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1.
Medicine (Baltimore) ; 100(10): e24853, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33725841

RESUMO

BACKGROUND: Rituximab is an induction immunosuppressant essential for ABO-incompatible kidney transplantation (ABOi KT). However, studies on its dosing, which differs among countries and transplant centers, are lacking. Therefore, we retrospectively investigated the effectiveness of the induction dose of rituximab against patient mortality, graft failure, and adverse events. METHODS: We included the studies referring to at least 2 of eligible induction doses (200 mg, 200-500 mg, or 500 mg) of rituximab during ABOi KT and relevant outcomes such as patient survival, graft failure, and bacterial and viral infections. We performed direct and indirect network meta-analyses using Bayesian models and ranked different rituximab doses using generation mixed treatment comparison. Publications were retrieved using CENTRAL, MEDLINE, EMBASE, and Science Citation Index Expanded databases from 1970 to February 2020 and analyzed. The GRADE of network meta-analysis approach specified 4 levels of certainty for a given result: high, moderate, low, and very low. RESULTS: Among the 4256 patients from 21 trials, glomerular filtration rate, graft loss, antibody-mediated rejection, T-cell mediated rejection, fungal infection, bacterial infection, and CMV infection did not differ among ABOi groups treated with different rituximab doses. The effect on mortality was significantly higher in rituximab 200 to 500 mg, and rituximab 500 mg groups (odds ratios [OR] 3.5, 95% CrI: 1.3-9.8, and OR 3.0, 95% CrI 1.1-9.8), but not in rituximab 20 mg group (OR 0.45, 95% CrI 0.036-2.5). The incidence of BK virus was significantly lower in the rituximab 200-mg group than in the other groups. DISCUSSION: In ABO-incompatible kidney transplantation, low-dose rituximab is more efficacious than higher doses and reduces serious infection risks. Additional randomized controlled trials might be needed to confirm these findings due to small sample size.


Assuntos
Sistema ABO de Grupos Sanguíneos , Incompatibilidade de Grupos Sanguíneos , Imunossupressores/administração & dosagem , Transplante de Rim , Complicações Pós-Operatórias/prevenção & controle , Rituximab/administração & dosagem , Infecções Bacterianas/prevenção & controle , Teorema de Bayes , Esquema de Medicação , Taxa de Filtração Glomerular , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Humanos , Quimioterapia de Indução , Transplante de Rim/efeitos adversos , Doadores Vivos , Micoses/prevenção & controle , Metanálise em Rede , Viroses/prevenção & controle
2.
BMJ ; 371: m3734, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087345

RESUMO

OBJECTIVE: To assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model. DESIGN: Investigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13). SETTING: Charité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union). PARTICIPANTS: Recipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9). INTERVENTIONS: CD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48. MAIN OUTCOME MEASURES: The primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio. RESULTS: For all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire. CONCLUSIONS: The application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies. TRIAL REGISTRATION: NCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).


Assuntos
Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim/métodos , Linfócitos T Reguladores/transplante , Tacrolimo/administração & dosagem , Adulto , Aloenxertos/imunologia , Estudos de Viabilidade , Feminino , Alemanha , Sobrevivência de Enxerto/imunologia , Humanos , Infusões Intravenosas , Rim/imunologia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Resultado do Tratamento , Suspensão de Tratamento
3.
PLoS One ; 15(8): e0234396, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756556

RESUMO

INTRODUCTION: Early conversion to a CNI-free immunosuppression with SRL was associated with an improved 1- and 3- yr renal function as compared with a CsA-based regimen in the SMART-Trial. Mixed results were reported on the occurrence of donor specific antibodies under mTOR-Is. Here, we present long-term results of the SMART-Trial. METHODS AND MATERIALS: N = 71 from 6 centers (n = 38 SRL and n = 33 CsA) of the original SMART-Trial (ITT n = 140) were enrolled in this observational, non-interventional extension study to collect retrospectively and prospectively follow-up data for the interval since baseline. Primary objective was the development of dnDSA. Blood samples were collected on average 8.7 years after transplantation. RESULTS: Development of dnDSA was not different (SRL 5/38, 13.2% vs. CsA 9/33, 27.3%; P = 0.097). GFR remained improved under SRL with 64.37 ml/min/1.73m2 vs. 53.19 ml/min/1.73m2 (p = 0.044). Patient survival did not differ between groups at 10 years. There was a trend towards a reduced graft failure rate (11.6% SRL vs. 23.9% CsA, p = 0.064) and less tumors under SRL (2.6% SRL vs. 15.2% CsA, p = 0.09). CONCLUSIONS: An early conversion to SRL did not result in an increased incidence of dnDSA nor increased long-term risk for the recipient. Transplant function remains improved with benefits for the graft survival.


Assuntos
Inibidores de Calcineurina/administração & dosagem , Imunossupressão/métodos , Imunossupressores/administração & dosagem , Transplante de Rim , Sirolimo/administração & dosagem , Adulto , Especificidade de Anticorpos , Esquema de Medicação , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fatores de Tempo , Doadores de Tecidos
4.
Science ; 369(6503)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732394

RESUMO

The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become "educated" in the thymus to recognize a great diversity of peptide antigens bound to the body's own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.


Assuntos
Imunoterapia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Linfócitos B/imunologia , Diferenciação Celular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Linfoma/imunologia , Linfoma/terapia , Camundongos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transplante de Pele , Subpopulações de Linfócitos T/citologia , Timo/citologia
5.
Transplantation ; 104(8): 1566-1573, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732833

RESUMO

BACKGROUND: Xenogeneic organ transplantation has been proposed as a potential approach to fundamentally solve organ shortage problem. Xenogeneic immune responses across species is one of the major obstacles for clinic application of xeno-organ transplantation. The generation of glycoprotein galactosyltransferase α 1, 3 (GGTA1) knockout pigs has greatly contributed to the reduction of hyperacute xenograft rejection. However, severe xenograft rejection can still be induced by xenoimmune responses to the porcine major histocompatibility complex antigens swine leukocyte antigen class I and class II. METHODS: We simultaneously depleted GGTA1, ß2-microglobulin (ß2M), and major histocompatibility complex class II transactivator (CIITA) genes using clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins technology in Bamma pig fibroblast cells, which were further used to generate GGTA1ß2MCIITA triple knockout (GBC-3KO) pigs by nuclear transfer. RESULTS: The genotype of GBC-3KO pigs was confirmed by polymerase chain reaction and Sanger sequencing, and the loss of expression of α-1,3-galactose, SLA-I, and SLA-II was demonstrated by flow cytometric analysis using fluorescent-conjugated lectin from bandeiraea simplicifolia, anti-ß2-microglobulin, and swine leukocyte antigen class II DR antibodies. Furthermore, mixed lymphocyte reaction assay revealed that peripheral blood mononuclear cells from GBC-3KO pigs were significantly less effective than (WT) pig peripheral blood mononuclear cells in inducing human CD3CD4 and CD3CD8 T-cell activation and proliferation. In addition, GBC-3KO pig skin grafts showed a significantly prolonged survival in immunocompetent C57BL/6 mice, when compared with wild-type pig skin grafts. CONCLUSIONS: Taken together, these results demonstrate that elimination of GGTA1, ß2M, and CIITA genes in pigs can effectively alleviate xenogeneic immune responses and prolong pig organ survival in xenogenesis. We believe that this work will facilitate future research in xenotransplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Xenoenxertos/imunologia , Transplante de Órgãos/métodos , Transplante Heterólogo/métodos , Aloenxertos/provisão & distribução , Animais , Animais Geneticamente Modificados/imunologia , Sistemas CRISPR-Cas/genética , Modelos Animais de Doenças , Feminino , Galactosiltransferases/genética , Galactosiltransferases/imunologia , Técnicas de Inativação de Genes/métodos , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Xenoenxertos/transplante , Humanos , Masculino , Camundongos , Transplante de Órgãos/efeitos adversos , Suínos/genética , Suínos/imunologia , Transplante Heterólogo/efeitos adversos , Microglobulina beta-2/genética , Microglobulina beta-2/imunologia
6.
Transplantation ; 104(8): 1580-1590, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732835

RESUMO

BACKGROUND: Although short-term outcomes for liver transplantation have improved, patient and graft survival are limited by infection, cancer, and other complications of immunosuppression. Rapid induction of tolerance after liver transplantation would decrease these complications, improving survival and quality of life. Tolerance to kidneys, but not thoracic organs or islets, has been achieved in nonhuman primates and humans through the induction of transient donor chimerism. Since the liver is considered to be tolerogenic, we tested the hypothesis that the renal transplant transient chimerism protocol would induce liver tolerance. METHODS: Seven cynomolgus macaques received immune conditioning followed by simultaneous donor bone marrow and liver transplantation. The more extensive liver surgery required minor adaptations of the kidney protocol to decrease complications. All immunosuppression was discontinued on postoperative day (POD) 28. Peripheral blood chimerism, recipient immune reconstitution, liver function tests, and graft survival were determined. RESULTS: The level and duration of chimerism in liver recipients were comparable to those previously reported in renal transplant recipients. However, unlike in the kidney model, the liver was rejected soon after immunosuppression withdrawal. Rejection was associated with proliferation of recipient CD8 T effector cells in the periphery and liver, increased serum interleukin (IL)-6 and IL-2, but peripheral regulatory T cell (Treg) numbers did not increase. Antidonor antibody was also detected. CONCLUSIONS: These data show the transient chimerism protocol does not induce tolerance to livers, likely due to greater CD8 T cell responses than in the kidney model. Successful tolerance induction may depend on greater control or deletion of CD8 T cells in this model.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Transplante de Fígado/efeitos adversos , Quimeras de Transplante/imunologia , Condicionamento Pré-Transplante/métodos , Aloenxertos/imunologia , Animais , Medula Óssea/imunologia , Transplante de Medula Óssea/métodos , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Fígado/imunologia , Transplante de Fígado/métodos , Macaca fascicularis , Linfócitos T Citotóxicos/imunologia , Tolerância ao Transplante , Transplante Homólogo/efeitos adversos
7.
Transplantation ; 104(8): 1591-1603, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732836

RESUMO

BACKGROUND: Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. METHODS: A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. RESULTS: A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). CONCLUSIONS: Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/epidemiologia , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Preservação de Órgãos/métodos , Idoso , Aloenxertos/imunologia , Aloenxertos/provisão & distribução , Isquemia Fria/instrumentação , Isquemia Fria/métodos , Isquemia Fria/estatística & dados numéricos , Doença Hepática Terminal/complicações , Estudos de Viabilidade , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/imunologia , Humanos , Rim/imunologia , Transplante de Rim/ética , Transplante de Rim/métodos , Transplante de Rim/estatística & dados numéricos , Transplante de Fígado/ética , Transplante de Fígado/métodos , Transplante de Fígado/estatística & dados numéricos , Masculino , Futilidade Médica/ética , Pessoa de Meia-Idade , Preservação de Órgãos/instrumentação , Preservação de Órgãos/estatística & dados numéricos , Perfusão/instrumentação , Perfusão/métodos , Perfusão/estatística & dados numéricos , Insuficiência Renal/etiologia , Insuficiência Renal/cirurgia , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/ética , Transplante Homólogo/métodos , Resultado do Tratamento
8.
Transplantation ; 104(8): 1633-1643, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732841

RESUMO

BACKGROUND: The cellular infiltrate in protocol liver biopsies (PB) following pediatric liver transplantation remains mostly uncharacterized, yet there is increasing concern about the role of inflammation and fibrosis in long-term liver allografts. We aimed to define cell types in PB and to analyze their relationship with donor-specific antibodies (DSA) and histological phenotype. METHODS: PB were performed at least 1 year after transplantation. We identified 4 phenotypes: normal, fibrosis, inflammation, inflammation with fibrosis. Cell types were counted after immunostaining for CD3, CD4, CD8, CD68, CD20, MUM1, and FoxP3. RESULTS: Forty-four patients underwent 1 PB between 2000 and 2015. Eleven percent (5/44) of PB displayed normal histology, 13.6% (6/44) fibrosis, 34.1% (15/44) inflammation, and 40.9% (18/44) inflammation and fibrosis. The main cell types in the portal tracts and lobules were CD3+ and CD68+ cells. Frequency of de novo DSA was 63% (27/44). The presence of CD8+ cells in the lobules was associated with fibrosis. Inflammation and fibrosis in PB were associated with the presence of circulating de novo DSA, number of de novo DSA, and C1q binding activity when compared to other phenotypes. CONCLUSIONS: T cells (CD3+) and macrophages (CD68+) were the most prevalent cell-types in PB. In the presence of inflammation, portal tracts were enriched in CD3+, CD20+ but displayed fewer CD68+. This coincided with the presence and number of de novo DSA. How these cellular and humoral actors interact is unclear, but peripheral DSA may be a marker of immune cellular activity in the seemingly quiescent allograft.


Assuntos
Doença Hepática Terminal/cirurgia , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Fígado/efeitos adversos , Sistema Porta/imunologia , Adolescente , Adulto , Aloenxertos/irrigação sanguínea , Aloenxertos/imunologia , Aloenxertos/patologia , Biópsia , Criança , Pré-Escolar , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/etiologia , Feminino , Fibrose , Seguimentos , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/estatística & dados numéricos , Humanos , Imunidade Celular , Lactente , Isoanticorpos/análise , Fígado/irrigação sanguínea , Fígado/imunologia , Fígado/patologia , Doadores Vivos/estatística & dados numéricos , Macrófagos/imunologia , Masculino , Sistema Porta/citologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Transplantados/estatística & dados numéricos , Transplante Homólogo/efeitos adversos , Adulto Jovem
9.
Transplantation ; 104(8): 1703-1711, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732850

RESUMO

BACKGROUND: There are limited data on the outcome of transplant recipients with familial Mediterranean fever (FMF)-associated AA amyloidosis. The aim of the present study is to evaluate demographic, clinical, laboratory, and prognostic characteristics and outcome measures of these patients. METHODS: Eighty-one renal transplant recipients with FMF-associated AA amyloidosis (group 1) and propensity score-matched transplant recipients (group 2, n = 81) with nonamyloidosis etiologies were evaluated in this retrospective, multicenter study. Recurrence of AA amyloidosis was diagnosed in 21 patients (group 1a), and their features were compared with 21 propensity score-matched recipients with FMF amyloidosis with no laboratory signs of recurrence (group 1b). RESULTS: The risk of overall allograft loss was higher in group 1 compared with group 2 (25 [30.9%] versus 12 [14.8%]; P = 0.015 [hazard ratio, 2.083; 95% confidence interval, 1.126-3.856]). Patients in group 1 were characterized by an increased risk of mortality compared with group 2 (11 [13.6%] versus 0%; P = 0.001 [hazard ratio, 1.136; 95% confidence interval, 1.058-1.207]). Kaplan-Meier analysis revealed that 5- and 10-year patient survival rates in group 1 (92.5% and 70.4%) were significantly lower than in group 2 (100% and 100%; P = 0.026 and P = 0.023, respectively). Although not reaching significance, overall, 5- and 10-year graft survival rates (57.1%, 94.7%, and 53.8%, respectively) in group 1a were worse than in group 1b (76.2%, 95%, and 77.8%, respectively; P = 0.19, P = 0.95, and P = 0.27, respectively). CONCLUSIONS: AA amyloidosis is associated with higher risk of mortality after kidney transplantation. Inflammatory indicators should be monitored closely, and persistent high levels of acute-phase reactants should raise concerns about amyloid recurrence in allograft.


Assuntos
Amiloidose/cirurgia , Febre Familiar do Mediterrâneo/complicações , Rejeição de Enxerto/mortalidade , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos/imunologia , Aloenxertos/patologia , Amiloidose/imunologia , Amiloidose/mortalidade , Amiloidose/patologia , Biópsia , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/mortalidade , Febre Familiar do Mediterrâneo/cirurgia , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/imunologia , Humanos , Estimativa de Kaplan-Meier , Rim/imunologia , Rim/patologia , Falência Renal Crônica/imunologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Proteína Amiloide A Sérica/imunologia , Proteína Amiloide A Sérica/metabolismo , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
Transplantation ; 104(8): 1726-1737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732853

RESUMO

BACKGROUND: De novo donor-specific antibodies (DSAs) are associated with antibody-mediated rejection (AMR) and allograft loss. Whether monitoring of de novo DSA (dnDSA) paired with systematic kidney biopsy should become routine remains to be established. METHODS: A retrospective multicentric study (9 French kidney transplant units of the Spiesser group) included patients without graft dysfunction biopsied because of the presence of dnDSA (One Lambda, mean fluorescence intensity [MFI], >1000). RESULTS: One hundred twenty-three patients (85 male/38 female; mean age, 49.5 ± 13.1 y old) were biopsied after the detection of a dnDSA, 65.3 months (median) after kidney transplantation. Graft function was stable within 3 months before biopsy (estimated glomerular filtration rate, 55.3 ± 18.9 mL/min/1.73 m). Fifty-one subclinical AMRs (sAMRs) (41.4%) were diagnosed, of which 32 (26%) active and 19 (15.5%) chronic active sAMR. Seventy-two biopsies revealed no AMR (58.5%). Predictive factors associated with the diagnosis of active sAMR were MFI of immunodominant DSA >4000, MFI of the sum of DSA >6300, age of the recipient <45 years old, and the absence of steroids at biopsy. The presence of proteinuria >200 mg/g was predictive of chronic active sAMR. The decrease of estimated glomerular filtration rate at 5 years post-biopsy was significantly higher in patients with acute sAMR (-25.2 ± 28.3 mL/min/1.73 m) and graft survival significantly lower. CONCLUSIONS: Performing a kidney graft biopsy for the occurrence of dnDSA without renal dysfunction leads to the diagnosis of a sAMR in over 40% of cases. Nevertheless, we did not observe any effect of standard treatment in acute sAMR.


Assuntos
Protocolos Clínicos , Rejeição de Enxerto/diagnóstico , Isoanticorpos/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Aloenxertos , Biópsia , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/terapia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Teste de Histocompatibilidade/normas , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/imunologia , Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento
11.
Emerg Top Life Sci ; 4(2): 207-227, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32691841

RESUMO

Human pregnancy, critical for our species survival, is inefficient and prone to complications such as infertility, spontaneous miscarriages and preeclampsia (PE). Immunological factors may be important as the embryo is 50% paternal and foreign to the mother. Mouse pregnancy models, and in particular the murine CBA/J x DBA/2 mating combination, has been widely used to investigate mechanisms causing and preventing partner-specific recurrent miscarriages (RM) and PE. Occult losses can represent T cell-mediated rejection, and antigen-specific regulatory T cells (Tregs) with classical αß T cell receptors (TcR) activated by semen antigens at the time of mating are protective. If there is no occult loss, an inadequate Treg response can also predispose to RM. In RM, proinflammatory cytokines from natural killer (NK)-type cells and macrophages of the innate immune system are responsible and cells with γδ TcR protect via release of TGF-ß-type molecules. Immunization of abortion-prone female CBA/J mice or administration of cell-associated or soluble CD200, an immune check point inhibitor, can prevent abortions by augmenting uterine decidual suppressor cell activity. Human studies suggest that is also true in couples with RM. Environmental activators of the innate immune system, such as bacterial LPS and stress, can cause abortions as well as occult losses. The endogenous level of Tregs and activation of Tregs specific for the male H-Y antigen may determine success rates and alter the male:female birth ratio. Intralipid alters LPS clearance, prevents abortions in the CBAxDBA/2 model, and is effective in increasing live birth rates in couples undergoing IVF treatment.


Assuntos
Aborto Habitual/imunologia , Modelos Animais de Doenças , Eclampsia/imunologia , Infertilidade/imunologia , Aborto Habitual/prevenção & controle , Aborto Habitual/terapia , Animais , Antígenos CD/metabolismo , Citocinas/metabolismo , Eclampsia/prevenção & controle , Eclampsia/terapia , Implantação do Embrião , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Infertilidade/prevenção & controle , Infertilidade/terapia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Gravidez , Complicações na Gravidez , Resultado da Gravidez , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Razão de Masculinidade , Linfócitos T Reguladores/metabolismo
12.
Scand J Immunol ; 92(5): e12923, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32593197

RESUMO

Antibody-mediated rejections (AMR) in the absence of circulating anti-HLA-DSA have highlighted the role of non-HLA antibodies, particularly those directed against endothelial cells. Of these, MICA (major histocompatibility complex class I chain-related molecule A) antibodies are the most notable and important because of their potential in promoting graft rejections. Limited studies have focused on the impact of MICA donor-specific antibodies (DSA) on graft outcome as compared to those that are not donor-specific (NDSA). We evaluated pre- and post-transplant sera at POD 7, 30, 90, 180 and the time of biopsy from 206 consecutive primary live donor renal transplant recipients for anti-MICA and anti-HLA antibodies using single antigen bead assay on a Luminex platform. Recipients who developed MICA antibodies and their donors were phenotyped for MICA alleles. For the purpose of antibody analysis, patients were categorized into three major groups: biopsy-proven AMR, acute cellular rejection (ACR) and those with no rejection episodes (NRE). During the mean follow-up period of 17.37 ± 6.88 months, 16 of the 206 recipients developed AMR, while ACR was observed in only 13 cases. A quarter (25%) of the AMR cases had anti-MICA antibodies as compared to 7.7% of those experiencing ACR and 6.2% of the NRE group. Allelic typing revealed that all MICA Ab +ve AMR cases were due to the presence of donor-specific antibodies. MICA-DSA even in the absence of HLA-DSA was significantly associated with AMR but not with ACR when compared with the NRE group (P = <.01).


Assuntos
Anticorpos/imunologia , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transplante de Rim/métodos , Doadores Vivos/estatística & dados numéricos , Adulto , Alelos , Anticorpos/sangue , Células Endoteliais/imunologia , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Teste de Histocompatibilidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto Jovem
13.
Transplant Proc ; 52(6): 1749-1756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32402452

RESUMO

BACKGROUND: BK virus (BKV)-associated nephropathy is a significant complication of kidney transplantation that progresses to graft dysfunction and graft loss. The aim of this study was to know the infection rate and progression of BKV according to our strategy. MATERIALS AND METHODS: This study included 302 patients who received kidney transplantation between August 2010 and October 2012. Patients were divided into 4 groups: no BK infection, BK viruria only, low BK viremia, and high BK viremia. RESULTS: In this study, 57 patients had BK viremia (18.9%), and 18 patients had BK nephropathy (5.9%) during a 2-year follow-up period. Age, sex, cytomegalovirus (CMV) viremia, existence of donor-specific antibodies, type of transplantation, and delayed graft function were not significantly different. Disappearance of BKV infection was better in the viruria and low viremia groups than in the high viremia group (P = .001), and duration of BK infection was longer in the high viremia group than the low viremia group (P = .002). CONCLUSION: All diagnosed cases of BKV nephropathy were in the high BK viremia group. For BK viruria and viremia, early detection of BK infection together with early intervention by reduced immunosuppressant is a useful strategy to maintain allograft function. Long-term follow up is required to identify the risk factors for BK infection and graft survival after kidney transplantation.


Assuntos
Vírus BK , Imunossupressores/efeitos adversos , Nefropatias/induzido quimicamente , Infecções por Polyomavirus/induzido quimicamente , Complicações Pós-Operatórias/induzido quimicamente , Infecções Tumorais por Vírus/induzido quimicamente , Viremia/induzido quimicamente , Adulto , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/virologia , Fatores de Risco , Infecções Tumorais por Vírus/virologia , Viremia/virologia
14.
Transplantation ; 104(6): 1294-1303, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32433232

RESUMO

BACKGROUND: Hepatitis C virus-positive (HCV+) kidney transplant (KT) recipients are at increased risks of rejection and graft failure. The optimal induction agent for this population remains controversial, particularly regarding concerns that antithymocyte globulin (ATG) might increase HCV-related complications. METHODS: Using Scientific Registry of Transplant Recipients and Medicare claims data, we studied 6780 HCV+ and 139 681 HCV- KT recipients in 1999-2016 who received ATG or interleukin-2 receptor antagonist (IL2RA) for induction. We first examined the association of recipient HCV status with receiving ATG (versus IL2RA) using multilevel logistic regression. Then, we studied the association of ATG (versus IL2RA) with KT outcomes (rejection, graft failure, and death) and hepatic complications (liver transplant registration and cirrhosis) among HCV+ recipients using logistic and Cox regression. RESULTS: HCV+ recipients were less likely to receive ATG than HCV- recipients (living donor, adjusted odds ratio [aOR] = 0.640.770.91; deceased donor, aOR = 0.710.810.92). In contrast, HCV+ recipients who received ATG were at lower risk of acute rejection compared to those who received IL2RA (1-y crude incidence = 11.6% versus 12.6%; aOR = 0.680.820.99). There was no significant difference in the risks of graft failure (adjusted hazard ratio [aHR] = 0.861.001.17), death (aHR = 0.850.951.07), liver transplant registration (aHR = 0.580.971.61), and cirrhosis (aHR = 0.730.921.16). CONCLUSIONS: Our findings suggest that ATG, as compared to IL2RA, may lower the risk of acute rejection without increasing hepatic complications in HCV+ KT recipients. Given the higher rates of acute rejection in this population, ATG appears to be safe and reasonable for HCV+ recipients.


Assuntos
Soro Antilinfocitário/administração & dosagem , Rejeição de Enxerto/epidemiologia , Hepatite C/tratamento farmacológico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Condicionamento Pré-Transplante/métodos , Adulto , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/imunologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/antagonistas & inibidores , Receptores de Interleucina-2/imunologia , Sistema de Registros/estatística & dados numéricos , Análise de Sobrevida , Transplantados/estatística & dados numéricos , Resultado do Tratamento , Estados Unidos/epidemiologia
15.
Transplant Proc ; 52(6): 1650-1654, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32444117

RESUMO

INTRODUCTION: The Living Kidney Donor Profile Index (LKDPI) was recently proposed in the United States to evaluate living donor quality. Japan has a largely different renal transplant circumstance, such as a high ABO incompatibility rate. The aim of this study was to validate the LKDPI among the Japanese population and adjust the score. METHODS: We performed a retrospective analysis of 133 living donors in renal transplant in our institution. We analyzed the clinical characteristics and outcomes, and created a modified LKDPI score considering the favorable ABO incompatible kidney transplant outcomes in Japan. RESULTS: Median (interquartile range [IQR]) donor age was 59 (51 to 65) and median (IQR) body mass index was 22.9 kg/m2 (20.9 to 25.2). ABO incompatibility rate was 28.5%. Median (IQR) donor estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration equation) was 108.7 mL/min/1.73 m2 (99.9 to 115.5). The 1-year graft survival rate was 98.5%, and the 3-year graft survival rate was 97%. The incidence of antibody mediated rejection was 5.2%. The median (IQR) LKDPI score was 30.2 (11.8 to 46.8). This was significantly higher than the previously reported score in the United States, which was 12.8 (-0.8 to 27.2). The modified LKDPI (mLKDPI) score was 23.2 (4.1 to 35.1). LKDPI and mLKDPI did not show a diagnostic value in graft survival; however, LKDPI and mLKDPI showed significant diagnostic value in eGFR at 1 year (area under the curve [AUC]=0.627, P = .017; and AUC=0.673, P = .01). CONCLUSION: Our outcomes had better survival even though with higher ABO incompatibility rate. According to original LKDPI, our donor pool is higher than the general US population. In this study, lower LKDPI tended to be associated with good allograft function, and mLKDPI has better diagnostic value than LKDPI. To compare internationally, an adjusted model for Japan might be necessary based on the outcomes of a large population.


Assuntos
Testes de Função Renal , Transplante de Rim , Doadores Vivos , Índice de Gravidade de Doença , Idoso , Área Sob a Curva , Feminino , Sobrevivência de Enxerto/imunologia , Humanos , Japão , Transplante de Rim/mortalidade , Doadores Vivos/provisão & distribução , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Estados Unidos
16.
Transplantation ; 104(7): e208-e213, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32235257

RESUMO

BACKGROUND: Histologic criteria for diagnosing acute rejection in vascularized composite tissue allograft (VCA) have been established by the Banff 2007 Working Classification of Skin-Containing Composite Tissue Allograft, but the role of early vascular lesions in graft rejection warrants additional analysis. METHODS: We performed a retrospective study of 34 skin biopsies performed over 430 d for rejection surveillance, in Canada's first face allotransplant recipient. Three observers reviewed all biopsies to assess the nature and intensity of the inflammatory skin infiltrate. A complete histological and immunohistochemical review of the vascular components was performed with a focus on lymphocytic vasculitis, intravascular fibrin, vessel caliber, extent of injury, C4d positivity, and inflammatory cell phenotyping. We then correlated these data points to clinical and immunosuppression parameters. RESULTS: Acute vascular damage in biopsies that would be classified as mild acute rejection correlates with troughs in immunosuppression and subsides when immunosuppressive tacrolimus doses are increased. Grade 0 Banff rejection and Grade I without lymphocytic vasculitis were almost indistinguishable, whereas Grade I with lymphocytic vasculitis was an easy and reproducible histologic finding. CONCLUSIONS: Our results highlight the possible relevance of vascular injury in the context of VCA, as its presence might underlie a more aggressive form of immune rejection. If these findings are validated in other VCA patients, vascular injury in mild rejection might warrant a different clinical approach.


Assuntos
Transplante de Face/efeitos adversos , Rejeição de Enxerto/diagnóstico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Vasculite/complicações , Idoso , Biópsia , Canadá , Aloenxertos Compostos/irrigação sanguínea , Aloenxertos Compostos/patologia , Relação Dose-Resposta a Droga , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Humanos , Imunossupressores/farmacocinética , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Pele/irrigação sanguínea , Pele/patologia , Tacrolimo/farmacocinética , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Vasculite/diagnóstico , Vasculite/tratamento farmacológico , Vasculite/imunologia
17.
Transplant Proc ; 52(5): 1370-1375, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32245621

RESUMO

BACKGROUND: In simultaneous pancreas-kidney transplantation (SPKT), persistence or recurrence of pancreatic autoantibodies (PAs) has been associated with pancreas graft (PG) autoimmune-driven injury. Our aim was to analyze the impact of PAs on PG survival. METHODS: Between January 1, 2000, and December 31, 2017, we studied 139 patients with post-SPKT anti-glutamic acid decarboxylase (GAD) autoantibody. Alloimmune (ALI) events were defined as PG rejection and/or de novo donor-specific antibodies (DSA). Hence, 3 groups were defined: patients without ALI events or anti-GAD (n = 42), those with ALI events (n = 14), or those only with autoimmune events (positive for anti-GAD and no ALI events; n = 83). RESULTS: Male sex was predominant (n = 72, 52%). Median age was 35 years (interquartile range: 31-39) and median follow-up was 6-7 years (interquartile range: 4.1-9.2). Regarding anti-GAD positivity post-SPKT (n = 90, 65%), no differences were observed concerning age, sex, anti-HLA antibodies, HLA mismatch number and de novo DSA. ALI events were present in 10% (n = 14). PG survival 15 years post-SPKT was better in patients without immune events (96%) followed by those with ALI (69%) and autoimmune events (63%) (P = .025). Anti-GAD was associated to higher annualized mean Hb1AC (P = .006) and lower mean C-peptide (P = .013). According to pre- and post-SPKT anti-GAD status, conversion from negative to positive was associated to worse (63%) 10-year PG survival (P = .044), compared to persistence of negative (100%) or positive anti-GAD (88%). Anti-islet cell and anti-insulin autoantibodies had no impact. CONCLUSION: Anti-GAD presence post-SPKT was associated to higher pancreas disfunction and lower PG survival. De novo anti-GAD seems to offer a particular risk of PG failure.


Assuntos
Autoanticorpos/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Rim , Transplante de Pâncreas , Adulto , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Feminino , Glutamato Descarboxilase/imunologia , Rejeição de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
18.
Sci Rep ; 10(1): 4464, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32161272

RESUMO

Adenosine is widely known as a potent modulator of innate and acquired immunity. It is released during transplants, and acts on four subtype receptors. In previous studies, we demonstrated that pharmacological preconditioning (PPC), pre-administration of the selective A1 receptor (A1R) agonist led to A1R desensitization, is followed by upregulation of the adenosine A2A receptor. This immunosuppressive effect resulted in lymphopenia, and it reduced T-cell reactivity. The aim of the current study was to challenge the immunosuppressive effects of A1R-PPC in models of allogeneic grafts. PPC mice were treated by intraperitoneal injection using specific adenosine A1R agonist 24 h and 12 h before starting any procedure. We challenged our method in novel allogeneic muscle and skin grafts models. Mice and grafts were assessed by complete blood counts, MLR from PPC splenocytes, and pathological evaluation. We found a significant reduction in WBC and lymphocyte counts in PPC-treated mice. Two-way MLR with splenocytes from PPC grafted mice showed decreased proliferation and anergy. Histology of PPC allogeneic grafts revealed profoundly less infiltration and even less muscle necrosis compared to vehicle treated allografts. Similar results observed in PPC skin transplantation. To conclude, PPC moderated graft rejection in separate allogeneic challenges, and reduced lymphocytes infiltration and ischemic damage.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Imunossupressão , Imunossupressores/farmacologia , Condicionamento Pré-Transplante , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/imunologia , Células Sanguíneas/metabolismo , Proliferação de Células , Camundongos , Modelos Animais , Receptor A1 de Adenosina/metabolismo , Transplante de Pele , Condicionamento Pré-Transplante/métodos , Transplante Homólogo
19.
Transplant Proc ; 52(4): 1140-1142, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32220481

RESUMO

BACKGROUND: Pretransplant anti-HLA antibodies are a risk factor for graft rejection and loss, and its percentage estimate is known as panel-reactive antibody (PRA). Our objective was to evaluate the influence of PRA on the survival of renal grafts from living donors over a period of 10 years. METHODS: Retrospective analysis was completed in all living donor transplants with PRA class I and class II from October 2008 to December 2018 with follow-up until June 2019. The methods used for the PRA were flow cytometry and Luminex. Graft survival (not censored) was evaluated by Kaplan-Meier (log-rank) and Cox regression. P < .05 was considered significant. RESULTS: The study included 393 patients. PRA class I mean was 9.8 ± 20% (0%-98%) and class II mean was 8.6 ± 17.8% (0%-97.8%). Of the patients, 81.9% had a PRA <20% for any class. Uncensored graft survival at 1, 5, and 10 years was 90.3%, 76.2%, and 69.3%, respectively. Mean estimated uncensored graft survival in PRA <20% patients (103.9 ± 2.7, 95% confidence interval [CI] 96.6-11.2) was higher than that of PRA >20% patients (61.5 ± 5.7, 95% CI 50.3-72.8) (P = .005 log-rank). Cox regression (univariate) was statistically significant for PRA class I (Exp [B] 1.01, 95% CI 1.003-1.02, P = .009) and for PRA >20% any class (Exp [B] 2.074, 95% CI 1.222-3.520, P = .007). CONCLUSION: PRA class I and PRA >20% any class are associated with lower graft survival. PRA must be considered to determine immunologic risk and to choose an immunosuppressive regimen in kidney transplantation.


Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Isoanticorpos/imunologia , Transplante de Rim , Adolescente , Adulto , Idoso , Feminino , Rejeição de Enxerto/mortalidade , Humanos , Isoanticorpos/sangue , Transplante de Rim/mortalidade , Doadores Vivos , Masculino , México , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplantes/imunologia , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 117(11): 6042-6046, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32111690

RESUMO

Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/efeitos adversos , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Aloenxertos/imunologia , Aloenxertos/metabolismo , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/sangue , Rejeição de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Tolerância Imunológica , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Isoantígenos/imunologia , Isoantígenos/metabolismo , Camundongos , Miocárdio/imunologia , Miocárdio/metabolismo , Mutação Puntual , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Transplante Homólogo/efeitos adversos
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