RESUMO
Thirteen percent of individuals of African ancestry express two variant copies of the gene encoding apolipoprotein 1 (APOL1) that has been associated with an increased risk of end-stage renal disease (ESRD) in the general population. Limited studies suggest that the survival of transplanted kidneys from donors expressing two APOL1 risk alleles is inferior to that of kidneys from donors with zero or one risk allele. In living kidney donation, two case reports describe donors expressing two APOL1 risk alleles who developed ESRD. Given the potential impact of APOL1 variants on the utility and safety of kidney transplantation and living kidney donation, the American Society of Transplantation convened a meeting with the goals of summarizing the current state of knowledge with respect to transplantation and APOL1, identifying knowledge gaps and studies to address these gaps, and considering approaches to integrating APOL1 into clinical practice. The authors recognize that current data are not sufficient to support traditional evidence-based guidelines but also recognize that it may require several years to generate the necessary data. Thus, approaches as to how APOL1 might currently be integrated into the clinical decision-making process were considered. This report summarizes the group's deliberations.
Assuntos
Apolipoproteína L1/genética , Tomada de Decisão Clínica , Variação Genética , Falência Renal Crônica/diagnóstico , Transplante de Rim , Padrões de Prática Médica/normas , Congressos como Assunto , Humanos , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/genéticaRESUMO
We previously reported that two B cell receptor genes, IGKV1D-13 and IGKV4-1, were associated with tolerance following kidney transplantation. To assess the potential utility of this "signature," we conducted a prospective, multicenter study to determine the frequency of patients predicted tolerant within a cohort of patients deemed to be candidates for immunosuppressive minimization. At any single time point, 25-30% of patients were predicted to be tolerant, while 13.7% consistently displayed the tolerance "signature" over the 2-year study. We also examined the relationship of the presence of the tolerance "signature" on drug use and graft function. Contrary to expectations, the frequency of predicted tolerance was increased in patients receiving tacrolimus and reduced in those receiving corticosteroids, mycophenolate mofetil, or Thymoglobulin as induction. Surprisingly, patients consistently predicted to be tolerant displayed a statistically and clinically significant improvement in estimated glomerular filtration rate that increased over time following transplantation. These findings indicate that the frequency of patients consistently predicted to be tolerant is sufficiently high to be clinically relevant and confirm recent findings by others that immunosuppressive agents impact putative biomarkers of tolerance. The association of a B cell-based "signature" with graft function suggests that B cells may contribute to the function/survival of transplanted kidneys.
Assuntos
Tolerância Imunológica/genética , Imunossupressores/administração & dosagem , Transplante de Rim , Receptores de Antígenos de Linfócitos B/genética , Sequência de Bases , Estudos de Coortes , Primers do DNA , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Identification of biomarkers that assess posttransplant risk is needed to improve long-term outcomes following heart transplantation. The Clinical Trials in Organ Transplantation (CTOT)-05 protocol was an observational, multicenter, cohort study of 200 heart transplant recipients followed for the first posttransplant year. The primary endpoint was a composite of death, graft loss/retransplantation, biopsy-proven acute rejection (BPAR), and cardiac allograft vasculopathy (CAV) as defined by intravascular ultrasound (IVUS). We serially measured anti-HLA- and auto-antibodies, angiogenic proteins, peripheral blood allo-reactivity, and peripheral blood gene expression patterns. We correlated assay results and clinical characteristics with the composite endpoint and its components. The composite endpoint was associated with older donor allografts (p < 0.03) and with recipient anti-HLA antibody (p < 0.04). Recipient CMV-negativity (regardless of donor status) was associated with BPAR (p < 0.001), and increases in plasma vascular endothelial growth factor-C (OR 20; 95%CI:1.9-218) combined with decreases in endothelin-1 (OR 0.14; 95%CI:0.02-0.97) associated with CAV. The remaining biomarkers showed no relationships with the study endpoints. While suboptimal endpoint definitions and lower than anticipated event rates were identified as potential study limitations, the results of this multicenter study do not yet support routine use of the selected assays as noninvasive approaches to detect BPAR and/or CAV following heart transplantation.
Assuntos
Biomarcadores/metabolismo , Doença da Artéria Coronariana/diagnóstico , Rejeição de Enxerto/diagnóstico , Cardiopatias/cirurgia , Transplante de Coração/efeitos adversos , Adulto , Western Blotting , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Endotelina-1/metabolismo , Feminino , Perfilação da Expressão Gênica , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio VascularRESUMO
Facial transplantation is a life-changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow-up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti-HLA antibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon-γ/interleukin-17-producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein-1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novo donor-specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon-γ/interleukin-17-mediated acute cellular rejection process. Despite that, medium-term outcomes are promising with no evidence of de novo donor-specific antibody development.
Assuntos
Transplante de Face/efeitos adversos , Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto/imunologia , Interferon gama/imunologia , Interleucina-17/imunologia , Células Th1/imunologia , Adulto , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Humanos , Testes de Função Renal , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , TransplantadosRESUMO
BACKGROUND: Up to 20% of renal transplant recipients (RTR) will develop human BK polyomavirus (BKPyV) viremia. BKPyV viremia is a pre-requisite of polyomavirus-associated nephropathy (PyVAN). Risk of BKPyV infections increases with immunosuppression. Currently, the only effective therapy against PyVAN is reductions in immunosuppression, but this may increase the risk of rejection. In vitro data have shown that pravastatin dramatically decreased caveolin-1 expression in human renal proximal tubular epithelial cells (HRPTEC) and suppressed BKPyV infection in these cells. Based on these data, we postulated that statin therapy may prevent the progression of BKPyV viremia to PyVAN. PATIENTS AND METHODS: A multicenter, retrospective study was conducted in adult RTR transplanted between July 2005 and March 2012. All patients with documented BKPyV viremia (viral load >500 copies/mL on 2 consecutive tests) were included. Group I consisted of patients taking a statin before the BKPyV viremia diagnosis (n = 32), and Group II had no statin exposure before or after the BKPyV viremia diagnosis (n = 36). The primary endpoint was the incidence of PyVAN. RESULTS: Demographic data, transplant characteristics, and the degree of immunosuppression (i.e., induction/maintenance therapies, rejection treatment) were similar between the groups, with the exception of more diabetics in Group I. The incidence of PyVAN was comparable between the 2 groups (Group I = 28.1% vs. Group II = 41.7%; P = 0.312). CONCLUSIONS: Despite the proven in vitro effectiveness of pravastatin preventing BKPyV infection in HRPTEC, statins at doses maximized for cholesterol lowering, in RTR with BKPyV viremia, did not prevent progression to PyVAN.
Assuntos
Vírus BK , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Nefropatias/prevenção & controle , Transplante de Rim , Infecções por Polyomavirus/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Infecções Tumorais por Vírus/prevenção & controle , Adulto , Idoso , Vírus BK/isolamento & purificação , Progressão da Doença , Feminino , Humanos , Incidência , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/etiologia , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Pravastatina/uso terapêutico , Resultado do Tratamento , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/etiologia , Viremia/diagnóstico , Viremia/epidemiologia , Viremia/etiologia , Viremia/prevenção & controleRESUMO
The purine nucleotide adenosine triphosphate (ATP) is a universal source of energy for any intracellular reaction. Under specific physiological or pathological conditions, ATP can be released into extracellular spaces, where it binds and activates the purinergic receptors system (i.e. P2X, P2Y and P1 receptors). Extracellular ATP (eATP) binds to P2X or P2Y receptors in immune cells, where it mediates proliferation, chemotaxis, cytokine release, antigen presentation and cytotoxicity. eATP is then hydrolyzed by ectonucleotidases into adenosine diphosphate (ADP), which activates P2Y receptors. Ectonucleotidases also hydrolyze ADP to adenosine monophosphate and adenosine, which binds P1 receptors. In contrast to P2X and P2Y receptors, P1 receptors exert mainly an inhibitory effect on the immune response. In transplantation, a prominent role has been demonstrated for the eATP/P2X7R axis; the targeting of this pathway in fact is associated with long-term graft function and reduced graft versus host disease severity in murine models. Novel P2X receptor inhibitors are available for clinical use and are under assessment as immunomodulatory agents. In this review, we will focus on the relevance of the purinergic system and on the potential benefits of targeting this system in allograft rejection and tolerance.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Órgãos , Receptores Purinérgicos/fisiologia , Tolerância ao Transplante/fisiologia , Animais , Rejeição de Enxerto/etiologia , Humanos , Transplante HomólogoRESUMO
We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.
Assuntos
Transplante de Face , Rejeição de Enxerto/imunologia , Aloenxertos , Feminino , Humanos , Imunidade Celular , Pessoa de Meia-IdadeRESUMO
BACKGROUND: A correlation exists between polyomavirus BK (BKV) viremia in renal transplant recipients (RTR) and the degree of immunosuppression. However, the impact of pre-transplant desensitization on the incidence of BKV viremia is unknown. METHODS: This retrospective study evaluated living-donor RTR between January 2004 and December 2008 receiving routine BKV viral load monitoring. Patients were divided into those who underwent pre-transplant desensitization (n = 20) and those who did not (n = 71). The primary endpoint was the incidence of BKV viremia at 1 year post transplant. RESULTS: All demographic data were similar, except for more female patients (65% vs. 36.6%; P = 0.0392) in the desensitized group. More desensitized patients had a previous transplant (75% vs. 12.7%; P < 0.0001) and were more likely to be induced with basiliximab (75% vs. 35.2%; P = 0.0021). Following transplantation, antibody-mediated rejection (AMR) rates were highest in the desensitized group (55% vs. 1.4%; P < 0.0001). The incidence of BKV viremia at 1 year post transplant was significantly higher in desensitized patients (45% vs. 19.7%; P = 0.0385). Desensitization was also associated with a higher prevalence of BKV viremia at any time post transplant (50% vs. 22.5%; P = 0.0245), polyomavirus-associated nephropathy (20% vs. 2.8%; P = 0.0198) and BKV-related allograft loss (10% vs. 0%; P = 0.0464). Also of note, in a subgroup analysis of only our desensitized patients, it did not appear that development of AMR significantly impacted the incidence of BKV viremia in these individuals. CONCLUSIONS: This analysis reveals that pre-transplant desensitization significantly increases the risk for BKV viremia and nephropathy.
Assuntos
Vírus BK , Imunoglobulinas Intravenosas/administração & dosagem , Transplante de Rim/efeitos adversos , Plasmaferese/estatística & dados numéricos , Viremia/epidemiologia , Adulto , Idoso , Vírus BK/genética , Vírus BK/isolamento & purificação , Feminino , Humanos , Terapia de Imunossupressão , Incidência , Nefropatias/epidemiologia , Nefropatias/virologia , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/virologia , Resultado do Tratamento , Infecções Tumorais por Vírus/epidemiologia , Infecções Tumorais por Vírus/virologia , Viremia/virologiaRESUMO
Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Dyslipidemia is a common finding after renal transplantation and a significant risk factor in the development of coronary heart disease. Although a causal relationship with cardiovascular mortality has not been proven in the transplant population, it is reasonable to extrapolate data from the general population and aggressively treat posttransplant dyslipidemia. Statins are considered the agents of choice, though their use may be complicated by drug misadventures. Pravastatin, fluvastatin and pitavastatin are considered to be the safest statins to use in this population; however, given their low-potency, a high-potency statin, such as atorvastatin, may be necessary in patients with significant dyslipidemia. In this article, we discuss the etiology of and treatment strategies for dyslipidemia in renal transplant recipients based on a literature review of potential therapeutic adverse effects and benefits in this population. We will also evaluate the reasons for and consequences of the latest Food and Drug Administration (FDA) warnings regarding the use of simvastatin.
Assuntos
Dislipidemias/complicações , Falência Renal Crônica/complicações , Transplante de Rim , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipolipemiantes/efeitos adversos , Hipolipemiantes/uso terapêutico , Falência Renal Crônica/cirurgia , Guias de Prática Clínica como AssuntoRESUMO
Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.
Assuntos
Receptor de Morte Celular Programada 1/fisiologia , Linfócitos T Reguladores/imunologia , Sobrevivência de Enxerto , Humanos , Tolerância Imunológica , Ativação Linfocitária , Transplante de Órgãos , Receptor de Morte Celular Programada 1/metabolismo , Transdução de SinaisRESUMO
Blockade of the B7:CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, results from the belatacept phase III clinical trial demonstrated a higher rejection rate when compared to cyclosporine, raising concern about potential deleterious effects of this agent. In this study, we investigated the consequences of B7:CD28 blockade by hCTLA4Ig on regulator T cell (Treg) generation in different major histocompatibility complex (MHC) mismatch transplant models. Administration of hCTLA4Ig significantly decreased the amount of Tregs in B6 WT animals and this effect was predominant in thymus-induced Tregs (Helios(+) ). Although hCTLA4Ig prevented rejection in a fully allogeneic mismatch model, it accelerated rejection in a MHC class-II mismatch model (MST = 26, p < 0.0001), in which long-term allograft survival is dependent on Tregs. This accelerated rejection was associated with a marked reduction in thymus-induced Tregs and led to a higher effector/regulatory T-cell ratio in secondary lymphoid organs and in the allograft. This study confirms the importance of the B7:CD28 pathway in Treg homeostasis in an in vivo transplant model and suggests that hCTLA4Ig therapy may be deleterious in circumstances where engraftment is dependent on Tregs.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Linfócitos T Reguladores/imunologia , Timo/imunologia , Abatacepte , Animais , Antígeno B7-1/imunologia , Antígenos CD28/imunologia , Citometria de Fluxo , Genes MHC da Classe II/imunologia , Rejeição de Enxerto/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Th17/imunologia , Timo/citologia , Timo/metabolismo , Transplante HomólogoRESUMO
Apolipoprotein L-1 (APOL1) gene variants are associated with end-stage renal disease in African Americans (AAs). Here we investigate the impact of recipient APOL1 gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 AA kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5-year posttransplant for recipients with high-risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation.
Assuntos
Apolipoproteínas/genética , População Negra/genética , Sobrevivência de Enxerto/genética , Transplante de Rim , Lipoproteínas HDL/genética , Adulto , Apolipoproteína L1 , Genótipo , Humanos , Pessoa de Meia-IdadeRESUMO
The PD1:PDL1 pathway is an essential negative costimulatory pathway that plays a key role in regulating the alloimune response. PDL1 is expressed not only on antigen-presenting cells (APCs) but also cardiac endothelium. In this study, we investigated the importance of PDL1 expression on donor cardiac allograft in acquired transplantation tolerance in a fully MHC-mismatched model. We generated PDL1 chimeric mice on B6 background that expressed PDL1 on either hematopoietic cells or nonhematopoietic cells of the heart. Sham animals were used as controls. These hearts were then transplanted into BALB/c recipients and treated with CTLA4-Ig to induce tolerance. Cardiac endothelium showed significant expression of PDL1, which was upregulated upon transplantation. While the absence of PDL1 on hematopoietic cells of the heart resulted in delayed rejection and prevented long-term tolerance in most but not all recipients, we observed an accelerated and early graft rejection of all donor allografts that lacked PDL1 on the endothelium. Moreover, PDL1-deficient endothelium hearts had significant higher frequency of IFN-γ-producing alloreactive cells as well as higher frequency of CD8(+) effector T cells. These findings demonstrate that PDL1 expression mainly on donor endothelium is functionally important in a fully allogeneic mismatched model for the induction of cardiac allograft tolerance.
Assuntos
Antígeno B7-1/fisiologia , Medula Óssea/metabolismo , Endotélio Vascular/metabolismo , Transplante de Coração , Glicoproteínas de Membrana/fisiologia , Peptídeos/fisiologia , Tolerância ao Transplante , Animais , Antígeno B7-H1 , Citometria de Fluxo , Imunofluorescência , Rejeição de Enxerto , Células-Tronco Hematopoéticas/metabolismo , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante HomólogoRESUMO
A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex-mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4(+) lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.
Assuntos
Transplante de Medula Óssea , Linfócitos T CD4-Positivos/imunologia , Deleção Clonal , Rejeição de Enxerto/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoconjugados , Quimera por Radiação/imunologia , Abatacepte , Animais , Antígenos CD , Antígenos de Diferenciação/imunologia , Ligante de CD40 , Antígeno CTLA-4 , Linhagem da Célula , Hematopoese , Glicoproteínas de Membrana/imunologia , Camundongos , Transplante de Pele/imunologiaRESUMO
Blockade of the B7: CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, this pathway has also been demonstrated to be important for the generation and maintenance of regulatory T cells. In this study, we investigated the role of the B7: CD28 pathway in the 'bm12 into B6' MHC class II-mismatched vascularized cardiac transplant model of chronic rejection. Allograft rejection was remarkably accelerated in B6 background B7DKO and CD28KO recipients compared with B6 wild-type (WT) recipients. Allograft rejection was associated with a significantly enhanced Th1/Th2 alloreactivity and marked reduction in the ratio of regulatory T cells to CD4(+) effector/memory cells. We noted that administration of anti-B7-1 and anti-B7-2 mAb prior to transplantation also accelerated allograft rejection. Furthermore, depleting CD25(+) cells in B6 WT recipients of bm12 hearts prior to transplant also precipitated rejection at a similar rate. Neither B7/CD28 deficiency nor CD25 depletion affected graft survival in single MHC class I-mismatched (bm1 into B6) recipients. This study highlights the paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched model, in which the B7: CD28 pathway is demonstrated to be important in preventing rejection through the generation and maintenance of Tregs.
Assuntos
Antígeno B7-1/imunologia , Antígenos CD28/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/imunologia , Genes MHC da Classe II , Sobrevivência de Enxerto/imunologia , Camundongos , Camundongos Knockout , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Ischemia/reperfusion injury associated with organ retrieval and storage influences the development of chronic graft dysfunction, the major clinical problem in solid organ transplantation. The potential role of mononuclear cells (T cells and monocyte/macrophages) in this type of injury is unknown. Inbred male Lewis rats were uninephrectomized and the left kidney perfused in situ with 10 ml of iced University of Wisconsin solution. Immunohistological studies showed mononuclear cell infiltration of the ischemic organs associated with the upregulation of MHC class II antigen expression. Reverse transcriptase-PCR indicated that T cell associated cytokines and monocyte/macrophage activation markers/products are upregulated early after the ischemic insult. B7 expression occurred within 24 h and peaked at 3 d. Plasma creatinine levels rose transiently with complete recovery of renal function by 5 d. Animals began to develop progressive proteinuria after 8-12 wk, indicative of the long-term functional consequences of early ischemia/reperfusion injury. Blockade of T cell CD28-B7 costimulation with CTLA4Ig resulted in significant inhibition of T cell and macrophage infiltration and activation in situ. Treated animals did not exhibit transient renal dysfunction, nor developed proteinuria over time. This is the first demonstration that blocking T cell costimulatory activation in the absence of alloantigen can prevent the early and late consequences of ischemia/reperfusion injury.
Assuntos
Antígeno B7-1/fisiologia , Imunoconjugados , Rim/irrigação sanguínea , Traumatismo por Reperfusão/etiologia , Abatacepte , Animais , Antígenos CD , Antígenos de Diferenciação/farmacologia , Antígeno CTLA-4 , Antígenos de Histocompatibilidade Classe II/análise , Isquemia/complicações , Masculino , Ratos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/prevenção & controleRESUMO
Early blockade of T cell-costimulatory activation pathways prevents development of experimental chronic allograft rejection. Ongoing T cell recognition of alloantigen and activation may also play an important role in progression of chronic rejection, but definitive evidence is lacking. We used the fusion protein CTLA4Ig to block CD28-B7 T cell costimulation late after the onset of initial graft injury. Using the F334 into LEW rat model of chronic renal allograft rejection, transplant recipients were treated with a 10-d course of cyclosporine, and a subgroup received a single injection of CTLA4Ig at 8 wk after transplant. Functionally, CTLA4Ig administration prevented development of progressive proteinuria (14.3+/-4.1 mg/24 h versus 41.0+/-12.0 mg/24 h at 24 wk after transplant, P < 0.05). Histologically, graft mononuclear cell infiltration, glomerular hypertrophy, focal and segmental glomerulosclerosis, and intimal vascular hyperplasia were all attenuated in CTLA4Ig-treated animals. Lastly, reverse transcriptase-PCR and immunohistologic studies showed a significant reduction in the intragraft expression of key products of T cell and macrophage activation, and upregulation of what have recently been termed as "protective" genes, including the bcl family members, Bcl-2 and Bcl-xL, and hemoxygenase. Our data are the first to demonstrate that blocking T cell-costimulatory activation late after transplantation, after initial graft injury, prevents progression of chronic allograft rejection supporting the hypothesis that ongoing T cell recognition of alloantigen and activation are key mediators of ongoing chronic allograft rejection.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunoconjugados , Ativação Linfocitária , Linfócitos T/imunologia , Abatacepte , Animais , Antígenos CD , Antígenos de Diferenciação/fisiologia , Antígeno B7-1/fisiologia , Antígenos CD28/fisiologia , Antígeno CTLA-4 , Ciclosporina/uso terapêutico , Masculino , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Transplante HomólogoRESUMO
We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.