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

• 批准号: 7805276
• 负责人: James I Kim
• 金额: $ 0.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/7805276
• 关键词: Address; Adoptive Transfer; Advisory Committees; Allogenic; Allograft Tolerance; Allografting; Antigen-Presenting Cells; Attention; Cell Transplantation; Cell physiology; Cells; Communities; Data; Development; 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; T-Cell Receptor; T-Lymphocyte; Therapeutic; Therapeutic immunosuppression; Training; Training Programs; Transgenic Organisms; Transplantation; Transplantation Tolerance; Treatment Protocols; Tumor Necrosis Factor Receptor; Universities; base; clinical application; clinically relevant; design; graduate student; in vivo; novel; post-doctoral training; receptor; research study; response; skin allograft

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)： 这份提案详细说明了申请者从研究调查员过渡到独立调查员的五年培训计划。首席研究员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，现在继续他的移植免疫学培训。 目前的培训强调移植耐受的机制。詹姆斯·马克曼博士将指导首席研究员的科学发展。马克曼博士是移植研究领域公认的领导者。他培养了包括研究员和研究生在内的许多年轻科学家。一个由来自该机构基础免疫学社区的三名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用于发现的直接临床应用。 这项研究的重点是利用调节性T细胞(Tregs)的独特特性来产生同种异体移植耐受。具体地说，我们的论文认为，通过炎症信号使Treg失去功能是免疫系统促进免疫反应启动的标准机制。我们根据初步数据表明，在同种异体器官移植的背景下，伴随着器官移植过程的先天炎症信号通过其配体(GITRL)触发糖皮质激素诱导的TNFR家族相关基因(GITR)而干扰Tregs的功能。此外，我们的初步数据表明，阻断GITR触发会导致长期的同种异体皮肤移植存活，这是Treg依赖的。因此，我们建议描述GITR阻断对移植耐受有益影响的潜在机制，并评估靶向这种受体-配体对是否可以在标准移植耐受模型中用于治疗益处。首先，我们将评估使用一组移植耐受模型靶向GITR-GITRL所产生的益处的范围。其次，我们将描述免疫机制，细胞和分子，通过破坏体内GITR-GITRL相互作用来增强Treg抑制活性。 对于免疫生物学家来说，保持移植耐受状态而不需要维持免疫抑制治疗仍然是一个难以实现的目标。我们的研究着眼于一种新的和潜在的临床相关的方法来达到这一目的。

项目成果

Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.

• DOI: 10.1126/scitranslmed.3002270
• 发表时间: 2011-06-15
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Zhao G;Moore DJ;Kim JI;Lee KM;O'Connor MR;Duff PE;Yang M;Lei J;Markmann JF;Deng S
• 通讯作者: Deng S

Anti-CD45RB/anti-TIM-1-induced tolerance requires regulatory B cells.

• DOI: 10.1111/j.1600-6143.2012.04055.x
• 发表时间: 2012-08
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Lee KM;Kim JI;Stott R;Soohoo J;O'Connor MR;Yeh H;Zhao G;Eliades P;Fox C;Cheng N;Deng S;Markmann JF
• 通讯作者: Markmann JF