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: 8094481
• 负责人: Robert J Binder
• 金额: $ 32.85万
• 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/8094481
• 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; 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(申请人提供)：热休克蛋白(HSP70)、热休克蛋白90(HSP90)和钙网织蛋白家族的热休克蛋白(HSPs)是丰富的可溶性细胞内蛋白，可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成分以及它的下调。热休克蛋白具有伴侣多肽和结合抗原提呈细胞上的内化受体的能力，这是它们能够引发免疫反应的两个关键特性。2005年还设想并证明了热休克蛋白在T细胞反应期间交叉启动抗原方面的关键作用。在这项应用中，我们的目标是(I)研究HSP受体CD91在小鼠系统交叉激发中的作用，(Ii)检测CD91配体α2-巨球蛋白(A2M)的免疫原性的机制，以及(Iii)检测血清a2M水平对小鼠建立免疫应答的能力的作用。目的1：探讨热休克蛋白受体CD91在T细胞应答交叉激发中的作用。A.确定表达RAP(CD91的竞争性抑制物)的细胞跨越现有抗原并建立有效的T细胞反应的能力；b.建立CD91条件基因敲除小鼠，并对该小鼠的免疫学反应进行鉴定。目的：探讨a2M介导的免疫原性机制及其在肿瘤和传染病免疫治疗中的应用。A.研究a2M共刺激激活的机制；b.研究a2M-肽复合体在细胞内的运输和加工。C.检测肿瘤衍生多肽与a2M的复合体在预防和治疗癌症中的作用；d.检测内源性形成的a2M-肽复合体作为免疫原。目的3：探讨血a2M水平对免疫系统的影响。A.检测血液a2M水平对肿瘤接种后小鼠激发T细胞反应能力的影响；b.检测血液a2M水平对HSP-多肽复合体免疫小鼠诱导T细胞反应能力的影响。 公共卫生相关性：我们已经确定了热休克蛋白在交叉引发中的作用，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。在这项建议中，我们的目标是研究涉及的热休克蛋白受体(S)，以及我们如何通过这一途径引导其他配体，如α2-巨球蛋白来利用这一受体。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。