Role of CD91 and its ligands in immune response

CD91及其配体在免疫反应中的作用

• 批准号: 7727754
• 负责人: Robert J Binder
• 金额: $ 33.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727754
• 关键词: Antigen-Presenting Cells; Antigens; Blood; Cell Surface Receptors; Cells; Communicable Diseases; Complex; Cross-Priming; Down-Regulation; Event; Family; Heat shock proteins; Immune response; Immune system; Immunization; Knockout Mice; Ligands; Macroglobulins; Malignant Neoplasms; Mediating; Molecular Chaperones; Mus; Pathway interactions; Peptides; Process; Property; Prophylactic treatment; Proteins; Role; Serum; System; T-Lymphocyte; Testing; Therapeutic Agents; Tumor-Derived; alpha 2-Glucoproteins; calreticulin; cancer immunotherapy; cancer therapy; immunogenicity; inhibitor/antagonist; novel therapeutics; public health relevance; receptor; response; trafficking; tumor

DESCRIPTION (provided by applicant): Heat shock proteins (HSPs) of the hsp70, hsp90 and calreticulin families are abundant soluble intracellular proteins that elicit powerful immunological responses. These responses include components of both the innate and adaptive aspects of T cell responses as well as its down regulation. The ability of HSPs to chaperone peptides and engage internalizing receptors on antigen presenting cells are two key properties that allow them to elicit immune responses. A key role for HSPs in cross- priming of antigens during T cell responses was also envisaged and demonstrated in 2005. In this application we aim to (i) investigate the role of the HSP receptor, CD91, in cross-priming in the murine system, (ii) examine the mechanism of immunogenicity of alpha2-macroglobulin (a2M), a CD91 ligand, complexed either endogenously and artificially to various peptides, and (iii) test the role of serum levels of a2M on the ability of mice to mount immune responses. Aim 1: To investigate the role of the HSP receptor CD91 in cross-priming of T cell responses. a. Determine the ability of RAP (a competitive inhibitor of CD91) -expressing cells to cross present antigens and mount effective T cell responses; b. Creation of a CD91 conditional knock-out mouse and the characterization of immunological responses in this mouse. Aim 2: To investigate the mechanism of a2M-mediated immunogenicity and its application to immunotherapy of cancer and infectious disease. a. Examine the mechanism of co-stimulatory activation by a2M; b. Examination of the intracellular trafficking and processing of a2M -peptide complexes. c. Test the complexes of tumor derived-peptides with a2M in prophylaxis and therapy of cancers; d. Examination of endogenously formed a2M -peptide complexes as immunogens. Aim 3: To investigate the role of blood a2M levels on immune system. a. Test the effects of blood a2M levels on the ability of mice to elicit T cell responses after tumor inoculation; b. Test the effects of blood a2M levels on the ability of mice to elicit T cell responses after immunization with HSP-peptide complexes. PUBLIC HEALTH RELEVANCE: We have identified a role for heat shock proteins in cross-priming, an event that is central to the initiation of adaptive immune responses against cancer and infectious disease. In this proposal we aim to examine the HSP receptor(s) involved and how we may exploit this receptor by channeling other ligands, such as a2-macroglobulin through this pathway. This will allow one to generate novel therapeutic agents against cancer and infectious disease by targeting cell surface receptors.

描述（由申请人提供）： hsp70、hsp90 和钙网蛋白家族的热休克蛋白 (HSP) 是丰富的可溶性细胞内蛋白，可引发强大的免疫反应。这些反应包括 T 细胞反应的先天和适应性方面及其下调的组成部分。 HSP 陪伴肽和接合抗原呈递细胞上的内化受体的能力是它们能够引发免疫反应的两个关键特性。 2005 年，我们还设想并证明了 HSP 在 T 细胞反应期间抗原交叉引发中的关键作用。在本应用中，我们的目标是 (i) 研究 HSP 受体 CD91 在小鼠系统交叉引发中的作用，(ii) 检查 α2-巨球蛋白 (a2M)（一种 CD91 配体）的免疫原性机制，内源性或人工与各种肽复合，以及 (iii) 测试血清 a2M 水平对小鼠免疫反应能力的影响。目标 1：研究 HSP 受体 CD91 在 T 细胞反应交叉启动中的作用。一个。确定 RAP（CD91 的竞争性抑制剂）表达细胞交叉呈递抗原并引发有效 T 细胞反应的能力； b. CD91 条件敲除小鼠的创建以及该小鼠免疫反应的表征。目标2：研究a2M介导的免疫原性机制及其在癌症和传染病免疫治疗中的应用。一个。检查a2M的共刺激激活机制； b.检查a2M-肽复合物的细胞内运输和加工。 c.测试肿瘤源肽与a2M的复合物在癌症预防和治疗中的作用； d.检查内源形成的α2M-肽复合物作为免疫原。目标 3：研究血液 a2M 水平对免疫系统的作用。一个。测试血液a2M水平对小鼠肿瘤接种后引发T细胞反应能力的影响； b.测试血液 a2M 水平对小鼠在 HSP-肽复合物免疫后引发 T 细胞反应的能力的影响。 公共健康相关性：我们已经确定了热休克蛋白在交叉启动中的作用，交叉启动是启动针对癌症和传染病的适应性免疫反应的核心事件。在本提案中，我们的目标是检查所涉及的 HSP 受体，以及我们如何通过该途径引导其他配体（例如 α2-巨球蛋白）来利用该受体。这将使人们能够通过靶向细胞表面受体来产生针对癌症和传染病的新型治疗剂。