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及其肽决定因素产生自发性脾Th1细胞反应，然后在T1DM过程中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NOD小鼠可引发Th2反应，并诱导Th2反应扩散到其他不相关的β细胞抗原，这与疾病进展的抑制有关。然而，对于NOD小鼠中抗原呈递细胞（APC）在T细胞自身免疫的决定性扩散中的作用知之甚少。B细胞可能是介导T细胞自身免疫决定性扩散的良好候选者，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，仅表现为轻微的胰岛素炎。此外，我们的初步研究表明，接受幼年NOD小鼠（TB NOD/scid小鼠）分离的幼稚T细胞和B细胞的NOD/scid小鼠（TB NOD/scid小鼠），而单独接受幼稚T细胞的NOD/scid小鼠（T NOD/scid小鼠），会发生自发性T细胞自身免疫反应和T1DM。用同基因的骨髓细胞和从年轻NOD小鼠（Ig mu-/- BMB NOD小鼠）分离的成熟B细胞重组的Ig mu-/- NOD小鼠（Ig mu-/- BMB NOD小鼠），而不是单独用骨髓细胞重组的细胞（Ig mu-/- BM NOD小鼠），对β细胞抗原表现出自发的T细胞反应，并发生糖尿病。我们假设，在T1DM的自然过程和抗原免疫治疗后，B细胞是T细胞自身免疫对β细胞抗原的决定性扩散的必要组成部分。

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.