Targeting GITR-GITRL to promote regulatory T cell transplantation tolerance

描述（由申请人提供）： 该提案详细说明了申请人从研究调查员向独立调查员过渡的五年培训计划。主要研究者已经完成了分子免疫学的博士培训和分子胚胎学的博士后培训，现在继续接受移植免疫学的培训。 目前的培训强调移植耐受的机制。James Markmann MD，PhD将指导主要研究者的科学发展。Markmann博士是移植研究领域公认的领导者。他培养了许多年轻的科学家，包括研究员和研究生。一个由来自该机构基础免疫学界的三位知名科学家组成的咨询委员会将提供必要的科学和专业指导。宾夕法尼亚大学外科系为培训研究调查人员提供了良好的环境，并有将他们转变为独立调查人员的悠久历史。该环境结合了基础探索性研究以及直接的临床应用。 该研究的重点是利用调节性T细胞（Tcells）的独特特性来产生同种异体移植耐受。具体来说，我们的论点是，通过炎症信号使TcB失去功能是免疫系统促进免疫应答启动的标准机制。我们的基础上的初步数据表明，在设置的同种异体器官移植，先天性炎症信号伴随着器官移植的过程中干扰的功能，通过触发糖皮质激素诱导的TNFR家族相关基因（GITR）的配体（GITRL）的TNFR家族相关基因（GITR）。此外，我们的初步数据表明，阻断GITR触发导致Treg依赖的长期皮肤移植物存活。因此，我们建议描述GITR阻断对移植耐受性的有益影响的机制，并评估靶向这种受体-配体对是否可以在标准移植耐受性模型中用于治疗益处。首先，我们将评估采用一组移植耐受模型靶向GITR-GITRL的获益范围。其次，我们将描述通过破坏体内GITR-GITRL相互作用来增强Treg抑制剂活性的细胞和分子免疫机制。 对于免疫生物学家来说，不需要维持免疫抑制治疗的移植耐受状态仍然是一个难以捉摸的目标。我们的研究集中在一种新的和潜在的临床相关的方法，以达到这一目的。

DESCRIPTION (provided by applicant): This proposal details a five year training program for the applicant's transition from research investigator to independent investigator. The principal investigator has completed doctoral training in molecular immunology and post-doctoral training in molecular embryology, and now continues his training in transplant immunology. The present training emphasizes mechanisms of transplantation tolerance. James Markmann MD, PhD will mentor the scientific development of the principal investigator. Dr Markmann is a recognized leader in the field of transplantation research. He has trained numerous young scientists including research fellows and graduate students. An advisory committee of three well-recognized scientists from the institution's basic immunology community will provide necessary scientific and professional guidance. The Department of Surgery at the University of Pennsylvania provides an excellent environment for training research investigators and has a long history of transitioning them into independent investigators. The environment combines basic exploratory research as well as direct clinical applications for discovery. The research focuses on capitalizing on the unique properties of regulatory T cells (Tregs) to generate allograft tolerance. Specifically, our thesis is that rendering Tregs nonfunctional by inflammatory signals is a standard mechanism by which the immune system promotes initiation of an immune response. We base this on preliminary data suggesting that in the setting of allogeneic organ transplantation, innate inflammatory signals accompanying the procedure of organ transplantation interfere with the function of Tregs by triggering of the glucocorticoid-induced TNFR family-related gene (GITR) by its ligand (GITRL). Moreover, our preliminary data demonstrate that blockade of GITR triggering results in long-term skin allograft survival that is Treg-dependent. Thus we propose to delineate the mechanisms underlying the beneficial impact of GITR blockade on transplantation tolerance and to evaluate whether targeting this receptor-ligand pair can be exploited for therapeutic benefit in standard transplant tolerance models. First, we will assess the scope of the benefit derived from targeting GITR-GITRL employing a panel of transplantation tolerance models. Second, we will characterize the immunological mechanisms, cellular and molecular, by which Treg suppressor activity is augmented through disruption of GITR-GITRL interaction in vivo. A state of transplantation tolerance without the need for maintenance immunosuppressive therapy remains an elusive goal for immunobiologists. Our research focuses a novel and potentially clinically relevant approach to this end.