Role for alpha2-Macroglobulin in Immune Responses and Cancer Immunotherapy

描述（由申请人提供）： α 2巨球蛋白（α 2 M）与免疫原性热休克蛋白共享其细胞表面受体CD 91。基于这一观察结果，我们已经测试并表明，用α 2 M免疫的小鼠引发T细胞对由其陪伴的肽的应答。针对该项目提出的初步研究已经表明，α 2 M与CD 91的接合和α 2 M与伴侣肽的能力是引发免疫应答所必需的两个关键特性。尚未提供其他机械程序，该项目的目的是首先了解这些自体蛋白与抗原递呈细胞的相互作用以启动免疫反应，其次了解这些蛋白在引发免疫反应中的生理相关性。该项目的一部分将测试利用这些免疫反应来设计针对癌症和传染病的疫苗。我的主要短期目标还包括在其他CD 91配体（如HSPs）的背景下研究a2 M，以及它们在交叉呈递和交叉引发中的各种作用。在这方面，我们已经开发并发表了许多这项工作所需的工具：α 2 M和肽抗原的纯化程序，α 2 M-肽复合物的产生程序，预防和治疗中的肿瘤排斥模型，以及目前制备的CD 91缺陷敲除小鼠。长期目标是将我实验室的基础研究转化为治疗癌症的临床应用，并了解为什么这些自身蛋白质首先具有免疫原性。 我们的实验室和办公室位于匹兹堡大学生物医学科学塔的10楼。该实验室拥有600平方英尺的空间，并配备了细胞免疫学和分子生物学研究以及本项目中描述的所有项目。它与免疫学系的其他实验室相邻，我们可以使用通用设备和大量的研究支持设施。由该大学运行的无病原体动物设施位于同一BST大楼内，并获得AAALAC认证。 相关性：该项目中描述的研究完成后，将深入了解α 2-巨球蛋白激发T细胞免疫反应的机制，以及如何利用这种反应来产生针对癌症和感染因子的疫苗。这些研究将为癌症患者使用自体α 2-巨球蛋白疫苗进行临床试验提供初步数据。

DESCRIPTION (provided by applicant): Alpha2 macroglobulin (a2M) shares its cell surface receptor CD91 with the immunogenic heat shock proteins. Based on this observation we have tested and shown that mice immunized with a2M elicit T cell responses to peptides that are chaperoned by it. Preliminary studies presented for this project have shown that the engagement of CD91 by a2M and the ability of a2M to chaperone peptides are two key properties necessary for elicitation of the immune response. No other mechanistic procedure has been provided and the aims of this project are designed to understand first the interaction of these autologous proteins with antigen presenting cells to initiate the immune response and second what the physiological relevance of these proteins are in the elicitation of immune responses. A part of this project will test the harnessing of these immune responses for vaccine design targeting cancer and infectious disease. My primary short term goals also include studying a2M in context of other CD91 ligands such as the HSPs, and their various roles in cross-presentation and cross-priming. In this regard we have developed and published numerous tools necessary for this work: purification procedures for a2M and peptide antigens, procedures for the creation of a2M-peptide complexes, tumor rejection models in both prophylaxis and therapy and currently preparing CD91 deficient knock out mice. A long term goal is the translation of the basic research of my lab into clinical applications for the treatment of cancer and an understanding of why these self proteins are immunogenic in the first place. Our laboratory and office are located on the 10th floor of the Biomedical Science Tower of the University of Pittsburgh. The laboratory has 600 sq ft of space and is fully equipped for cellular immunology and molecular biology research and for all the projects described in this project. It is contiguous with other laboratories with the Department of Immunology and we have access to common use equipment and vast research support facilities. A pathogen-free animal facility run by the University is available in the same BST building and is AAALAC accredited. RELEVANCE: The studies described in this project, when completed, will provide an insight to the mechanism by which alpha2-macroglobulin elicits T cell immune responses and how this response can be harnessed to generate vaccines against cancer and infectious agents. These studies will provide preliminary data leading to clinical trials in cancer patients with autologous alpha2-macroglobulin-based vaccines.