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

 描述(由申请人提供)：受者T细胞对供者抗原的识别(同种识别)启动适应性免疫反应，导致移植排斥反应。很明显，理想的移植耐受方案应该依赖于操纵同种异体识别，而不是抑制正在进行的抗捐赠者免疫反应。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是至关重要的。我们的初步研究表明，在皮肤和心脏移植后(第1天)，供体来源的囊泡携带异体MHC分子(外切体)从移植物流向受者淋巴器官。随后，受体细胞占据这些小泡，并将供体MHC呈现在它们的表面，这种现象被称为MHC交叉穿戴。我们的项目是1)研究参与这一过程的细胞和分子，2)研究这一现象在T细胞同种异体识别、同种异体反应和同种异体排斥反应中的作用。至 为了测试这一点，我们提出了以下具体目标：目的1.鉴定移植后涉及变装的抗原和细胞。目的2.为了测试外切体和交叉修饰在同种异体免疫和排斥反应中的作用，我们的项目将利用结合Cre-Lox基因工程小鼠模型、外切体生产抑制剂和流式成像技术的创新方法来研究供体APC与外切体运输和MHC交叉修饰在供体抗原提呈、T细胞激活和皮肤和心脏移植排斥反应中的作用。我们期待我们的提案将为同种异体免疫和移植排斥反应的启动机制带来新的见解。这一知识将有助于在移植和潜在的自身免疫及其他免疫疾病中设计新的耐受方案。

 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.