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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

基本信息

批准号：
6733555
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
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-15 至 2006-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6733555
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

项目摘要

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）：我们之前的研究以及其他人的研究发现，NOD 小鼠对 GAD 及其肽决定簇产生自发的脾 Th1 细胞反应，然后在 T1DM 过程中在分子内和分子间传播到其他 β 细胞自身抗原。用单一 β 细胞抗原治疗年轻的 NOD 小鼠会引发 Th2 反应，并且诱导的 Th2 反应会扩散到其他不相关的 β 细胞抗原，这与抑制疾病进展有关。然而，人们对抗原呈递细胞 (APC) 在 NOD 小鼠 T 细胞自身免疫的决定性传播中的作用知之甚少。 B 细胞可能是介导 T 细胞自身免疫决定簇传播的良好候选者，因为 B 细胞可以通过其抗原受体捕获抗原来浓缩抗原，有效地处理抗原并将其呈递给 T 细胞。最近的研究表明，Ig mu-/- NOD 小鼠不会患上糖尿病，仅表现出轻微的胰岛炎。此外，我们的初步研究表明，接受从年轻NOD小鼠（TB NOD/scid小鼠）中分离出的初始T细胞和B细胞的NOD/scid小鼠，而不是仅接受初始T细胞（T NOD/scid小鼠）的NOD/scid小鼠，会产生自发的T细胞自身免疫反应和T1DM。 Ig mu-/- NOD 小鼠用同基因骨髓细胞和从年轻 NOD 小鼠分离的成熟 B 细胞（Ig mu-/- BMB NOD 小鼠）重建，但不使用单独的骨髓细胞（Ig mu-/- BM NOD 小鼠），显示出对 β 细胞抗原的自发 T 细胞反应并成为糖尿病。我们假设，在 T1DM 的自然过程中以及基于抗原的免疫治疗后，B 细胞是 T 细胞自身免疫对 β 细胞抗原的决定性传播的必要组成部分。在本提案中，我们将在 TB NOD/scid 和 T NOD/scid 小鼠以及 Ig mu-/- BMB NOD 和 Ig mu-/- BM NOD 小鼠中检查 T1DM 自发发展期间以及基于抗原的免疫治疗后，B 细胞在 Th1 和 Th2 免疫的决定性传播中的作用。这些研究将解决有关 B 细胞在 T 细胞自身免疫中的作用的基本问题，并可能为开发用于干预人类 IDDM 的新型免疫疗法提供基础。