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（由申请方提供）：受体T细胞识别供体抗原（同种异体识别）启动适应性免疫应答，导致移植排斥。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供体免疫反应。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至关重要。我们的初步研究表明，皮肤和心脏移植后（第1天），供体来源的囊泡携带allo-MHC分子（外泌体）交通从移植到受体淋巴器官。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 cross-dressing。我们的项目是1）研究参与这一过程的细胞和分子，2）研究这一现象对T细胞同种异体识别，同种异体反应和同种异体排斥反应的贡献。到 为了检验这一点，我们提出了以下具体目标：目标1。目的研究移植后异装的抗原和细胞。目标2.为了测试外泌体和交叉敷料对同种免疫和同种异体移植排斥的贡献，我们的项目将利用结合Cre-Lox基因工程小鼠模型、外泌体产生抑制剂和流动成像技术的创新方法来研究供体APC相对于外泌体运输和MHC交叉敷料在供体抗原呈递、T细胞活化和皮肤和心脏移植排斥中的作用。我们预计，我们的建议将带来新的见解的机制启动同种异体免疫和移植排斥反应。这些知识将有助于设计新的移植耐受方案和潜在的自身免疫性和其他免疫性疾病。