Myelin specific T and B cell differentiation during EAE

EAE 期间髓磷脂特异性 T 细胞和 B 细胞分化

• 批准号: 8718451
• 负责人: Ryan J Martinez
• 金额: $ 4.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718451
• 关键词: Adhesions; Affinity; Alleles; Animals; Antibodies; Antigen-Presenting Cells; Antigens; Applications Grants; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cell Communication; Cell Differentiation process; Cell physiology; Cells; Complex; Data; Demyelinating Diseases; Demyelinations; Development; Disease; Disease Progression; Engineering; Environment; Epitopes; Experimental Autoimmune Encephalomyelitis; Fellowship; Figs - dietary; Frequencies; Generations; Goals; Health; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Immune; Immune response; Immune system; Inflammatory; Kinetics; Length; MHC binding peptide; MS4A1 gene; Major Histocompatibility Complex; Measurement; Measures; Mediator of activation protein; Modeling; Multiple Sclerosis; Mus; Myelin; Pathogenesis; Patients; Peptide/MHC Complex; Peptides; Phenotype; Play; Population; Process; Proliferating; Proteins; Recombinants; Relative (related person); Research; Risk; Role; Severity of illness; Signal Transduction; Symptoms; T cell differentiation; T cell response; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Testing; Thymus Gland; Training; Transgenic Mice; Work; base; central tolerance; clinical effect; differentiated B cell; fluorophore; functional outcomes; mouse model; mouse myelin oligodendrocyte glycoprotein; novel; oligodendrocyte-myelin glycoprotein; prevent; receptor binding; research study; response; rituximab; therapy design; two-dimensional

DESCRIPTION (provided by applicant): T cells are strongly implicated in autoimmune diseases, as T cell immunomodulatory treatments are efficacious in reducing symptoms and there is an increased risk of developing autoimmunity by having certain alleles of the major histocompatibility complex (MHC), the antigen presenting protein for T cells. MHC alleles that increase the risk of autoimmune disease are hypothesized to poorly delete or inactivate self-reactive T cells during T cell development, allowing functional, self-reactive T cells to exist in he periphery. The process of T cell inactivation during development is called central tolerance and is a dominant mechanism in preventing autoimmunity. Currently, the functional consequences of T cell central tolerance are unknown in polyclonal mouse models of autoimmune demyelinating disease, but many groups argue that central tolerance changes the T cell populations T cell receptor (TCR) affinity for peptide-MHC (pMHC). The affinity of TCR:pMHC binding effects the proliferation and differentiation of the T cells, subsequently T cells that undergo central tolerance may differentiate differently than T cells that have not. In this grant proposal, I will investigate how the differentiation of polyclonal myelin-specific CD4 T cells is different with and without central tolerance and how CD4 T cell differentiation effects B cells contribution to a model of autoimmune demyelinating disease, experimental autoimmune encephalomyelitis (EAE). By using fluorophore tetramer enrichment and a novel micropipette adhesion frequency assay to measure the frequency and relative two-dimensional affinity (2D) of antigen-specific CD4 T cells during autoimmune demyelinating disease, we aim to demonstrate differences of T cell expansion, effector function and differentiation when central tolerance to myelin antigens is absent. In this proposal, I have outlined a strong training plan that together, with the completion of the research aims, prepares the fellowship applicant to attain the goal of becoming a research-oriented neuroimmunologist.

描述（由申请人提供）：T细胞与自身免疫性疾病密切相关，因为T细胞免疫调节治疗在减轻症状方面有效，并且由于具有主要组织相容性复合体（MHC）（T细胞的抗原呈递蛋白）的某些等位基因，发生自身免疫的风险增加。假设增加自身免疫性疾病风险的MHC等位基因在T细胞发育期间缺失或破坏自身反应性T细胞，从而允许功能性自身反应性T细胞存在于外周中。发育过程中T细胞失活的过程称为中枢耐受，是预防自身免疫的主要机制。目前，在自身免疫性脱髓鞘疾病的多克隆小鼠模型中，T细胞中枢耐受的功能后果尚不清楚，但许多研究小组认为，中枢耐受改变了T细胞群T细胞受体（TCR）对肽-MHC（pMHC）的亲和力。TCR：pMHC结合的亲和力影响T细胞的增殖和分化，随后经历中枢耐受的T细胞可以与未经历中枢耐受的T细胞不同地分化。在这项拨款申请中，我将研究多克隆髓鞘特异性CD 4 T细胞的分化与 没有中枢耐受以及CD 4 T细胞分化如何影响B细胞对自身免疫性脱髓鞘疾病、实验性自身免疫性脑脊髓炎（EAE）模型的贡献。通过使用荧光团四聚体富集和一种新的微管粘附频率测定，以测量频率和相对二维亲和力（2D）的抗原特异性CD 4 T细胞在自身免疫性脱髓鞘疾病，我们的目的是证明差异的T细胞扩增，效应器功能和分化时，中枢耐受髓鞘抗原是缺席。在这个建议中，我概述了一个强有力的培训计划， 研究目标的一部分，为奖学金申请人实现成为一名研究型神经免疫学家的目标做好准备。