NOD B Cells in Determinant Spreading of T Cell Immunity

描述（由申请人提供）：我们之前的研究以及其他研究发现，NOD小鼠对GAD及其肽决定簇产生自发性脾Th 1细胞应答，然后在T1 DM过程中分子内和分子间扩散至其他β细胞自身抗原。用单一β细胞抗原处理年轻NOD小鼠引发Th 2应答，并且诱导的Th 2应答扩散到其他无关的β细胞抗原，这与疾病进展的抑制有关。然而，很少有人知道抗原呈递细胞（APC）在NOD小鼠T细胞自身免疫的决定簇传播的作用。B细胞可能是介导T细胞自身免疫的决定簇扩散的良好候选者，因为B细胞可以通过其抗原受体捕获抗原来浓缩抗原，有效地加工抗原并将抗原呈递给T细胞。最近的研究表明，IG mu-/- NOD小鼠不会发生糖尿病，仅显示轻微的胰岛炎。此外，我们的初步研究已经表明，接受从年轻NOD小鼠分离的幼稚T和B细胞的NOD/scid小鼠（TB NOD/scid小鼠），而不是接受单独的幼稚T细胞的NOD/scid小鼠（T NOD/scid小鼠），发展自发的T细胞自身免疫应答和T1 DM。用同基因骨髓细胞和分离自年轻NOD小鼠的成熟B细胞重建的IG mu-/- NOD小鼠（IG mu-/- BMB NOD小鼠），而不是用单独的骨髓细胞重建的细胞（IG mu-/- BM NOD小鼠），表现出对β细胞抗原的自发T细胞应答并变得糖尿病。我们假设B细胞是T1 DM自然过程中和基于抗原的免疫治疗后T细胞自身免疫对β细胞抗原决定簇扩散的必要组成部分。 在本研究中，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，研究B细胞在T1 DM自发发展过程中以及基于抗原的免疫治疗后，在Th 1和Th 2免疫决定簇扩散中的作用。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IDDM的新型免疫疗法提供基础。

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.