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）：该研究提案基于以下假设：自身免疫的机制可用于控制或杀死转移性肾脏细胞癌（RCC），并且具有与自身免疫性疾病有关的基因型或生物免疫疾病相关的RCC患者在接受免疫抑制药物后的治疗可能更有可能与自身免疫性疾病相关。该项目从我们发布的数据中演变出来，表明携带两个自身免疫相关的HLA II类单倍型的IV期RCC患者具有对细胞因子疗法的反应显着改善，并且享有长时间的生存。该假设将使用HLA I类和II类型淋巴细胞细胞系（LCL）的融合集合从80名IV级IV RCC患者组成，其结果跨越了长期无疾病生存的频谱，从而快速肿瘤进展和死亡。这些LCL将用作本文描述的分子和遗传研究的DNA来源。本申请中提出的研究研究了RCC结果与临床文献中提出的三种自身免疫机制的关联。在特定目标1中检查的第一种机制表明，肿瘤坏死因子的多态性导致高tnfalpha表达驱动自身免疫性炎症过程。我们假设携带这些高表达多态性的RCC患者在免疫刺激治疗后具有有利的结果。这将通过PCR和相关启动子区域的测序来解决。在特定目标2中检查的第二种机制涉及补体成分C4A和C4B的缺陷，在自身免疫性疾病的患者中经常观察到它们。我们建议在C4A或C4B中患有遗传缺陷的RCC患者具有良好的预后。该假设将通过C4等位基因的分子分析和定量来研究。在特定目标3中解决的第三种机制是基于微思维的概念，即同种异体细胞在个体的循环或组织中的持久性。已经提出，淋巴样的微chimimeric细胞是自身免疫组织破坏的介体。我们假设携带微脑细胞的RCC患者具有有利的结果。设计实验是通过HLA CW基因分型来检测微chimeric DNA的，而FISH/IHC的肿瘤浸润微chimimeric白细胞。这些数据将在预测RCC患者的预后以及对宿主衍生肿瘤控制的基本机制的理解上在临床上有用。