Exosomes and Donor Antigen Cross-dressing in Pancreatic Islet Transplantation

胰岛移植中的外泌体和供体抗原异装

基本信息

批准号：
10062499
负责人：
GILLES A BENICHOU
金额：
$ 45.44万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-06 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062499
关键词：
Alloantigen Allogenic Antigens Autoantigens Autoimmune B-Lymphocytes Beta Cell Cells Data Dendritic Cells Diabetes Mellitus Diabetic mouse Diphtheria Toxin Drug toxicity Dual-role transvestism Engraftment FOXP3 gene Failure Genes Goals Graft Rejection Guanosine Triphosphate Phosphohydrolases Heart Homologous Transplantation Immune Immune System Diseases Immune Tolerance Immune response Immunosuppression In Vitro Infection Inflammation Inflammatory Inflammatory Response Injections Insulin Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knockout Mice Laboratories Leukocytes Maintenance Mediating Methods Modeling Monkeys Mus Nature Pancreas Play Process Production Proteins Protocols documentation Publishing RNA Regulatory T-Lymphocyte Reporting Rodent Role Skin Source Surface T-Lymphocyte Testing Tissue Grafts Transplantation Vesicle base cell killing design diabetic exosome extracellular vesicles heart allograft in vivo insight islet islet allograft isoimmunity kidney allograft migration novel response success trafficking transplant model transplantation therapy

项目摘要

PROJECT SUMMARY / ABSTRACT The ultimate goal of islet transplantation is to achieve tolerance defined as long-tem engraftment without maintenance immunosuppression. Several studies suggest that certain extracellular vesicles (exosomes) play an essential role in the immune responses involved in both rejection and tolerance of allogeneic transplants. Recently, we reported that, after pancreatic islet transplantation in mice, many recipient cells, take up donor vesicles and present allogeneic MHC molecules on their surface (allo-MHC cross-dressing); a process leading to activation of alloreactive T cells in vivo. In addition, exosomes released by pancreatic insulin-secreting beta cells are known to promote inflammation and diabetes through transfer of auto-antigens and RNA. Altogether, this suggests that exosomes might play a key role in the rejection of islet allografts. Supporting this view, we have obtained preliminary evidence that in vivo blocking of donor exosome production with 2 agents, GW4869 and cambinol, inhibited allo-MHC cross-dressing and prolonged survival of heart allografts in mice (up to 80 days). Most relevant to this proposal, we have obtained preliminary data showing that treatment of allogeneic islets in vitro (pre-injection) with these GW4869 suppressed donor MHC cross-dressing and nearly abrogated activation of alloreactive T cells in mice recipient of these islets. Contrasting with their role in rejection, exosomes have also been shown to promote immune tolerance. For instance, exosomes derived from FoxP3+ regulatory T cells (Treg-exosomes) suppress inflammation and can mediate immune tolerance of auto- and allo-antigens in rodents. On the other hand, to our knowledge, the tolerogenicity of exosomes produced by regulatory B cells (Breg-exosomes) has never been investigated. Our objectives are: 1) to investigate the nature of the cells and antigens involved in donor exosome release and cross-dressing after islet transplantation and, 2) test whether long-term islet allograft survival could be achieved through inhibition of donor exosome production and/or MHC cross-dressing or via recipient administration with tolerogenic exosomes. Aim 1. Investigate the mechanisms involved in donor antigen cross-dressing of recipient cells after islet transplantation Aim 2. Inhibit donor exosome release and cross-dressing in islet-transplanted mice Aim 3. Achieve long-term islet allograft survival using exosomes derived from regulatory cells We anticipate that our proposal will 1) bring new insights into the mechanisms underlying the initiation of alloimmunity and rejection process after pancreatic islet transplantation and, 2) set the path for the design of novel exosome-based tolerance protocols in islet transplantation and potentially autoimmune and other inflammatory immunological disorders.

项目摘要 /摘要胰岛移植的最终目的是实现定义为长Tem植入的公差维护免疫抑制。几项研究表明，某些细胞外囊泡（外泌体）播放同种异体移植物的排斥和耐受性涉及的免疫反应中的重要作用。最近，我们报道说，在小鼠中胰岛移植后，许多受体细胞占用供体囊泡并在其表面上呈现同种异体MHC分子（Allo-MHC横切）；一个过程领导在体内激活同种异体T细胞。此外，胰腺胰岛素分泌β发行的外泌体已知细胞通过转移自身抗原和RNA促进炎症和糖尿病。总之，这表明外泌体可能在拒绝同种异体移植物中起关键作用。支持这个观点，我们获得了初步证据，表明在体内阻止了供体外泌体产生的2个代理， GW4869和cambinol，抑制了小鼠心脏同种异体移植物的同种异体生存期的Allo-MHC。（最多80天）。与该提案最相关的是，我们获得了初步数据，表明这些GW4869的体外（预注入）同种异体胰岛抑制了供体MHC的交叉点，几乎这些胰岛受益者的小鼠接受者消除了同种反应性T细胞的激活。与它们在排斥反应中的作用相反，外泌体也已证明可以促进免疫耐受性。为了实例，源自Foxp3+调节性T细胞（Treg-exosomes）的外泌体抑制炎症，可以介导啮齿动物中自动和异抗原的免疫耐受性。另一方面，据我们所知从未研究过由调节B细胞产生的外泌体的耐受性。我们的目标是：1）研究供体外泌体释放中涉及的细胞和抗原的性质和胰岛移植后的透明，2）测试长期胰岛同种异体移植生存是否可以是通过抑制供体外泌体产生和/或MHC透明或通过接受者来实现具有耐受性外泌体的给药。目标1。研究受体细胞供体抗原抗原交叉点的机制胰岛移植 AIM 2。抑制供体外泌体释放和在胰岛移植的小鼠中进行透明 AIM 3。使用源自调节细胞的外泌体实现长期同种异体移植存活我们预计我们的建议将1）带来新的见解胰岛移植后的同种免疫力和拒绝过程，2）为设计的途径设定了途径胰岛移植和潜在的自身免疫和其他的新型基于外泌体的公差方案炎症免疫疾病。