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Targeting GITR-GITRL to promote regulatory T cell transplantation tolerance

靶向 GITR-GITRL 促进调节性 T 细胞移植耐受

基本信息

批准号：
7475154
负责人：
James I Kim
金额：
$ 13.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7475154
关键词：
Address Adoptive Transfer Advisory Committees Allogenic Allograft Tolerance Allografting Antigen-Presenting Cells Attention Cell Transplantation Cell physiology Cells Communities Data Development Disruption Doctor of Philosophy Embryology Environment Family Fostering Genes Glucocorticoids Goals Graft Survival Heart Transplantation Immune response Immune system Immunology In Vitro Inflammation Inflammatory Institution Intervention Investigation Ligands Maintenance Mediating Mentors Modeling Molecular Molecular Immunology Mus Operative Surgical Procedures Organ Organ Transplantation Pennsylvania Play Principal Investigator Procedures Process Property Reagent Recording of previous events Regulation Research Research Personnel Research Training Role Scientist Signal Transduction Skin Skin Transplantation Skin graft Solid Standards of Weights and Measures Students T-Cell Receptor T-Lymphocyte Therapeutic Therapeutic immunosuppression Thinking Training Training Programs Transgenic Organisms Transplantation Transplantation Tolerance Treatment Protocols Tumor Necrosis Factor Receptor Universities base clinical application clinically relevant design in vivo novel post-doctoral training receptor research study response skin allograft

项目摘要

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.

描述（由申请人提供）：