Genomics of Chronic Renal Allograft Rejection

慢性同种异体移植肾排斥的基因组学

基本信息

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
项目类别：
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

项目摘要

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。但是，该术语不能描述特定的潜在病理过程，而是指由多个潜在因素造成的慢性损伤。最近，有人提出，慢性同种异体肾小球病，慢性同种异体移植动脉炎和周围毛细管毛细管基底膜的层压的病理发现是由于慢性免疫学过程而引起的，因此应称为真实的慢性拒绝。有广泛的动物和最初的人类研究表明，间接识别同种抗原和/或同种抗体反应介导了这一过程。但是，没有研究前瞻性地检查慢性同种异体移植抑制的发展是否与免疫相关反应性。该项目的主要假设是，慢性排斥反应是由同种肽特异性CD4+ T细胞克隆（间接途径）驱动的持续的懒惰特异性免疫反应性（间接途径），这引起了针对嫁接的不匹配的MHC MHC抗原的细胞介导的抗体反应；该提案的具体目的是：1。确定细胞介导的和抗体介导的免疫反应在慢性排斥反应中的作用：我们将确定慢性排斥的病理发现是否与间接同种异体反应性和/或从头DSA的发展有关； 2。确定与慢性排斥反应发展相关的基因表达谱：我们将研究在移植时和移植后前瞻性转移时涉及的关键基因的内部内部表达模式，以定义内部事件和免疫反应之间的关联水平。我们将通过微阵列分析来确定特定的基因表达谱是否可以预测慢性排斥的发展； 3。确定特定免疫基因的多态性变异是否赋予慢性排斥反应的敏感性：我们计划前瞻性地定义了特定免疫学基因的移植受者基因型基因型，以识别与慢性排斥相关的基因型以及针对嫁接的免疫反应的发展。这些研究的结果将对导致慢性排斥的潜在机制有更大的了解，并有助于区分罐头的原因。