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

The role of CAR-expressing Tregs on antigen-specific immune suppression

表达 CAR 的 Tregs 在抗原特异性免疫抑制中的作用

基本信息

批准号：
9335669
负责人：
Brenal Singh
金额：
$ 4.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9335669
关键词：
Address Adoptive Transfer Affect Antibody Formation Antigens Autoantibodies Autoimmune Process Autoimmunity B-Cell Leukemia B-Lymphocytes Binding Biological Biological Assay Biology Body Weight Changes Bone Marrow Bypass CD19 gene CD4 Positive T Lymphocytes Cells Chronic Clinic Clinical Cues Development Disease Disease remission Engineering Enzyme-Linked Immunosorbent Assay FOXP3 gene Flow Cytometry Goals Homeostasis Human Immune Immune response Immunosuppression Immunosuppressive Agents In Vitro Inbred DBA Mice Infection Inflammation Inflammatory Knockout Mice Laboratories Lead Link Lymphoproliferative Disorders Malignant Neoplasms Measurement Measures Mediating Modeling Molecular Monitor Mus Parents Production Publishing Receptor Signaling Refractory Regulation Regulatory T-Lymphocyte Research Resolution Role Signal Transduction Signaling Molecule Specificity Syndrome System Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Uses Thymus Gland Time Transplantation Work adaptive immune response cancer therapy cellular transduction chimeric antigen receptor cytokine experimental study extracellular fitness graft vs host disease in vivo insight interest killings leukemia/lymphoma loss of function mutation lupus-like mouse model novel therapeutics prevent receptor response treatment strategy

项目摘要

Project Summary Regulatory T cells (Tregs) are a key subset of T cells important for the regulation of adaptive immune responses. Loss of function mutations in the Foxp3 gene, as seen in Scurfy murine strains and humans with immune dysregulation, polyendocrinopathy, and X-linked (IPEX) syndrome, lead to a systemic and fatal T cell-dependent lymphoproliferative disease, thus emphasizing the importance of Tregs in maintaining immune homeostasis. Given that Tregs are important in limiting overexcessive immune responses, understanding the biological signals that drive Treg function and expansion is key, especially in autoimmune and transplant settings in which modulation of Tregs could be beneficial for resolution of those disease states. Previously published work from our laboratory has shown that TCR signaling is critical for maintaining optimal Treg suppressive function and proliferation. In addition to TCR-mediated signals, our lab has shown that co-stimulation is also important in modulation of Treg expansion and persistence. While insight into the molecular cues that drive Treg biology has been slowly emerging, harnessing these cues to utilize Tregs as a potential therapy for the treatment of chronic inflammatory diseases still poses significant challenges. The expansion of polyclonal Tregs has been shown to ameliorate autoimmunity in mouse model, the suppression is not antigen- specific. Furthermore, it is technically challenging to selectively provide co-stimulatory signals only to Tregs and not to Tconvs. The main goal of this proposal is to utilize chimeric antigen receptors (CAR) to endow Treg with antigen specificity and enhance Treg function and expansion through the addition of co-stimulatory domains in the constructs. We will identify whether T cells transduced with CD19- CAR in conjunction with Foxp3 (CART19-Foxp3) will suppress antigen-specific conventional T cell (Tconv) proliferation in a B cell-dependent manner without CD19-specific killing of B cells by CART19-Foxp3 cells. Additionally, we will determine how the presence of co-stimulatory domains in the CAR construct influences CART19-Foxp3 function, persistence, and expansion. Furthermore, we will determine whether CART19-Foxp3 cells can, in turn, suppress B cell responses, such as antibody production, in vivo by modulation of conventional T cell activation. Further application of the studies in this aim will be extended to identifying the potential therapeutic use of CART-Foxp3 cells in treating chronic inflammation seen in a lupus-like model of chronic graft versus host (GVHD) that is dependent on autoantibody production by B cells. Through the proposed research plan, we will provide proof-of-principle that CAR- expressing Tregs suppress immune responses in an antigen-specific manner, which could be used as a novel therapeutic strategy for treatment of inflammatory conditions.

项目总结