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（通过应用程序提供）：I型糖尿病（T1DM）的胰岛移植疗法的成功取决于其控制T细胞介导的同种反应性和�Cell自身免疫性的能力。诱导型共刺养因子（ICO）/B7相关蛋白1（B7RP-1）信号传导对于调节效应子Th1和Th2细胞功能至关重要。 ICO拮抗剂治疗抑制Th1和Th2介导的注射，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疫反应。我们假设对胰岛局部表达可溶性ICOS-IG的遗传修饰可能会保护胰岛移植物免受免疫反应的影响。该保护的基础机制可能涉及通过促进其凋亡和/或厌食的效应T细胞失活。我们将使用重组腺相关病毒（RAAV）将ICOS-IG或其他控制基因传递到胰岛细胞。 AAV是一种非致病病毒，没有免疫原性，因此在临床应用中可能是安全的。最近的研究表明，通过RAAV翻译对胰岛进行遗传修饰导致体内报告基因的长期表达，这不会干扰胰岛素的产生。最后，ICOS-IG的局部表达可能不会影响全身免疫功能，从而提供了一种安全的手段来延长移植胰岛存活。因此，基于ICOS-IG表达胰岛移植以抑制效应T细胞的免疫疗法可能特别有效地维持合同性和同种异体胰岛移植耐受性。在此应用中，我们将：1）。优化生成一般修饰的小鼠胰岛的条件，这些小鼠胰岛表达共刺激抑制剂ICOS-Ig； 2）。检查表达同源性和同种异体胰岛的ICOS-Ig的移植是否可以防止糖尿病的复发；和3）。确定ICOS-IG在移植胰岛功能维持中的作用。这些研究将解决有关ICOS/B7RP-1信号在同种异体和自身免疫T细胞反应上的调节功能的基本问题。我们的发现可能为预防和抑制人类胰岛移植物免疫的新型免疫疗法提供了基础。