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（通过应用程序提供）：受体T细胞对供体抗原的识别（同种识别）启动了适应性免疫响应，导致移植排斥反应。显然，理想的移植公差方案应依赖于操纵同种异体认知，而不是抑制正在进行的抗抑制免疫反应。因此，阐明T细胞同种异体认识的机制对于设计移植的耐受性策略至关重要。我们的初步研究表明，在皮肤和心脏移植后立即（第1天），供体衍生的蔬菜携带异晶MHC分子（外部）流量从移植物到受体淋巴机器人。随后，受体细胞吸收了这些蔬菜，并在其表面上表现出供体MHC，这一现象称为MHC交叉涂层。我们的项目是1）研究此过程中涉及的细胞和分子，以及2）研究这种现象对T细胞同种异体认知，同种异体响应和分类抑制的贡献。到 对此进行测试，我们提出以下特定目的：目标1。表征移植后涉及的抗原和细胞。目的2。为了测试外泌体和对同种免疫性和同种释放拒绝的贡献，我们的项目将利用与Cre-lox基因工程鼠标模型相结合的创新方法心脏移植。我们预计我们的建议将为同种免疫和移植拒绝的倡议的基础机制带来新的见解。这些知识将有助于设计新的耐受性方案，以进行移植以及潜在的自身免疫性和其他免疫疾病。