权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Decay accelerating factor dependent inhibition of T cell immunity

T 细胞免疫的衰变加速因子依赖性抑制

基本信息

批准号：
9282415
负责人：
DIRK HOMANN
金额：
$ 21.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282415
关键词：
Address Alloantigen Anaphylatoxins Animals Autoantigens Autoimmune Diseases Autoimmune Process Biological C3AR1 gene CD55 Antigens CD80 gene CTLA4 gene Cell surface Cells Complement Complement 3a Complement 5a Complement Activation Complement Factor D Data Development Disease Down-Regulation Eragrostis Exhibits Graft Rejection Grant Health Hematopoietic Homologous Gene Hour Human Immune Immune Tolerance Immune response Immunity Inflammatory Injury Knowledge LIF gene Link Literature Modeling Mus Organ Transplantation Outcome Patients Peptide/MHC Complex Physiological Process Production Proteins Publishing Reagent Regulatory T-Lymphocyte Reporting Research Solid Surface T cell response T memory cell T-Cell Receptor T-Lymphocyte TNFRSF5 gene Testing To autoantigen Transgenic Mice Transplantation Viral Virus Virus Diseases Work adaptive immunity anergy cytokine experimental study high reward high risk improved in vivo inhibitor/antagonist innovation insight killings mouse model novel novel therapeutic intervention novel therapeutics pathogen prevent receptor response tool

项目摘要

Abstract Decay accelerating factor (DAF, CD55) is a glycophosphatidylinositol (GPI)-linked, cell surface-expressed protein with a known primary function as an intrinsic (on the cell surface on which it is expressed) regulator of complement cascade activation. We among others discovered that DAF crucially modulates T cell immune responses by locally regulating complement activation. We also showed that during cognate T cell/APC interactions surface DAF expression is rapidly (within hours) yet transiently (24-48h) downregulated. We hypothesize that this transient downregulation crucially permits local complement activation to drive induction of effector T cells (Teff) while simultaneously inhibiting induction, function and stability of regulatory T cells (Treg). While DAF deficient animals have been produced and exhibit enhanced T cell immune responses, formal testing of this hypothesis requires the ability to constitutively enforce stable DAF expression on immune cell surfaces in vivo. Our hypothesis predicts that this enforced DAF expression will inhibit APC activation and limit induction of Teff immunity and simultaneously will permit and facilitate Treg induction/stability, together dampening protective anti-viral T cell immunity while favoring immunological tolerance directed toward allo- or autoantigens. If our working model is correct, the findings will be conceptually innovative and significant in that they would support a novel mechanism that exerts control over T cell immunity in vivo. The proposed work will result in production of a mouse with an inducible, stable surface expressed form of DAF, thereby adding an essential missing tool to the toolbox of biological reagents available for studying links between adaptive immunity and complement activation. We propose to test this hypothesis in this R21 application through 2 aims: 1) To modulate T cell immunity by enforced DAF expression in hematopoietic cells and 2) To produce and analyze T cell immune responses in an inducible, conditional, DAF transgenic mouse. The findings derived from this “high-risk high-reward” R21 application are likely to provide new insight into the impact of DAF expression (rather than its absence) on in vivo T cell immune responses, an issue that has not been addressed and represents a gap in our current knowledge. If our working model is correct, the findings would provide the basis for novel therapeutic strategies to increase DAF expression in efforts to induce tolerogenic responses that prevent and/or treat autoimmune disease, transplant rejection and graft vs. host disease. In addition, at the completion of this R21 grant we will have produced novel biological tools including inducible DAF transgenic mice that will permit us to test DAF-dependent tolerogenic strategies in autoimmune and transplant models, determine whether and how DAF impacts induction of naïve and/or memory T cell activation and function in each situation, and provide insight into mechanisms underlying physiological DAF downregulation.

摘要