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: 8290437
• 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/8290437
• 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）是丰富的Solulle 这些反应的细胞内蛋白质包括 TCELL响应的先天和适应性方面的组成部分，因为它是降低的调节。 HSP能够在抗原呈递上伴侣肽并吸引内在受体的能力 细胞是引起免疫反应的两个关键特性。 在2005年，还设想并证明了T细胞应对过程中抗原的启动。 在此应用中，我们旨在（i）研究HSP受体CD91在交叉中的作用 鼠系统，（ii）检查α2-巨球蛋白（2M）的免疫原性的机制，CD91 配体，内源性内源和人为地与各种肽进行复合，（iii）测试 血清水平� 2M小鼠安装免疫反应的能力。 目的1：研究HSP受体CD91在T细胞反应的交叉过程中的作用。 a。 抗原和固定有效的T细胞反应； b。 该鼠标的响应。 目标2：研究»的机制2M介导的免疫原性，并应用于 癌症和传染病的免疫疗法。 A.检查通过„共刺激激活的机制2m; b。 2m肽复合物。 c。 2M预防和癌症治疗； d。 2M肽复合物作为免疫原子。 目标3：调查Blodd»的作用免疫系统上有2M水平。 答：测试血液的影响»小鼠在肿瘤后引起T细胞反应的能力的2M水平 接种； b。在小鼠引起T细胞反应的能力上的2M水平 用HSP肽复合物免疫。