in the MFH1 group (85.21%) and the other groups. The survival time of the MFH2 group (51.62±2.28 days) and MFH1 group (43.10±1.57 days) was increased compared to that of the PH, MF and PT groups. The results obtained show that MFH induced by RCF may serve as a potential and promising method for the treatment of tumors.

  14. Alloantibody induced platelet responses in transplants: potent mediators in small packages.

    PubMed

    Kuo, Hsiao-Hsuan; Morrell, Craig N; Baldwin, William M

    2012-12-01

    The early histological studies of organ allografts noted platelets attached to vascular endothelium. Platelets adhere to vessels before any morphological evidence of endothelial injury. Subsequently, in vitro and in vivo experiments have demonstrated that alloantibodies can induce exocytosis of von Willebrand factor and P-selectin from endothelial cells and attachment of platelets within minutes. Platelets also adhere to and stimulate leukocytes. These interactions are increased by complement activation. After attachment platelets degranulate, releasing preformed mediators. Some chemokines stored together in platelet granules can form heteromers with synergistic functions. Heteromers containing platelet factor 4 (PF4; CXCL4) are specific to platelets and provide insights to unique platelet functions and opportunities for therapeutic intervention. Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

  15. Cell transplantation therapies for spinal cord injury focusing on induced pluripotent stem cells.

    PubMed

    Nakamura, Masaya; Okano, Hideyuki

    2013-01-01

    Stimulated by the 2012 Nobel Prize in Physiology or Medicine awarded for Shinya Yamanaka and Sir John Gurdon, there is an increasing interest in the induced pluripotent stem (iPS) cells and reprograming technologies in medical science. While iPS cells are expected to open a new era providing enormous opportunities in biomedical sciences in terms of cell therapies and regenerative medicine, safety-related concerns for iPS cell-based cell therapy should be resolved prior to the clinical application of iPS cells. In this review, the pre-clinical investigations of cell therapy for spinal cord injury (SCI) using neural stem/progenitor cells derived from iPS cells, and their safety issues in vivo, are outlined. We also wish to discuss the strategy for the first human trails of iPS cell-based cell therapy for SCI patients.

  16. Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue

    PubMed Central

    Korutla, Laxminarayana; Habertheuer, Andreas; Yu, Ming; Rostami, Susan; Yuan, Chao-Xing; Reddy, Sanjana; Korutla, Varun; Koeberlein, Brigitte; Trofe-Clark, Jennifer; Rickels, Michael R.; Naji, Ali

    2017-01-01

    In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody–conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue. PMID:28319051

  17. Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue.

    PubMed

    Vallabhajosyula, Prashanth; Korutla, Laxminarayana; Habertheuer, Andreas; Yu, Ming; Rostami, Susan; Yuan, Chao-Xing; Reddy, Sanjana; Liu, Chengyang; Korutla, Varun; Koeberlein, Brigitte; Trofe-Clark, Jennifer; Rickels, Michael R; Naji, Ali

    2017-04-03

    In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody-conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet β cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.

  18. Clinical Operational Tolerance After Renal Transplantation

    PubMed Central

    Orlando, Giuseppe; Hematti, Peiman; Stratta, Robert J.; Burke, George W.; Di Cocco, Pierpaolo; Pisani, Francesco; Soker, Shay; Wood, Kathryn

    2015-01-01

    In solid organ transplantation, the achievement of an immunosuppression (IS)-free state [also referred to as clinical operational tolerance (COT)] represents the ultimate goal. Although COT is feasible and safe in selected cases after liver transplantation, it is an exceptional finding after other types of solid organ transplantation. In the field of renal transplantation (RT), approximately 100 cases of COT have been reported to date, mainly in patients who were not compliant with their immunosuppressive regimens or in individuals who had previously received a bone marrow transplant for hematological disorders. On the basis of promising results obtained in animal models, several tolerogenic protocols have been attempted in humans, but most have failed to achieve robust and stable COT after RT. Molecule-based regimens have been largely ineffective, whereas cell-based regimens have provided some encouraging results. In these latter regimens, apart from standard IS, patients usually receive perioperative infusion of donor bone marrow–derived stem cells, which are able to interact with the immune cells of the host and mitigate their response to engraftment. Unfortunately, most renal transplant patients who developed acute rejection—occurring either during the weaning protocol or after complete withdrawal of IS—eventually lost their grafts. Currently, the immune monitoring necessary for predicting the presence and persistence of donor-specific unresponsiveness is not available. Overall, the present review will provide a conceptual framework for COT and conclude that stable and robust COT after RT remains an elusive goal and that the different strategies attempted to date are not yet reproducibly safe or effective. PMID:21107102

  19. Pediatric liver transplantation: a North American perspective.

    PubMed

    Kerkar, Nanda; Lakhole, Arathi

    2016-08-01

    Liver transplantation (LT) is an important component in the therapeutic armamentarium of managing end-stage liver disease. In North American children, biliary atresia remains the most common indication for LT compared to hepatitis C in adults, while hepatoblastoma is the most common liver tumor requiring LT, versus Hepatocellular carcinoma in adults. Rejection, lymphoproliferative disease, renal insufficiency, metabolic syndrome, recurrent disease, 'de novo' autoimmune hepatitis and malignancy require careful surveillance and prompt action in adults and children after LT. In children, specific attention to EBV viremia, growth, development, adherence and transition to the adult services is also required. Antibody mediated rejection and screening for donor specific antibodies is becoming important in managing liver graft dysfunction. Biomarkers to identify and predict tolerance are being developed. Machine perfusion and stem cells (iPS) to synthesize organs are generating interest and are a focus for research.

  20. Lung transplantation

    PubMed Central

    Afonso, José Eduardo; Werebe, Eduardo de Campos; Carraro, Rafael Medeiros; Teixeira, Ricardo Henrique de Oliveira Braga; Fernandes, Lucas Matos; Abdalla, Luis Gustavo; Samano, Marcos Naoyuki; Pêgo-Fernandes, Paulo Manuel

    2015-01-01

    ABSTRACT Lung transplantation is a globally accepted treatment for some advanced lung diseases, giving the recipients longer survival and better quality of life. Since the first transplant successfully performed in 1983, more than 40 thousand transplants have been performed worldwide. Of these, about seven hundred were in Brazil. However, survival of the transplant is less than desired, with a high mortality rate related to primary graft dysfunction, infection, and chronic graft dysfunction, particularly in the form of bronchiolitis obliterans syndrome. New technologies have been developed to improve the various stages of lung transplant. To increase the supply of lungs, ex vivo lung reconditioning has been used in some countries, including Brazil. For advanced life support in the perioperative period, extracorporeal membrane oxygenation and hemodynamic support equipment have been used as a bridge to transplant in critically ill patients on the waiting list, and to keep patients alive until resolution of the primary dysfunction after graft transplant. There are patients requiring lung transplant in Brazil who do not even come to the point of being referred to a transplant center because there are only seven such centers active in the country. It is urgent to create new centers capable of performing lung transplantation to provide patients with some advanced forms of lung disease a chance to live longer and with better quality of life. PMID:26154550

  1. Thoracic transplantation.

    PubMed

    Shumway, N E

    2000-07-01

    Experimental orthotopic transplantation of the heart was accomplished in 1959. Long-term survival was achieved in 1965 with a chemical immunosuppression protocol substantially different from that used for renal and hepatic transplants. Performance characteristics of the transplanted denervated heart were found to differ only slightly from normal. It appeared by the time of the Clinical Congress of the American College of Surgeons in October 1967 that clinical heart transplantation might be justified if the concept of brain death could be legally recognized. The Stanford program in clinical heart transplantation was inaugurated on January 6, 1968 and has been in continuous operation. To date, more than 1000 patients have undergone transplantation of the heart with the 5-year survival at 75%. The first long-term success in lung transplantation occurred at Stanford in 1981, with transplantation of the heart and both lungs. In 1990 the concept of living pulmonary lobar donors was introduced and is slowly finding its clinical role. The steroid-sparing capability of cyclosporine made possible both successful lung and pediatric heart transplantation. Only the donor shortage remains as a substantial barrier to widespread thoracic transplantation. Xenotransplantation is under intense scrutiny, with some encouraging experimental results. Development of the artificial heart continues to offer some relief for patients with end-stage heart disease.

  2. Detection of blood chimerism after lung and heart-lung transplantation. The superiority of nested as compared with standard polymerase chain reaction amplification.

    PubMed

    Knoop, C; Andrien, M; Defleur, V; Antonine, M; de Francquen, P; Goldman, M; Estenne, M

    1994-12-27

    Migration of donor cells from the graft to various tissues of the recipient has been demonstrated after different types of solid organ transplants. Currently, the detection of donor cells in the recipient's tissues is most simply performed by polymerase chain reaction (PCR) amplification of a donor-specific gene. In the present study, we first determined in vitro the sensitivity of standard and nested PCR amplification with sequence-specific primers (PCR-SSP) of a donor-specific allele of the HLA-DRB1 gene and then used this technique to assess prospectively blood chimerism in two single-lung (SLT) and one heart-lung (HLT) transplant recipients. Standard PCR-SSP consisted in a single amplification round with sequence-specific primers for the donor-specific DRB1 allele. Nested PCR-SSP consisted in a first round of generic amplification of exon 2 of the DRB1 gene, followed by a second amplification round with primers specific for the donor allele. In vitro, nested PCR-SSP of the donor-specific allele was 1000-fold more sensitive than standard PCR-SSP and allowed the detection of 1 donor cell in 10(5) recipient cells. In vivo, standard PCR-SSP detected donor cells among the recipients' peripheral blood mononuclear cells (PBMCs) only during the first postoperative days, whereas nested PCR-SSP demonstrated their presence until the end of the first postoperative month in patients 1 and 2 and until 3 months after transplantation in patient 3. We conclude that donor cells can be detected in the peripheral blood of SLT and HLT recipients during the first postoperative months and that nested PCR-SSP amplification of a donor-specific HLA-DRB1 allele is much more sensitive than standard PCR-SSP to demonstrate such chimerism.

  3. Combination of monoclonal antibodies with DST inhibits accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice.

    PubMed

    Shao, Wei; Chen, Jibing; Dai, Helong; Peng, Yuanzheng; Wang, Feng; Xia, Junjie; Thorlacius, Henrik; Zhu, Qi; Qi, Zhongquan

    2011-08-30

    Donor-reactive memory T cells mediated accelerated rejection is known as a barrier to the survival of transplanted organs. We investigated the combination of different monoclonal antibodies (mAbs) and donor-specific transfusion (DST) in memory T cells-based adoptive mice model. In the presence of donor-reactive memory T cells, the mean survival time (MST) of grafts in the anti-CD40L/LFA-1/DST group was 49.8d. Adding anti-CD44/CD70 mAbs to anti-CD40L/LFA-1/DST treatment. The MST was more than 100 d (MST>100 d). Compared with anti-CD40L/LFA-1/DST group, anti-CD40L/LFA-1/CD44/CD70/DST group notably reduced the expansion of memory T cells, enhanced the proportion of CD4+Foxp3+ regulatory T cells (Tregs) and suppressed donor-specific responses. Our data suggest that anti-CD40L/LFA-1/CD44/CD70mAbs and DST can synergistically inhibit accelerated rejection mediated by memory T cells to induce long-lived heart allograft acceptance in mice.

  4. Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy.

    PubMed

    Mainra, R; Xu, Q; Chibbar, R; Hassan, A; Shoker, A

    2013-06-01

    Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.

  5. HLA Class I Sensitization in Islet Transplant Recipients – Report from the Collaborative Islet Transplant Registry

    PubMed Central

    Naziruddin, Bashoo; Wease, Steve; Stablein, Donald; Barton, Franca B.; Berney, Thierry; Rickels, Michael R.; Alejandro, Rodolfo

    2015-01-01

    Pancreatic islet transplantation is a promising treatment option for patients severely affected with type 1 diabetes. This report from CITR presents pre- and post-transplant human leukocyte antigen (HLA) class I sensitization rates in islet alone transplantation. Data came from 303 recipients transplanted with islet alone between January 1999 and December 2008. HLA class I sensitization was determined by the presence of anti-HLA class I antibodies. Panel-reactive antibodies (PRA) from prior to islet infusion and at 6 months, and yearly post-transplant was correlated to measures of islet graft failure. The cumulative number of mismatched HLA alleles increased with each additional islet infusion from a median of 3 for one infusion to 9 for three infusions. Pre-transplant PRA was not predictive of islet graft failure. However, development of PRA ≥20% post-transplant was associated with 3.6 fold (p=.001) increased hazard ratio for graft failure. Patients with complete graft loss who had discontinued immunosuppression had significantly higher rate of PRA ≥ 20% compared to those with functioning grafts who remained on immunosuppression. Exposure to repeat HLA class I mismatch at second or third islet infusions resulted in less frequent development of de novo HLA class I antibodies when compared to increased class I mismatch. The development of HLA class I antibodies while on immunosuppression is associated with subsequent islet graft failure. The risk of sensitization may be reduced by minimizing the number of islet donors used per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA class I mismatches with subsequent islet infusions. PMID:22080832

  6. [Quantitatively evaluating the evolution of the tumor perfusion in A549 lung adenocarcinoma transplantation model induced by antiangiogenic treatment].

    PubMed

    Xiong, Zeng; Deng, Pengbo; Hu, Chengping; Liu, Jinkang; Yang, Huaping; Zhou, Jianhua; Wang, Ying; Zhou, Hui; Zhu, Zhiming

    2016-01-26

    To quantitatively evaluate the evolution of the tumor perfusion in A549 lung adenocarcinoma transplantation model induced by antiangiogenic treatment. To establish the preclinical transplantation model of lung adenocarcinoma, 60 BALB/c nu/nu mice was inoculated with A549 cell lines via axilla. Sixty mice were randomly divided into 2 groups. The treatment group was treated with intravenous Bevacizumab (10 mg/kg weight, in a single injection), and the control group received saline only in the same dose. Five times of volume perfusion CT (VPCT) scan was performed before treatment, and on the second, forth, sixth and tenth days of treatment, respectively. The values of blood flow (BF) in the A549 tumors were measured after scanning. The microvessel density (MVD), vessel maturity index (VMI) in the tumors were determined using multiplexed QDs-based immunohistochemical staining. Comparing the values of BF, VMI and MVD between the two groups on the same day before treatment, the values of BF, VMI and MVD of the treatment group were (13.5±1.5) ml·(100 ml)(-1)·min(-1,) 0.14±0.04, (45.7±16.5)/HPF, respectively, and those in the control group were (13.4±1.6) ml·(100 ml)(-1)·min(-1) , 0.14±0.05, (48.0±7.0) /HPF , respectively. There was no significant difference between the two groups (all P>0.05). And on the second, forth, sixth, tenth days of treatment, the values of BF of the treatment group were (17.9±7.3), (32.2±6.9), (18.5±2.4) and (13.8±1.8) ml·(100 ml)(-1)·min(-1,) respectively, and those in the control group were (10.5±0.6), (9.6±0.8), (5.7±1.2) and (1.9±1.0) ml·(100 ml)(-1)·min(-1,) respectively. The values of VMI of the treatment group were 1.17±0.22, 3.25±0.23, 2.94±0.31 and 1.07±0.18, respectively, and those in the control group were 0.12±0.03, 0.13±0.03, 0.15±0.03, and 0.13±0.03, respectively. The values of MVD of the treatment group were (38.0±6.3), (24.3±5.4), (15.2±3.4) and (13.5±4.7)/HPF, respectively, and those in the

  7. Immune reconstitution/immunocompetence in recipients of kidney plus hematopoietic stem/facilitating cell transplants.

    PubMed

    Leventhal, Joseph R; Elliott, Mary J; Yolcu, Esma S; Bozulic, Larry D; Tollerud, David J; Mathew, James M; Konieczna, Iwona; Ison, Michael G; Galvin, John; Mehta, Jayesh; Badder, Mark D; Abecassis, Michael M I; Miller, Joshua; Gallon, Lorenzo; Ildstad, Suzanne T

    2015-02-01

    Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.

  8. The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives

    PubMed Central

    2017-01-01

    More than ten years after the initial description of the humoral theory of transplantation by Dr. Paul I. Terasaki, the significance of humoral alloimmunity in liver transplantation has yet to be clearly defined. The liver allograft has an inherent tolerogenic capacity which confers its resistance to cell-mediated as well as antibody-mediated rejection. Nevertheless, the protection against alloimmunity is not complete, and antibody-mediated tissue injury can occur in the liver graft under specific circumstances. In this article the evidence on the clinicopathologic effects of donor-specific alloantibodies in liver transplantation will be examined and interpreted in parallel with lessons learned from renal transplantation. The unique anatomic and immunologic features of the liver will be reviewed to gain new insights into the complex interactions between humoral immune system and the liver allograft. PMID:28164136

  9. Intrathecal Transplantation of Autologous Adherent Bone Marrow Cells Induces Functional Neurological Recovery in a Canine Model of Spinal Cord Injury.

    PubMed

    Gabr, Hala; El-Kheir, Wael Abo; Farghali, Haithem A M A; Ismail, Zeinab M K; Zickri, Maha B; El Maadawi, Zeinab M; Kishk, Nirmeen A; Sabaawy, Hatem E

    2015-01-01

    Spinal cord injury (SCI) results in demyelination of surviving axons, loss of oligodendrocytes, and impairment of motor and sensory functions. We have developed a clinical strategy of cell therapy for SCI through the use of autologous bone marrow cells for transplantation to augment remyelination and enhance neurological repair. In a preclinical large mammalian model of SCI, experimental dogs were subjected to a clipping contusion of the spinal cord. Two weeks after the injury, GFP-labeled autologous minimally manipulated adherent bone marrow cells (ABMCs) were transplanted intrathecally to investigate the safety and efficacy of autologous ABMC therapy. The effects of ABMC transplantation in dogs with SCI were determined using functional neurological scoring, and the integration of ABMCs into the injured cords was determined using histopathological and immunohistochemical investigations and electron microscopic analyses of sections from control and transplanted spinal cords. Our data demonstrate the presence of GFP-labeled cells in the injured spinal cord for up to 16 weeks after transplantation in the subacute SCI stage. GFP-labeled cells homed to the site of injury and were detected around white matter tracts and surviving axons. ABMC therapy in the canine SCI model enhanced remyelination and augmented neural regeneration, resulting in improved neurological functions. Therefore, autologous ABMC therapy appears to be a safe and promising therapy for spinal cord injuries.

  10. Multimodal Imaging Reveals Improvement of Blood Supply to an Artificial Cell Transplant Site Induced by Bioluminescent Mesenchymal Stem Cells.

    PubMed

    Gálisová, Andrea; Fábryová, Eva; Jirák, Daniel; Sticová, Eva; Lodererová, Alena; Herynek, Vít; Kříž, Jan; Hájek, Milan

    2017-02-01

    An artificial site for cell or pancreatic islet transplantation can be created using a polymeric scaffold, even though it suffers subcutaneously from improper vascularisation. A sufficient blood supply is crucial for graft survival and function and can be enhanced by transplantation of mesenchymal stem cells (MSCs). The purpose of this study was to assess the effect of syngeneic MSCs on neoangiogenesis and cell engraftment in an artificial site by multimodal imaging. MSCs expressing a gene for luciferase were injected into the artificial subcutaneous site 7 days after scaffold implantation. MRI experiments (anatomical and dynamic contrast-enhanced images) were performed on a 4.7-T scanner using gradient echo sequences. Bioluminescent images were acquired on an IVIS Lumina optical imager. Longitudinal examination was performed for 2 months, and one animal was monitored for 16 months. We confirmed the long-term presence (lasting more than 16 months) of viable donor cells inside the scaffolds using bioluminescence imaging with an optical signal peak appearing on day 3 after MSC implantation. When compared to controls, the tissue perfusion and vessel permeability in the scaffolds were significantly improved at the site with MSCs with a maximal peak on day 9 after MSC transplantation. Our data suggest that the maximal signal obtained by bioluminescence and magnetic resonance imaging from an artificially created site between 3 and 9 days after MSC transplantation can predict the optimal time range for subsequent cellular or tissue transplantation, including pancreatic islets.

  11. New-onset lupus nephritis in a kidney transplant recipient with cystinosis-differential diagnosis with cysteamine-induced lupus: case report.

    PubMed

    Rocha, S; Martins, L S; Vizcaíno, R; Dias, L; Almeida, M; Pedroso, S; Vidinha, J; Rocha, M; Rocha, G; Mota, C; Henriques, A; Cabrita, A

    2011-01-01

    A case of lupus nephritis in an adult female kidney transplant recipient with cystinosis under cysteamine therapy is reported. Previous reports of new-onset lupus in cystinotic patients have focused in a possible relationship of lupus with cysteamine therapy, but no obvious pathophysiological association has been disclosed. The authors present a case of a 19-year-old female kidney transplant recipient with cystinosis admitted for acute allograft dysfunction, with clinical and immunologic manifestations of lupus nephritis. Cysteamine was considered as a potential cause of drug-induced lupus, and we temporarily interrupted this drug. The clinical picture, the negativity of antihistone antibodies, the nondisappearance of antinuclear antibodies after discontinuation of the drug, and the clinical stability after resuming cysteamine therapy suggested that the underlying mechanism of lupus was unrelated to the drug. This may be the first report of new-onset lupus in a kidney transplant recipient with cystinosis. Clinicians should be aware of the association of autoimmune abnormalities in patients with cystinosis.

  12. [2-Deoxy-D-glucose combined with Taxol inhibits VEGF expression and induces apoptosis in orthotopically transplanted breast cancer in C3H mice].