Genetic Modification of Mouse Islets for Transplantation

用于移植的小鼠胰岛基因改造

基本信息

批准号：
6650359
负责人：
JIDE TIAN
金额：
$ 15.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-01 至 2004-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6650359
关键词：
NOD mouse T lymphocyte autoimmunity diabetes mellitus histocompatibility immunogenetics ligands pancreatic islet transplantation protein structure function reporter genes transfection transplant rejection transplantation immunology

项目摘要

DESCRIPTION (provided by applicant): The success of islet transplantation therapy for Type I diabetes mellitus (T1DM) depends on its ability to control both T cell-mediated alloreactivity and the ¿-cell autoimmunity. Inducible costimulator (ICOS)/B7-related protein 1(B7RP-1) signaling is crucial for regulation of effector Th1 and Th2 cell function. Treatment with ICOS antagonist inhibits Th1 and Th2 mediated inflammation, EAE, allergic airway disease, and mucosal inflammatory disease, and protects allogeneic heart grafts from immunorejection. We hypothesize that genetic modification of the islets to locally express soluble ICOS-Ig may protect the islet-grafts from immunorejection. The mechanism(s) underlying this protection may involve the inactivation of effector T cells by promoting their apoptosis and/or anergy. We will use recombinant adeno-associated virus (rAAV) to deliver the ICOS-Ig or other control genes to the islet cells. AAV is a non-pathogenic virus and has little immunogenicity, may therefore be safe in clinical applications. Recent studies have demonstrated that genetic modification of the islets by rAAV transduction results in the long-term expression of reporter genes in vivo, which does not interfere with insulin production. Finally, the local expression of ICOS-Ig may not affect systemic immunological function, providing a safe means to prolong transplanted islet survival. Therefore, immunotherapy based on transplantation with ICOS-Ig expressing islets to inhibit effector T cells may be especially effective for maintaining syngeneic and allogeneic islet-graft tolerance.In this application, we will: 1). optimize conditions for generation of genetically modified mouse islets which express costimulation inhibitor ICOS-Ig; 2). examine whether transplantation of ICOS-Ig expressing syngeneic and allogeneic islets prevents the recurrence of diabetes; and 3). determine the action of ICOS-Ig in the functional maintenance of transplanted islets. These studies will address fundamental questions concerning the regulatory function of ICOS/B7RP-1 signaling on alloreactive and autoimmune T cell responses. Our findings may provide the basis for novel immunotherapies for the prevention and inhibition of immunorejection of islet grafts in man.

描述（由申请人提供）：胰岛移植治疗 I 型糖尿病 (T1DM) 的成功取决于其控制 T 细胞介导的同种异体反应性和 ¿ -细胞自身免疫。诱导共刺激物 (ICOS)/B7 相关蛋白 1 (B7RP-1) 信号对于调节效应 Th1 和 Th2 细胞功能至关重要。ICOS 拮抗剂治疗可抑制 Th1 和 Th2 介导的炎症、EAE、过敏性气道疾病、和粘膜炎症性疾病，并保护同种异体心脏移植物免受免疫排斥。我们追求对胰岛进行基因改造以局部表达可溶性 ICOS-Ig 可以保护胰岛。这种保护的机制可能涉及通过促进效应 T 细胞凋亡和/或无反应性来灭活它们。胰岛细胞的控制基因是一种非致病性病毒，几乎没有免疫原性，因此最近的研究表明，通过rAAV转导对胰岛进行基因修饰的结果可能是安全的。最后，ICOS-Ig 的局部表达可能不会影响全身免疫功能，因此为延长移植胰岛的存活提供了安全的手段。移植表达 ICOS-Ig 的胰岛以抑制效应 T 细胞可能对维持同基因和同种异体胰岛移植物耐受性特别有效。在本申请中，我们将： 1) 优化转基因小鼠胰岛的生成条件。表达共刺激抑制剂ICOS-Ig；2)检查表达ICOS-Ig的同基因和同种异体胰岛的移植是否预防糖尿病的复发；以及3)确定ICOS-Ig在移植胰岛的功能维持中的作用。这些研究将解决有关 ICOS/B7RP-1 信号对同种异体反应和自身免疫 T 细胞反应的调节功能的基本问题，我们的研究结果可能为预防和抑制人类胰岛移植物免疫排斥的新型免疫疗法提供基础。