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: 8488395
• 负责人: Robert J Binder
• 金额: $ 30.88万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488395
• 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 cell response; Testing; Therapeutic Agents; Tumor-Derived; alpha 2-Glucoproteins; calreticulin; cancer immunotherapy; cancer therapy; immunogenicity; inhibitor/antagonist; novel therapeutics; receptor; response; trafficking; tumor

ABSTRACT 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 (¿2M), a CD91 ligand, complexed either endogenously and artificially to various peptides, and (iii) test the role of serum levels of ¿2M 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 ¿2M-mediated immunogenicity and its application to immunotherapy of cancer and infectious disease. a. Examine the mechanism of co-stimulatory activation by ¿2M; b. Examination of the intracellular trafficking and processing of ¿2M-peptide complexes. c. Test the complexes of tumor derived-peptides with ¿2M in prophylaxis and therapy of cancers; d. Examination of endogenously formed ¿2M-peptide complexes as immunogens. Aim 3: To investigate the role of blodd ¿2M levels on immune system. a. Test the effects of blood ¿2M levels on the ability of mice to elicit T cell responses after tumor inoculation; b. Test the effects of blood ¿2M levels on the ability of mice to elicit T cell responses after immunization with HSP-peptide complexes.

抽象的 hsp70、hsp90 和钙网蛋白家族的热休克蛋白 (HSP) 具有丰富的可溶性 引起强大免疫反应的细胞内蛋白质。这些回应包括 T 细胞反应的先天和适应性方面及其下调的组成部分。 HSP 陪伴肽并参与抗原呈递内化受体的能力 细胞有两个关键特性，使它们能够引发免疫反应。 HSP 在跨领域的关键作用 2005 年还设想并证实了 T 细胞反应期间抗原的启动。 在此应用中，我们的目标是 (i) 研究 HSP 受体 CD91 在交叉启动中的作用 小鼠系统，(ii) 检查 α2-巨球蛋白 (¿2M)（CD91）的免疫原性机制 配体，内源地或人工地与各种肽复合，并且（iii）测试 ¿2M 的血清水平对小鼠发起免疫反应的能力的影响。 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）表达细胞交叉存在的能力 抗原并引发有效的 T 细胞反应； b. CD91条件性敲除小鼠的构建及免疫学表征 这只老鼠的反应。 目标2：研究¿2M介导的免疫原性机制及其应用 癌症和传染病的免疫治疗。 一个。检查 ¿2M 的共刺激激活机制； b.检查 2M 肽复合物的细胞内运输和加工。 c.测试肿瘤源肽与¿2M的复合物在癌症预防和治疗中的作用； d.检查内源形成的 ¿2M-肽复合物作为免疫原。 目标 3：研究血液 ¿2M 水平对免疫系统的作用。 一个。测试血液 ¿2M 水平对小鼠肿瘤后引发 T 细胞反应能力的影响 接种； b.测试血液 ¿2M 水平对小鼠在注射后引发 T 细胞反应的能力的影响 用HSP-肽复合物进行免疫。