Genomics of Chronic Renal Allograft Rejection

慢性同种异体移植肾排斥的基因组学

• 批准号: 8100582
• 负责人: Barbara T. Murphy
• 金额: $ 31.8万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100582
• 关键词: Alloantigen; Allografting; Animals; Antibodies; Antibody Formation; Arteries; Arts; Basement membrane; Bioinformatics; Biological Assay; Biopsy; Blood capillaries; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Allograft Arteriopathy; Chronic rejection of renal transplant; Collaborations; Data; Development; Epitopes; Event; Frequencies; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Graft Survival; Human; Immune; Immune response; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Factors; Immunologics; Immunosuppressive Agents; Individual; Indolent; Inflammatory; Inherited; Injury; Isoantibodies; Kidney Transplantation; MHC antigen; Mediating; Microarray Analysis; Molecular Profiling; Mononuclear; Morphology; Nature; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Pattern; Peptide/MHC Complex; Peptides; Peripheral Blood Lymphocyte; Predisposition; Process; Prospective Studies; Protocols documentation; Research Personnel; Resources; Risk; Role; Stratification; System; T-Lymphocyte; Techniques; Time; Transplant Recipients; Transplantation; Transplantation Immunology; Variant; allograft rejection; base; capillary; complement C4d; enzyme linked immunospot assay; glomerular basement membrane; graft function; insight; isoimmunity; kidney allograft; novel; patient population; predictive modeling; prevent; programs; prospective; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Chronic allograft nephropathy (CAN) remains the most common cause of graft loss. However, the term CAN does not delineate the specific underlying pathologic process but rather refers to the chronic injury resulting from multiple potential factors. More recently it has been suggested that the pathologic findings of chronic allograft glomerulopathy, 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. There are extensive animal and initial human studies suggesting that indirect recognition of alloantigen and/or alloantibody responses mediate this process. There are however no studies which prospectively examine whether the development of the chronic allograft rejection correlates with immune reactivity. The principal hypothesis of this project is that chronic rejection is mediated by an ongoing indolent specific immune reactivity driven by allopeptide specific CD4+ T cell clones (indirect pathway), which gives rise to cell-mediated and antibody responses directed against the mismatched MHC antigens of the graft; The specific aims of this proposal are to: 1. Determine the role of cell mediated and antibody-mediated immune responses in chronic rejection: We will determine if the pathologic finding of chronic rejection is associated with indirect alloreactivity and/or the development of de novo DSA; 2. Determine the gene expression profile associated with the development of chronic rejection: We will study intragraft expression patterns of key genes involved in the alloimmune, innate and antibody mediated responses at the time of transplantation and prospectively post-transplant to define the level of association between intragraft events and immune responses. We will determine if specific gene expression profiles predict the development of chronic rejection using microarray analysis; 3. Determine whether polymorphic variants of specific immunological genes confer susceptibility to chronic rejection: We plan to prospectively define transplant recipients genotypes for specific immunological genes in order to identify those genotypes associated with chronic rejection and the development of an immune response directed toward the graft. The results of these studies will lend greater insight to the underlying mechanisms leading to chronic rejection and help differentiate one cause of CAN.

描述（由申请人提供）：慢性同种异体移植肾病（CAN）仍然是移植物损失的最常见原因。然而，CAN一词并不能描述特定的潜在病理过程，而是指由多种潜在因素引起的慢性损伤。最近有研究表明，慢性同种异体移植肾小球病变、慢性同种异体移植动脉病变和小管周围毛细血管基底膜层压的病理表现是由慢性免疫过程引起的，因此应被称为真正的慢性排斥反应。大量的动物和初步的人体研究表明，间接识别同种异体抗原和/或同种异体抗体反应介导了这一过程。然而，目前尚无研究前瞻性地探讨慢性同种异体移植排斥反应的发生是否与免疫反应相关