Role for alpha2-Macroglobulin in Immune Responses and Cancer Immunotherapy

描述（由申请人提供）：Alpha2巨球蛋白（a2M）与免疫原性热休克蛋白共享其细胞表面受体CD91。基于这一观察，我们已经测试并证明了用a2M免疫的小鼠会引起T细胞对它所伴随的肽的反应。本项目提出的初步研究表明，a2M与CD91的结合以及a2M对伴侣肽的能力是引发免疫反应所必需的两个关键特性。没有其他的机制程序被提供，这个项目的目的是首先了解这些自体蛋白与抗原提呈细胞的相互作用，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。这个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CD91配体（如热休克蛋白）的背景下研究a2M，以及它们在交叉呈递和交叉引物中的各种作用。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：a2M和肽抗原的纯化程序，a2M肽复合物的创建程序，预防和治疗中的肿瘤排斥模型，以及目前正在制备CD91缺陷敲除小鼠。我的长期目标是将我实验室的基础研究转化为癌症治疗的临床应用，并首先理解为什么这些自身蛋白具有免疫原性。

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.