Exosomes and Donor MHC Cross-Dressing of Recipient Cells in Allotransplantation

同种异体移植中受体细胞的外泌体和供体 MHC 交叉搭配

• 批准号: 9090279
• 负责人: GILLES A BENICHOU
• 金额: $ 25.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090279
• 关键词: Affect; Allografting; Antigen Presentation; Antigens; Autoimmune Process; B-Lymphocytes; Cells; Cre-LoxP; Dendritic Cells; Detection; Disease; Dual-role transvestism; Genetically Engineered Mouse; Graft Rejection; Graft Survival; Heart; Heart Transplantation; Image; Imagery; Imaging technology; Immune response; In Vitro; Isoantibodies; Knowledge; Leukocytes; Lymphoid; MHC antigen; Methods; Mus; Nature; Organ; Organ Transplantation; Process; Production; Protocols documentation; Receptors, Antigen, B-Cell; Role; Skin; Skin Transplantation; Skin graft; Spleen; Surface; T-Cell Activation; T-Lymphocyte; Testing; Transplantation; Vesicle; adaptive immunity; allograft rejection; base; design; exosome; heart allograft; in vivo; in vivo imaging; inhibitor/antagonist; innovation; insight; isoimmunity; mouse model; multi-photon; novel; public health relevance; response; skin allograft; trafficking

 DESCRIPTION (provided by applicant): Recognition of donor antigens by recipient T cells (allorecognition) initiates the adaptive immune response leading to transplant rejection. It is clear that ideal transplant tolerance protocols should rely on manipulating allorecognition rather than suppressing an ongoing anti-donor immune response. Therefore, elucidation of the mechanisms underlying T cell allorecognition is essential in designing tolerance strategies in transplantation. Our preliminary studies show that, immediately after skin and heart transplantation (day 1), donor-derived vesicles carrying allo-MHC molecules (exosomes) traffic from the graft to the recipient lymphoid organs. Subsequently, recipient cells take up these vesicles and present donor MHC on their surface, a phenomenon called MHC cross-dressing. Our project is to 1) study the cells and molecules involved in this process and 2) investigate the contribution of this phenomenon to T cell allorecognition, alloresponse and allograft rejection. To test this, we propose the following specific aims: Aim 1. To characterize the antigens and cells involved in cross-dressing after transplantation. Aim 2. To test the contribution of exosomes and cross-dressing to alloimmunity and allograft rejection Our project will make use of innovative approaches combining Cre-Lox genetically engineered mouse models, inhibitors of exosome production and flow imaging technologies to investigate the role of donor APCs versus exosome trafficking and MHC cross-dressing in donor antigen presentation, T cell activation and rejection of skin and heart transplants. We anticipate that our proposal will bring new insights into the mechanisms underlying the initiation of alloimmunity and transplant rejection. This knowledge will help design new tolerance protocols in transplantation and potentially autoimmune and other immunological disorders.

 描述（由申请人提供）：受体 T 细胞对供体抗原的识别（同种异体识别）启动适应性免疫反应，导致移植排斥。很明显，理想的移植耐受方案应依赖于操纵同种异体识别，而不是抑制正在进行的抗供体免疫。因此，阐明 T 细胞同种异体识别的机制对于设计移植耐受策略至关重要。携带同种异体 MHC 分子（外泌体）的囊泡从移植物运输到受体淋巴器官，随后，受体细胞吸收这些囊泡并在其表面呈现供体 MHC，这种现象称为 MHC 异装。参与该过程的细胞和分子，2) 研究该现象对 T 细胞同种异体识别、同种异体反应和同种异体移植排斥的贡献。 为了测试这一点，我们提出以下具体目标： 目标 1. 表征移植后异装所涉及的抗原和细胞 目标 2. 测试外泌体和异装对同种免疫和同种异体移植排斥的贡献。结合 Cre-Lox 基因工程小鼠模型、外泌体产生抑制剂和流式成像技术的创新方法，以研究供体 APC 与外泌体运输和 MHC 异装在供体抗原呈递中的作用，T我们预计我们的建议将为同种免疫和移植排斥的启动机制带来新的见解，这些知识将有助于设计新的移植和潜在的自身免疫性疾病和其他免疫性疾病的耐受方案。