Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 14.075
Filtrar
1.
Immunity ; 52(1): 136-150.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31940267

RESUMO

Effector CD8+ T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8+ T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcγRIIB following activation and multiple rounds of division. CD8+ T cell-intrinsic genetic deletion of Fcgr2b increased CD8+ effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcγRIIB in regulating CD8+ T cell immunity.


Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Fibrinogênio/imunologia , Receptores de IgG/imunologia , Adulto , Idoso , Animais , Caspase 3/imunologia , Caspase 7/imunologia , Linhagem Celular Tumoral , Feminino , Fibrinogênio/genética , Rejeição de Enxerto/imunologia , Humanos , Imunoglobulina G/imunologia , Imunossupressão , Masculino , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Receptores de IgG/genética , Adulto Jovem
2.
Nat Commun ; 10(1): 4712, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624262

RESUMO

Immune checkpoint inhibitor (ICI) use remains a challenge in patients with solid organ allografts as most would undergo rejection. In a melanoma patient in whom programmed-death 1 (PD-1) blockade resulted in organ rejection and colitis, the addition of the mTOR inhibitor sirolimus resulted in ongoing anti-tumor efficacy while promoting allograft tolerance. Strong granzyme B+, interferon (IFN)-γ+ CD8+ cytotoxic T cell and circulating regulatory T (Treg) cell responses were noted during allograft rejection, along with significant eosinophilia and elevated serum IL-5 and eotaxin levels. Co-treatment with sirolimus abated cytotoxic T cell numbers and eosinophilia, while elevated Treg cell numbers in the peripheral blood were maintained. Interestingly, numbers of IFN-γ+ CD4+ T cells and serum IFN-γ levels increased with the addition of sirolimus treatment likely promoting ongoing anti-PD-1 efficacy. Thus, our results indicate that sirolimus has the potential to uncouple anti-PD-1 therapy toxicity and efficacy.


Assuntos
Transplante de Rim/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/imunologia , Falência Renal Crônica/terapia , Melanoma/imunologia , Melanoma/terapia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Tolerância ao Transplante/efeitos dos fármacos , Tolerância ao Transplante/imunologia
3.
Med Oncol ; 36(11): 94, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31605245

RESUMO

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Rejeição de Enxerto/induzido quimicamente , Transplante de Fígado , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Rejeição de Enxerto/imunologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
4.
Nat Commun ; 10(1): 4357, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554807

RESUMO

Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors' and patients' HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington's disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain.


Assuntos
Rejeição de Enxerto/imunologia , Doença de Huntington/terapia , Células-Tronco Pluripotentes Induzidas/transplante , Complexo Principal de Histocompatibilidade/imunologia , Neurônios/transplante , Animais , Diferenciação Celular/imunologia , Citotoxicidade Imunológica/imunologia , Modelos Animais de Doenças , Teste de Histocompatibilidade , Humanos , Doença de Huntington/imunologia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/imunologia , Neurônios/citologia , Neurônios/imunologia , Primatas , Ratos Nus , Transplante Autólogo
5.
Khirurgiia (Mosk) ; (9): 80-85, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532171

RESUMO

This article discusses the need to implement effective methods for monitoring immune status and rehabilitation of patients after kidney transplantation. Induction of immunological tolerance which allows minimizing or even completely canceling supportive immunosuppressive therapy is one of the key tasks in the field of organ transplantation. Regulatory T-cells (TREGs) play an important role in maintaining immunological homeostasis, including limiting kidney transplant rejection, and potentially contribute to the development of immunological tolerance. At the same time, for the introduction of TREG therapy into clinical practice, it is necessary to overcome a number of unsolved problems, such as induction and cultivation of a sufficient number of TREG cells for therapeutic action as well as reducing the risks associated with TREG conversion to effector lymphocytes or an undesirable non-specific immunosuppressive effect. This review examines both the impact of common post-transplant pharmacological immunosuppression approaches on TREGs and the therapeutic potential of TREG cell cultures in prevention of kidney transplant rejection. The questions of ex vivo TREG manufacturing process and possible threats of applying cell technologies in this branch of transplantology were considered.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Rejeição de Enxerto/etiologia , Humanos , Tolerância Imunológica/imunologia , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim/reabilitação , Imunologia de Transplantes/imunologia
6.
Transplant Proc ; 51(8): 2624-2628, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31563242

RESUMO

INTRODUCTION: Mycophenolate mofetil has improved long-term outcomes of kidney transplantation. However, the impact of mycophenolic acid (MPA) trough level on the development of de novo donor-specific anti-HLA antibody (DSA) is unclear. We examined the relation between MPA trough level and de novo DSA development. METHOD: We retrospectively studied 617 kidney recipients whose MPA trough level and de novo DSA data were available. All patients underwent primary kidney transplant from living donors from 2008 to 2014, and were chronically treated with a calcineurin inhibitor, mycophenolate mofetil, and +/- steroids. They were equally divided into 4 groups according to the mean trough level of MPA (mMPA) at 1 year post-transplantation: Group 1, mMPA < 2.14 ng/mL (n = 152); Group 2, mMPA 2.14-2.83 ng/mL (n = 157); Group 3, mMPA 2.83-3.57 ng/mL (n = 153); and Group 4, mMPA ≥ 3.57 ng/mL (n = 155). The groups were compared by incidence rate of de novo DSA, graft survival rate, and renal function. RESULTS: The incidence rates of de novo DSA were 33.3% in Group 1, 23.7% in Group 2, 22.9% in Group 3, and 30.3% in Group 4 (P = .158). Although there was no significant difference in graft survival rates, a significant difference of renal functions was noted: the higher the renal function, the lower the MPA trough level. CONCLUSION: The mMPA trough level at 1 year post-transplantation was not statistically associated with the incidence rate of de novo DSA after kidney transplantation.


Assuntos
Soro Antilinfocitário/efeitos dos fármacos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/farmacocinética , Transplante de Rim/efeitos adversos , Ácido Micofenólico/farmacocinética , Adulto , Anticorpos/imunologia , Soro Antilinfocitário/imunologia , Inibidores de Calcineurina/administração & dosagem , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Humanos , Transplante de Rim/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
8.
Transplant Proc ; 51(8): 2648-2654, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31477418

RESUMO

BACKGROUND: The objective of this study was to determine whether perioperative immunologic markers monitoring could predict early acute cellular rejection (ACR) after living donor liver transplantation (LDLT). MATERIALS AND METHODS: From September 2010 to June 2013, a total of 172 patients underwent LDLT at our transplant center. Of them, 26 patients were excluded because of infection. We retrospectively reviewed the remaining 146 patients. CD4 lymphocyte activity, T cell subsets test, and serum cytokine panel were checked on the day before transplantation and at 20 days after transplantation. These patients were divided into 3 groups: 1. normal liver function test (LFT) group; 2. increased LFT without rejection group; and 3. early ACR group. We excluded the increased LFT without rejection group in order to rule out multiple factors influencing immunologic factors. RESULTS: CD4 lymphocyte activity (P = .004) was significantly increased while CD4+/CD25+/FOXP3+ cells (P < .001) and interleukin (IL)-17 (P = .002) levels were significantly decreased during the perioperative period. Pretransplant IL-6 (P = .014) and IL-17 (P = .029) levels in the early ACR group were significantly lower than those in the normal LFT group. The proportion of patients with increased IL-6 during perioperative period in the early ACR group was higher than that in the normal LFT group, although the difference was not statistically significant (P = .065). CONCLUSION: Our results suggest that IL-6 and IL-17 levels are associated with early ACR in LDLT patients. However, whether monitoring perioperative immunologic markers could predict early ACR remains unclear. Further prospective studies are needed to reach a definite conclusion.


Assuntos
Rejeição de Enxerto/imunologia , Interleucina-17/sangue , Interleucina-6/sangue , Transplante de Fígado/efeitos adversos , Adulto , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Feminino , Humanos , Transplante de Fígado/métodos , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Prospectivos , Estudos Retrospectivos , Subpopulações de Linfócitos T/imunologia
9.
Transplant Proc ; 51(8): 2671-2675, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31477419

RESUMO

OBJECTIVE: Delta neutrophil index (DNI), representing an elevated fraction of circulating immature granulocyte in acute infection, has been reported as a useful, predictable marker for mortality in patients with sepsis. We have hypothesized that an increased recipient DNI is associated with poor prognosis in cadaver donor kidney transplantation. METHODS: We investigated patients undergoing kidney transplantation from cadaver donors from March 2013 to January 2018. Rejection was diagnosed by kidney biopsy with Banff classification and excluded subclinical rejection. RESULTS: In a total of 73 patients undergoing cadaver kidney transplantation, 25 (34.2%) patients were diagnosed with rejection based on the Banff classification. Among them, 11 patients were diagnosed with early rejection. The recipients' postoperative DNI (%) was different between patients with early rejection and patients without rejection (0.18 vs 1.21, P < .001). In the univariate logistic regression analysis, cold ischemic time, donor preoperative last creatinine level, postoperative DNI level, and perioperative infection were predictive of early rejection. However, in a multivariate adjusted logistic regression test, only a high level of DNI (odds ratio 12.307, 95% confidence interval [CI] 1.22-129.82) was associated with early rejection. The C-statistic was 0.777 (95% CI 0.604-0.951, P = .004) for DNI. In multivariate Cox regression analysis, the donor's last creatinine level (hazard ratio 2.25, 95% CI 1.26-4.13) and preoperative DNI (hazard ratio 14.02 95% CI 2.62-75.26) were predictors of renal survival. CONCLUSIONS: Increased DNI in cadaver donor kidney transplantation recipients might be one of the predictive values of early kidney rejection and prognosis.


Assuntos
Rejeição de Enxerto/sangue , Transplante de Rim , Neutrófilos/citologia , Neutrófilos/imunologia , Adulto , Cadáver , Feminino , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/métodos , Transplante de Rim/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Doadores de Tecidos
10.
Transplant Proc ; 51(7): 2254-2256, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474291

RESUMO

OBJECTIVE: High panel-reactive antibody (PRA) levels limit patients' access to kidney transplantation from potential living donor candidates and decrease renal graft survival by causing acute antibody-mediated rejection (AAMR). In this article, we report our experiences about the efficiency of plasmapheresis (PP) and intravenous immunoglobulin (IVIG) in reduction of serum PRA levels in candidates for renal transplantation and in patients with AAMR. METHODS: We examined retrospectively 47 patients with high PRA levels (18 for desensitization (DS) and 29 with AAMR) at Ankara University. The reduction in PRA class 1 and PRA class 2 levels before and after the PP, IVIG, and rituximab or eculizumab therapy were evaluated. RESULTS: In the DS group, mean reduction in PRA class I ± SD was 28.0 ± 9.10 to 22.1 ± 8.14 (P <.05), and mean reduction in PRA class II ± SD was 40.3 ± 6.89 to 32.2 ± 5.68 (P < .05). In the AAMR group; mean reduction in PRA class I ± SD was 23.9 ± 9.56 to 17.8 ± 8.64 (P > .05), and mean reduction in PRA class II ± SD was 28.1 ± 8.37 to 26.7 ± 7.96 (P > .05). In total, mean reduction in PRA class I was 25.7 ± 6.66 to 19.7 ± 6.00 (P < .01). Mean reduction in PRA class II was 33.8 ± 5.93 to 29.2 ± 4.96 (P > .05). In the DS group, 3 (16.7%) patients were treated with rituximab. In the AAMR group, 9 (31.0%) patients were treated with rituximab, and 1 (5.5%) patient received eculizimab.In the DS group, the mean follow-up period in years ± SD was 5.06 ± 3.01 and no patient had graft loss. In the AAMR group, the mean follow-up period in years was 5.06 ± 2.74 and 6 (33.3%) patients had graft loss with acute rejection. CONCLUSIONS: PP and IVIG treatment provide significant reduction in PRA levels and can be used in DS protocols.


Assuntos
Dessensibilização Imunológica/métodos , Rejeição de Enxerto/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Transplante de Rim/efeitos adversos , Plasmaferese/métodos , Adulto , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Resultado do Tratamento
11.
Transplant Proc ; 51(7): 2274-2278, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474292

RESUMO

BACKGROUND: Retransplantation is a treatment option in patients with end-stage renal failure due to graft loss. Outcomes of these patients due to high immunologic risk remain unclear. The aim of this study was to evaluate outcomes of renal retransplantation patients retrospectively. METHODS: Renal retransplant patients in our unit were evaluated retrospectively between 2010 and 2018. Patients' demographic characteristics, primary diseases, the causes of prior graft loss, immunologic status, desensitization protocols, the induction and maintenance treatments, the complications during the follow-up period, numbers of acute rejections, and the clinical prognosis were all detected from the patients' files. RESULTS: We retrospectively evaluated 17 patients who underwent a second or third renal allograft. Of these, 16 received a second and the remaining 1 patient received a third renal allograft. Immunologically, all of the 17 patients had negative flow cytometry crossmatch, 1 patient had a positive complement-dependent cytotoxicity crossmatch (Auto 12%), 16 patients had positive panel reactive antibody, the median HLA-mismatch was 3.5, and the score of donor-specific antibody relative intensity score (RIS) was 6.4 ± 6.3. Ten pretransplant patients had desensitization treatment. While scores for HLA-MM and HLA-RIS in the patients who had a desensitization therapy were determined higher, no statistical difference was observed (respectively, P = .28 and .55). No acute rejection episode developed. BK virus DNA viremia was detected in 4 patients during the posttransplant 6th month. We observed no patient death or no graft loss during the follow-up period. CONCLUSION: Although the retransplant patients who had a graft loss previously have high immunologic risks, retransplantation is reliable in these patients, but they should be followed up carefully in terms of BKV nephropathy.


Assuntos
Dessensibilização Imunológica/estatística & dados numéricos , Rejeição de Enxerto/cirurgia , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Reoperação/métodos , Adulto , Dessensibilização Imunológica/métodos , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade/métodos , Humanos , Rim/imunologia , Falência Renal Crônica/etiologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
12.
Transplant Proc ; 51(7): 2241-2244, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400974

RESUMO

BACKGROUND: Accumulating evidence suggests that detection of human leukocyte antigen (HLA) antibodies by solid phase Luminex assays predicts renal allograft outcomes. However, several controversies exist regarding the interpretation, reproducibility, impact and financial feasibility of global utilization of this assay in pretransplant assessment. METHODS: We studied short-term patient-centered outcomes, medical standards of care, and financial plausibility of using Luminex-based screening for HLA antibodies in renal allograft recipients compared to outcomes in nontested patients. RESULTS: We included 1808 patients assessed for transplantation from 2011 to 2018. Luminex-tested patients had lower rates of rejection in the first post-transplant week (OR 0.36, P < .001) and lower odds of antibody-mediated rejection in the first 6 months (OR 0.4, P = .004). Forty-four patients with preformed, donor-specific antibodies were transplanted, and everolimus was introduced into our protocols for low-risk patients based on risk stratification by Luminex results. The number of tests needed to be performed to prevent 1 episode of antibody-mediated rejection in the first 6 months was 28 (P = .004), which was financially plausible. CONCLUSIONS: Routine pre-transplant assessment of HLA antibodies using Luminex assays may allow for better patient-centered, short-term graft outcomes and objective tailoring of immunosuppression at a financially plausible, cost-effective rate.


Assuntos
Anticorpos/análise , Rejeição de Enxerto/imunologia , Antígenos HLA/imunologia , Testes Imunológicos/métodos , Transplante de Rim/efeitos adversos , Anticorpos/imunologia , Análise Custo-Benefício , Estudos de Viabilidade , Feminino , Humanos , Testes Imunológicos/economia , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Reprodutibilidade dos Testes , Transplante Homólogo
13.
Ann Transplant ; 24: 454-460, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31383839

RESUMO

BACKGROUND The appearance of human leukocyte antigen (HLA) antibodies after solid organ transplantation predisposes recipients to graft dysfunction. In theory, vascular homografts, which are widely used in children with congenital heart defects, may cause allosensitization. MATERIAL AND METHODS In this single-center retrospective study, the presence of pre-existing HLA antibodies in pediatric heart transplant (HTx) recipients with a vascular homograft was evaluated in a cohort of 12 patients. HLA antibodies were screened before and after HTx and positive screening results were confirmed and identified using the Luminex® single antigen bead method. Endomyocardial biopsies (EMB) and coronary angiography studies were re-evaluated to assess the prevalence of acute rejections and coronary artery change in these patients. RESULTS At the time of HTx, 8 patients (67%) had HLA antibodies detected by the Luminex assay, none of which were heart donor specific (DSA). All patients had negative leukocyte crossmatch. One patient developed DSAs against homograft donor prior to HTx. After the HTx, 5 patients (42%) developed DSAs against the heart donor and 4 patients (40%) against the homograft donor. In 2 patients (17%), the antibodies were against both heart and homograft donors. The rejection rate or prevalence of coronary artery vasculopathy did not differ significantly between the homograft cohort and our historical controls. CONCLUSIONS Our results suggest that the prevalence of DSAs against homograft donor prior to HTx is relatively rare. However, almost half of the patients developed DSAs against homograft post-HTx. The clinical importance of these antibodies warrants further studies.


Assuntos
Antígenos HLA/imunologia , Transplante de Coração/efeitos adversos , Isoanticorpos/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Estudos Retrospectivos
14.
Transplant Proc ; 51(6): 1744-1753, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399162

RESUMO

INTRODUCTION: Depletion therapy in high immunologic risk (HR) patients by antithymocyte globulin (rATG) induces lymphopenia and subsequent compartmental repopulation of T-cell subsets. rATG is also given to patients receiving kidneys from donations after cardiac death (DCDs) to mitigate innate immune activation associated with the DCD process. METHODS: We compared the T-cell response with rATG in both HR and DCD kidney recipients. We examined the reconstitution of T-cell subsets after rATG treatment in HR and DCD recipients (n = 19 per group) by multicolor flow cytometry. RESULTS: Following treatment, there was a rapid drop in the frequency of T cells in both groups, which persisted over 28 days. HR patients had an early surge in the frequency of CD4+ naïve, effector-memory, and regulatory T cells. Although we found a significant proliferation of the T cells in both groups, the DCD cohort had a blunted response as well as reduced CD4+ T-cell immune-reactivity compare with the HR group. CONCLUSIONS: Our data suggest that there is a lack of significant homeostatic proliferative response in DCD recipients following rATG, and CD4+ T cells may be less reactive in the DCD group than previously thought, indicating that rATG treatment may not have to be considered a first-line induction therapy in DCD recipients.


Assuntos
Soro Antilinfocitário/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/métodos , Subpopulações de Linfócitos T/efeitos dos fármacos , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Doadores de Tecidos
15.
Transplant Proc ; 51(7): 2298-2301, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31405734

RESUMO

BACKGROUND: Renal transplantation (RT) in high-risk patients is increasingly performed due to an inadequate organ pool and increased rate of RT after a failed transplantation. Safety and prognosis of RT in such patients with high risk is an ongoing debate. Herein we aimed to present our single-center experience on RT of high-risk patients. METHODS: A total of 89 consecutive RT patients were included into this study in a 10-month period. Patients were divided into 3 groups: the low-risk group (n = 47) with negative panel reactive antibody (PRA), medium-risk group (n = 18) with positive PRA but mean fluorescence intensity (MFI) < 2000, and high-risk group (n = 24) with positive PRA and MFI >2000 or donor specific antibody (DSA) positivity. Groups were compared in terms of demographic features, serum creatinine levels, acute rejection rates, delayed graft function (DGF), and patient or graft loss. RESULTS: Age of the recipients were similar between the groups. Desensitization (7% vs 11% vs 42%, respectively, in low-, medium-, and high-risk groups; P = .001), plasmapheresis (6% vs 11% vs 46%, respectively, P < .001), and rituximab treatments (0% vs 0% vs 25%, respectively, P < .001) were significantly more frequently performed in high-risk patients. Serum creatinine levels at 1 month and 6 months after RT were similar between the groups (P = .43 and P = .71, respectively). Rates of acute rejection (6% vs 6% vs 16%, respectively, P = .52) and DGF (9% vs 11% vs 29%, respectively, P = .15) were similar between the groups. Frequencies of loss of patient or graft were also similar (0% vs 6% vs 4%, P = .15). CONCLUSION: RT may be successfully performed in high-risk patients without an increase in the risk of acute rejection, DGF, or patient/graft loss.


Assuntos
Dessensibilização Imunológica/estatística & dados numéricos , Rejeição de Enxerto/imunologia , Transplante de Rim/efeitos adversos , Plasmaferese/estatística & dados numéricos , Rituximab/uso terapêutico , Adulto , Anticorpos/imunologia , Função Retardada do Enxerto/imunologia , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
16.
Transplant Proc ; 51(8): 2555-2558, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31447191

RESUMO

BACKGROUND: Among foreigners undergoing kidney transplantation (KT) in Korea, Mongolians are the most common, and most of these cases are conducted at our center. We report the immunologic characteristics and clinical outcomes of these patients. METHODS: Consecutive Mongolian patients who underwent KT from September 2009 to August 2017 in our center were retrospectively analyzed. Pre- and post-transplant HLA antibody status and clinical data of the Mongolian patients were collected and compared with the Korean patients who underwent living donor KT during the same period. RESULTS: Sixty-two Mongolian and 85 Korean patients received KT and were followed up for 20.9 and 50.8 months (P = .01), respectively. Before transplantation, 17.7% of the Mongolian patients and 7.1% of the Korean patients were highly sensitized (P = .05). The patients were monitored consistently throughout the entire post-transplant period. Follow-up loss occurred in some cases. Of the patients, 32 Mongolian patients and 79 Korean patients were monitored for post-transplant HLA antibodies at any time point. Estimated glomerular filtration rates were comparable between Mongolian and Korean patients at 1 month (77.1 vs 71.5 mL/min/1.73m2, P = .21) and 1 year (64.6 vs 68.7 mL/min/1.73m2, P = .25) after transplantation but tended to be different at 3 years (57.2 vs 67.3 mL/min/1.73m2, P = .06) and 5 years (56.9 vs 73.1 mL/min/1.73m2, P = .04) post transplant. CONCLUSIONS: Mongolian patients undergoing KT in Korea were often highly sensitized. Mean follow-up time was short and follow-up loss was common in Mongolian patients compared with Korean patients. Cautious follow-up is needed for foreigner transplant recipients, especially for those at high-risk immunologically, to achieve better outcomes.


Assuntos
Emigrantes e Imigrantes/estatística & dados numéricos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Transplante de Rim/estatística & dados numéricos , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Mongólia/etnologia , Período Pós-Operatório , Período Pré-Operatório , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento
17.
Nat Biotechnol ; 37(10): 1137-1144, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427818

RESUMO

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.


Assuntos
DNA Mitocondrial/genética , Epitopos/genética , Epitopos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células-Tronco Pluripotentes Induzidas , Animais , Antígenos , Transplante de Células/métodos , Células-Tronco Embrionárias , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Transplante Autólogo
18.
Transplant Proc ; 51(8): 2660-2666, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31445765

RESUMO

BACKGROUND: Linear C4d staining in the peritubular capillaries is considered a sensitive and useful marker of active or chronic active antibody-mediated rejection (ABMR) in transplanted kidneys. However, the diagnostic significance of glomerular C4d deposits (gC4d) is still undetermined. The aim of this study is to evaluate the association of gC4d with clinicopathologic features and to assess its diagnostic value. METHODS: From 2013 to 2018, a total of 158 cases of allograft kidney biopsy specimens were obtained from the Korea University Anam Hospital. The histologic features were evaluated according to the Banff classification. The gC4d were determined through immunohistochemical analyses and classified based on scores of 0 to 3 according to the extent of gC4d. RESULTS: A total of 73 cases (46.2%) showed gC4d, and 37 cases (23.4%), 23 cases (14.6%), and 13 cases (8.2%) were classified with a score of 1+, 2+, and 3+, respectively. The gC4d showed a significant correlation with antibody-associated histologic lesions, including peritubular capillaritis, glomerulitis, and transplant glomerulopathy (P < .001). However, gC4d showed no significant association with cell-mediated injuries such as tubulitis, interstitial inflammation, acute tubular necrosis, and thrombotic microangiopathy. Although positive gC4d alone was associated with nonspecific findings without ABMR, most cases of gC4d combined with glomerulitis or transplant glomerulopathy showed typical histologic features of ABMR, clinically with higher antibody titers and severe functional deterioration. CONCLUSIONS: Glomerular C4d deposits may be an alternate useful marker in the diagnosis of active or chronic active ABMR when combined with histologic features of glomerular lesions.


Assuntos
Complemento C4b/análise , Glomerulonefrite/imunologia , Rejeição de Enxerto/diagnóstico , Transplante de Rim/efeitos adversos , Fragmentos de Peptídeos/análise , Complicações Pós-Operatórias/imunologia , Doença Aguda , Adulto , Anticorpos/imunologia , Biomarcadores/análise , Capilares/patologia , Doença Crônica , Complemento C4b/imunologia , Feminino , Glomerulonefrite/patologia , Rejeição de Enxerto/imunologia , Humanos , Rim/imunologia , Glomérulos Renais/imunologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologia , Complicações Pós-Operatórias/patologia , República da Coreia , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia , Transplante Homólogo
19.
Khirurgiia (Mosk) ; (8): 59-62, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31464276

RESUMO

The use of allogenic materials in reconstructive surgery is of great scientific interest due to high availability of donor tissues. The positive aspects of allogenous tissue transplantation are complicated by the histological incompatibility of donor tissue and recipient organism. This incompatibility results hypersensitivity reaction towards the allogenous transplant followed by rejection of allogenic tissue and even death in some cases. Cellular biological incompatibility may be managed by decellularization of allogenous organs and tissues prior to transplantation. The improvement of decellularization techniques will facilitate application of allogenous tissues in complex reconstructive procedures and significantly increase the capabilities of reconstructive surgery.


Assuntos
Aloenxertos/imunologia , Células/imunologia , Engenharia Tecidual/métodos , Imunologia de Transplantes , Transplante Homólogo/métodos , Aloenxertos/citologia , Rejeição de Enxerto/imunologia , Procedimentos Cirúrgicos Reconstrutivos , Tecidos Suporte , Imunologia de Transplantes/imunologia
20.
Nat Commun ; 10(1): 3495, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375697

RESUMO

Immune tolerance to allografts has been pursued for decades as an important goal in transplantation. Administration of apoptotic donor splenocytes effectively induces antigen-specific tolerance to allografts in murine studies. Here we show that two peritransplant infusions of apoptotic donor leukocytes under short-term immunotherapy with antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor and anti-interleukin 6 receptor antibody induce long-term (≥1 year) tolerance to islet allografts in 5 of 5 nonsensitized, MHC class I-disparate, and one MHC class II DRB allele-matched rhesus macaques. Tolerance in our preclinical model is associated with a regulatory network, involving antigen-specific Tr1 cells exhibiting a distinct transcriptome and indirect specificity for matched MHC class II and mismatched class I peptides. Apoptotic donor leukocyte infusions warrant continued investigation as a cellular, nonchimeric and translatable method for inducing antigen-specific tolerance in transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica , Transplante das Ilhotas Pancreáticas/efeitos adversos , Linfócitos T Reguladores/transplante , Transferência Adotiva , Aloenxertos/imunologia , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Feminino , Rejeição de Enxerto/imunologia , Humanos , Imunossupressores/uso terapêutico , Ilhotas Pancreáticas/imunologia , Macaca mulatta , Masculino , Linfócitos T Reguladores/imunologia , Doadores de Tecidos , Transplante Homólogo/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA