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：利用自身免疫机制来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 患者更有可能罹患转移性肾细胞癌。使用免疫刺激药物治疗后获得良好的结果。该项目源自我们已发表的数据，该数据表明携带两种自身免疫相关 HLA II 类单倍型成分的 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。该假设将使用由 80 名 IV 期 RCC 患者组成的队列开发的 HLA I 类和 II 型淋巴母细胞系 (LCL) 库进行检验，这些患者的结果涵盖延长无病生存期到肿瘤快速进展和死亡的范围。。这些 LCL 将用作本文所述分子和遗传学研究的 DNA 来源。本申请中提出的研究探讨了 RCC 结果与临床文献中提出的三种所谓的自身免疫机制的关联。具体目标 1 中检查的第一个机制表明，肿瘤坏死因子 a 启动子的多态性导致 TNFα 的高表达，从而驱动自身免疫炎症过程。我们假设携带这些高表达多态性的肾细胞癌患者在免疫刺激治疗后有良好的结果。这将通过 PCR 和相关启动子区域的测序来解决。具体目标 2 中研究的第二种机制涉及补体成分 C4A 和 C4B 的缺乏，这在自身免疫性疾病患者中经常观察到。我们认为具有 C4A 或 C4B 遗传缺陷的肾细胞癌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检验。具体目标 3 中阐述的第三种机制基于微嵌合的概念，即同种异体细胞在个体循环或组织中的持续存在。淋巴来源的微嵌合细胞已被认为是自身免疫组织破坏的介质。我们假设携带微嵌合细胞的肾细胞癌患者有良好的预后。实验旨在通过 HLA Cw 基因分型检测微嵌合 DNA，并通过 FISH/IHC 检测肿瘤浸润微嵌合白细胞。这些数据在临床上将有助于预测肾细胞癌患者的结果，以及了解宿主源性肿瘤控制的基本机制。