GENOMICS OF CHRONIC RENAL ALLOGRAFT REJECTION

慢性同种异体肾移植排斥的基因组学

• 批准号: 7953702
• 负责人: Barbara T. Murphy
• 金额: $ 0.29万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953702
• 关键词: Allografting; Antibodies; Antigens; Arteries; Basement membrane; Blood capillaries; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Allograft Arteriopathy; Chronic rejection of renal transplant; Classification; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Development; Epitopes; Fibrosis; Funding; Gene Activation; Genes; Genetic Polymorphism; Genomics; Graft Survival; Grant; Immune; Immune response; Immunologics; Individual; Indolent; Inflammatory; Inherited; Injury; Institution; Kidney; MHC antigen; Mediating; Mononuclear; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Peptides; Predisposition; Process; Research; Research Personnel; Resources; Source; Staging; Surrogate Markers; Therapeutic Intervention; Transplantation; Uncertainty; United States National Institutes of Health; capillary; complement C4d; glomerular basement membrane; kidney allograft; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal hypotheses are: 1. Chronic rejection is mediated by ongoing indolent specific immune reactivity against the mismatched MHC antigens of the graft; 2. The immune response underlying chronic rejection is driven by CD4+ T cell clones primed to donor allo-epitopes presented as peptides by recipient APCs (indirect allorecognition pathway), which give rise to cell and antibody mediated responses directed against the graft; 3. The development of chronic rejection can be predicted by quantitative analysis of pre-inflammatory gene activation in the graft during the course of transplantation; and 4. The susceptibility to chronic rejection is modified by inherited genetic polymorphisms that alter the level of response in genes that are known to modify the immune response. The term chronic allograft nephropathy (CAN), as defined by Banff classification, does not describe a specific pathological process but rather it comprises various types of chronic injury that may result from a variety of underlying pathogenic mechanisms. The pathogenesis of CAN is poorly understood, but involves both antigen dependent and independent mechanisms. The uncertainty about the pathogenic mechanisms involved in CAN is major obstacle to the development of specific therapeutic interventions. More recently it has been suggested that the pathologic findings of duplication of the glomerular basement membrane (chronic allograft glomerulopathy), intimal proliferation of arteries with a mononuclear infiltrate (chronic allograft arteriopathy), and lamination of the peritubular capillary basement membrane, arise due to a chronic immunologic process and therefore should be referred to as true chronic rejection. This has been further strengthened by the finding that C4d, which acts as a surrogate marker for antibody mediate rejection, may be found in up to 61% of cases of chronic rejection. Most studies to date examining causes of late graft loss have used graft survival or CAN as the endpoints. By using CAN as an endpoint individual pathological processes may be missed, or results may be ambiguous, due to the contribution of the multiple factors leading to fibrosis and the end stage kidney. By considering the distinct pathological picture of chronic rejection separately we may eliminate potential interference, allowing us to determine whether it truly is an immune mediated response.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 主要假设是： 1. 慢性排斥反应是由针对移植物错配MHC抗原的持续惰性特异性免疫反应介导的; 2. 作为慢性排斥反应基础的免疫应答是由CD 4 + T细胞克隆驱动的，所述CD 4 + T细胞克隆针对由受体APC（间接同种异体识别途径）呈递为肽的供体同种异体表位致敏，这引起针对移植物的细胞和抗体介导的应答; 3. 慢性排斥反应的发展可以通过移植过程中移植物中炎症前基因激活的定量分析来预测; 4. 对慢性排斥反应的易感性通过遗传的遗传多态性来改变，遗传多态性改变了已知改变免疫反应的基因中的反应水平。 术语慢性同种异体移植物肾病（CAN），如Banff分类所定义的，不描述特定的病理过程，而是它包括可能由各种潜在致病机制引起的各种类型的慢性损伤。CAN的发病机制知之甚少，但涉及抗原依赖性和非依赖性机制。CAN致病机制的不确定性是发展特异性治疗干预措施的主要障碍。最近有人提出，肾小球基底膜复制（慢性同种异体移植物肾小球病）、动脉内膜增生伴单核细胞浸润（慢性同种异体移植物动脉病）和管周毛细血管基底膜分层的病理学发现是由于慢性免疫过程引起的，因此应被称为真正的慢性排斥反应。C4d作为抗体介导的排斥反应的替代标志物，可以在高达61%的慢性排斥反应病例中发现，这一发现进一步加强了这一点。迄今为止，大多数检查晚期移植物丢失原因的研究都使用移植物存活率或CAN作为终点。通过使用CAN作为终点，由于导致纤维化和终末期肾脏的多种因素的作用，可能会遗漏单个病理过程，或者结果可能不明确。通过单独考虑慢性排斥反应的不同病理情况，我们可以排除潜在的干扰，使我们能够确定它是否真的是免疫介导的反应。