Genomics of Chronic Renal Allograft Rejection

描述（由申请人提供）：慢性移植物肾病（CAN）仍然是移植物丢失的最常见原因。然而，术语CAN并不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。最近有人提出，慢性移植物肾小球病、慢性移植物动脉病和肾小管周围毛细血管基底膜分层的病理结果是由于慢性免疫过程引起的，因此应称为真正的慢性排斥反应。有大量的动物和初步的人类研究表明，间接识别同种抗原和/或同种抗体反应介导这一过程。然而，没有研究前瞻性地检查慢性同种异体移植排斥反应的发生是否与免疫相关。 反应性本项目的主要假设是慢性排斥反应是由同种异体肽特异性CD 4 + T细胞克隆（间接途径）驱动的持续惰性特异性免疫反应介导的，其引起针对移植物的错配MHC抗原的细胞介导和抗体应答;本提案的具体目的是：1.确定细胞介导的和抗体介导的免疫应答在慢性排斥反应中的作用：我们将确定慢性排斥反应的病理发现是否与间接同种异体反应性和/或新发DSA的发展相关; 2.确定与慢性排斥反应发展相关的基因表达谱：我们将研究移植时和移植后参与同种免疫、先天性和抗体介导反应的关键基因的移植物内表达模式，以确定移植物内事件和免疫反应之间的相关性水平。我们将使用微阵列分析来确定特定基因表达谱是否预测慢性排斥反应的发展; 3.确定特定免疫基因的多态性变体是否赋予慢性排斥反应的易感性：我们计划前瞻性地定义移植受体的特定免疫基因的基因型，以确定与慢性排斥反应相关的基因型和针对移植物的免疫反应的发展。这些研究的结果将有助于更深入地了解导致慢性排斥反应的潜在机制，并有助于区分CAN的一个原因。

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.