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，引起强大的免疫反应。这些反应包括T细胞反应的先天和适应性方面的组成部分以及其下调调节。 HSP能够在抗原呈递细胞上伴侣肽并吸引内部化受体的能力是两个关键特性，使它们能够引起免疫反应。还设想并证明了HSP在T细胞反应过程中抗原交叉启动抗原中的关键作用。在此应用中，我们的目的是（i）研究HSP受体CD91在鼠系统中交叉宣传中的作用，（ii）检查Alpha2-Mocrogobulin（A2-Motarigigiation and Artrandity and Artrancy and Artrandiality and Artrandiality and cd91 ligation and Artrandiality cd91 lification and cd91 lification and cd911111111111111111111111111111111111111111111111111。肽和（iii）测试A2M血清水平在固定免疫反应能力上的作用。目的1：研究HSP受体CD91在T细胞反应的交叉过程中的作用。一个。确定RAP（CD91的竞争性抑制剂）表达细胞的能力，并跨越了有效的T细胞反应； b。创建CD91条件敲除小鼠的表征和该小鼠中免疫反应的表征。目的2：研究A2M介导的免疫原性的机制及其在癌症和传染病的免疫疗法中的应用。一个。检查A2M共刺激激活的机制； b。检查A2M肽复合物的细胞内贩运和加工。 c。在预防和癌症治疗中测试肿瘤衍生肽的复合物； d。检查内源形成的A2M肽复合物作为免疫原子。目标3：研究血液A2M水平在免疫系统上的作用。一个。测试血液A2M水平对小鼠接种后引起T细胞反应能力的影响； b。测试血液A2M水平对用HSP肽复合物免疫后引起T细胞反应能力的能力的影响。 公共卫生相关性：我们已经确定了热休克蛋白在交叉染色中的作用，这一事件对于启动针对癌症和传染病的适应性免疫反应至关重要。在此提案中，我们旨在检查所涉及的HSP受体以及如何通过通过该途径引导其他配体（例如A2-极球蛋白）来利用该受体。这将使人们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。