NOD B Cells in Determinant Spreading of T Cell Immunity

NODB 细胞在 T 细胞免疫的决定性传播中

• 批准号: 6597856
• 负责人: JIDE TIAN
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6597856
• 关键词: B lymphocyte; T lymphocyte; antigen presentation; autoantigens; autoimmunity; cell cell interaction; cellular pathology; disease /disorder model; enzyme linked immunosorbent assay; insulin dependent diabetes mellitus; laboratory mouse; pancreatic islets

DESCRIPTION (provided by applicant): Our previous studies, as well as those of others, have found that NOD mice develop spontaneous splenic Th1 cell responses to GAD and its peptide determinants, which then spread intra-molecularly and inter-molecularly to other beta-cell autoantigens during the process of T1DM. Treatment of young NOD mice with single beta-cell antigen primes Th2 responses and the induced Th2 responses spread to other unrelated beta cell antigens, which is associated with the inhibition of disease progression. However, little is known about the role of antigen presenting cells (APC) in the determinant spreading of T cell autoimmunity in NOD mice. B cells are likely to be good candidates for mediating determinant spreading of T cell autoimmunity as B cells can concentrate antigen by capturing antigen via its antigen receptor, efficiently process and present antigen to T cells. Recent studies have showed that Ig mu-/- NOD mice fail to develop diabetes, and showed only minor insulitis. In addition, our preliminary studies have showed that NOD/scid mice that received naive T and B cells isolated from young NOD mice (TB NOD/scid mice), but not NOD/scid mice that received naive T cell alone (T NOD/scid mice), develop spontaneous T cell autoimmune responses and T1DM. Ig mu-/- NOD mice reconstituted with syngeneic bone marrow cells and mature B cells isolated from young NOD mice (Ig mu-/- BMB NOD mice), but not with bone marrow cells alone cells (Ig mu-/- BM NOD mice), display spontaneous T cell responses to beta cell antigens and become diabetic. We hypothesize that B cells are a necessary component for determinant spreading of T cell autoimmunity to beta cell antigens during the natural process of T1DM and following antigen-based immunotherapy. In this proposal, we will examine the role of B cells in determinant spreading of Th1 and Th2 immunity during spontaneous development of T1DM and following antigen-based immunotherapy in the TB NOD/scid and T NOD/scid mice and in the Ig mu-/- BMB NOD and Ig mu-/- BM NOD mice. These studies will address fundamental questions concerning the role of B cells in T cell autoimmunity and may provide a basis to develop novel immunotherapies for the intervention of human IDDM.

描述（由申请人提供）：我们以前的研究以及其他研究发现，点头小鼠对GAD及其肽决定簇产生了自发的脾脏Th1细胞反应，然后在T1DM的过程中将其内部和全分子间和其他β-细胞自身抗原分散到其他β-细胞自身抗原。用单个β细胞抗原Primes Th2反应和诱导的Th2反应扩散到其他无关β细胞抗原的诱导TH2反应，对年轻小鼠进行治疗，这与疾病进展的抑制有关。然而，关于抗原呈递细胞（APC）在NOD小鼠中T细胞自身免疫性的决定因素扩散中的作用知之甚少。 B细胞可能是介导T细胞自身免疫性决定因素扩散的良好候选物，因为B细胞可以通过其抗原受体捕获抗原来浓缩抗原，从而有效地处理并将其抗原与T细胞进行抗原。最近的研究表明，Ig Mu - / - NOD小鼠无法患上糖尿病，仅显示少量胰岛炎。此外，我们的初步研究表明，从年轻的NOD小鼠（TB NOD/SCID小鼠）中分离出天真的T和B细胞的点头/SCID小鼠，而不是单独接受幼稚T细胞的NOD/SCID小鼠（TB nod/scID小鼠），会发展为自发的T细胞自发性T细胞自动免疫反应和T1DM。 Ig Mu - / - NOD小鼠与从幼体NOD小鼠（Ig Mu - / - BMB NOD小鼠）中分离出的同基因骨髓细胞和成熟的B细胞，但不会与单独的骨髓细胞细胞（Ig Mu - /-bm nod小鼠），表现为自发的T细胞Cell Celles Celles to beta Celles Antigemens和Bebectics抗原抗原和糖尿病。我们假设B细胞是在T1DM的自然过程中和基于抗原的免疫疗法之后，T细胞自身免疫到β细胞抗原的确定性扩散的必要组成部分。 在此提案中，我们将研究B细胞在T1DM自发发展过程中的Th1和Th2免疫确定性扩散以及基于抗原的免疫疗法在TB NOD/SCID和T NOD/SCID小鼠以及Ig Mu - /-BMB NOD和Ig-ig Mu - /-BM-BM nod小鼠中的作用。这些研究将解决有关B细胞在T细胞自身免疫性中的作用的基本问题，并可能为开发用于人IDDM干预的新型免疫疗法提供基础。