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Autoimmune Mechanisms in the Response to Renal Cancer

肾癌反应中的自身免疫机制

基本信息

批准号：
7058322
负责人：
JULIE A ELLERHORST
金额：
$ 10.32万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-25 至 2007-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This research proposal is based on the hypothesis that mechanisms of autoimmunity are utilized to control or kill metastatic renal cell carcinoma (RCC), and that RCC patients who have genotypic or biologic features associated with autoimmune disorders are more likely to have favorable outcomes after treatment with immune-stimulating drugs. This project evolves from our published data demonstrating that Stage IV RCC patients carrying components of two autoimmunity-associated HLA class II haplotypes have a significantly improved response to cytokine therapy and enjoy prolonged survival. The hypothesis will be examined using a banked collection of HLA Class I and II-typed lymphoblastoid cells lines (LCL) developed from a cohort of 80 Stage IV RCC patients whose outcomes span the spectrum of prolonged disease-free survival to rapid tumor progression and death. These LCL will be used as a source of DNA for the molecular and genetic studies described herein. The research proposed in this application examines the association of RCC outcomes with three purported mechanisms of autoimmunity put forth in the clinical literature. The first mechanism, examined in Specific Aim 1, suggests that polymorphisms of the tumor necrosis factor a promoter that lead to high TNFalpha expression drive autoimmune inflammatory processes. We hypothesize that RCC patients carrying these high-expression polymorphisms have favorable outcomes after immune stimulatory therapy. This will be addressed by PCR and sequencing of the involved promoter region. The second mechanism, examined in Specific Aim 2, involves deficiencies of the complement components C4A and C4B, which are frequently observed in patients with autoimmune disease. We propose that RCC patients with genetic deficiencies in C4A or C4B have favorable outcomes. This hypothesis will be examined by molecular analysis and quantitation of C4 alleles. The third mechanism, addressed in Specific Aim 3, is based on the concept of microchimerism, the persistence of allogeneic cells in the circulation or tissues of an individual. Microchimeric cells of lymphoid origin have been proposed to be mediators of autoimmune tissue destruction. We hypothesize that RCC patients who carry microchimeric cells have favorable outcomes. Experiments are designed to detect microchimeric DNA by HLA Cw genotyping, and tumor infiltrating microchimeric leukocytes by FISH/IHC. These data will be clinically useful in predicting outcomes of RCC patients, as well as in the understanding of basic mechanisms of host-derived tumor control.

描述（由申请人提供）：本研究提案基于以下假设：利用自身免疫机制控制或杀死转移性肾细胞癌（RCC），并且具有与自身免疫性疾病相关的基因型或生物学特征的RCC患者在使用免疫刺激药物治疗后更有可能获得有利的结局。该项目从我们发表的数据中发展而来，这些数据表明携带两种自身免疫相关HLA II类单倍型组分的IV期RCC患者对细胞因子治疗的反应显着改善，并享有延长的生存期。将使用从80名IV期RCC患者的队列中开发的HLA I类和II类淋巴母细胞样细胞系（LCL）的库存集合来检查该假设，这些患者的结局跨越无病生存期延长到肿瘤快速进展和死亡的范围。这些LCL将用作本文所述的分子和遗传研究的DNA来源。本申请中提出的研究检查了RCC结果与临床文献中提出的三种自身免疫机制的相关性。第一种机制，在特异性目的1中研究，表明导致高TNF α表达的肿瘤坏死因子α启动子的多态性驱动自身免疫性炎症过程。我们推测，肾细胞癌患者携带这些高表达的多态性免疫刺激治疗后有良好的结果。这将通过对相关启动子区域进行PCR和测序来解决。第二种机制，在特定目标2中检查，涉及补体成分C4 A和C4 B的缺乏，这在自身免疫性疾病患者中经常观察到。我们认为C4 A或C4 B基因缺陷的RCC患者具有良好的预后。这一假设将通过分子分析和C4等位基因的定量来检验。第三种机制在具体目标3中阐述，基于微嵌合体的概念，即同种异体细胞在个体循环或组织中的持续存在。淋巴起源的微嵌合细胞被认为是自身免疫性组织破坏的介质。我们假设携带微嵌合体细胞的RCC患者有良好的预后。实验设计为通过HLA Cw基因分型检测微嵌合DNA，以及通过FISH/IHC检测肿瘤浸润微嵌合白细胞。这些数据将在临床上有用的预测结果RCC患者，以及在宿主源性肿瘤控制的基本机制的理解。