NOD B Cells in Determinant Spreading of T Cell Immunity

描述(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及其多肽决定簇产生自发的脾Th1细胞反应，然后在T1 DM过程中通过分子内和分子间扩散到其他β细胞自身抗原。用单一的β细胞抗原启动Th2应答和诱导的Th2应答扩散到其他无关的贝塔细胞抗原治疗NOD幼鼠，这与抑制疾病进展有关。然而，抗原提呈细胞(APC)在NOD小鼠T细胞自身免疫决定簇扩散中的作用尚不清楚。B细胞可以通过其抗原受体捕获抗原而浓缩抗原，有效地处理抗原并将抗原呈递给T细胞，因此B细胞很可能是介导T细胞自身免疫决定簇扩散的良好候选细胞。最近的研究表明，IGMU/NOD小鼠不会发展成糖尿病，并且只表现出轻微的胰岛炎症。此外，我们的初步研究表明，接受NOD小鼠幼年T细胞和B细胞的NOD/SCID小鼠(TB NOD/SCID小鼠)，而不是仅接受NOD/SCID小鼠原始T细胞的NOD/SCID小鼠(T NOD/SCID小鼠)，可以产生自发的T细胞自身免疫反应和T1 DM。用同基因骨髓细胞和从幼年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)，但不使用单独的骨髓细胞(Ig MU-/-BM NOD小鼠)，表现出对β细胞抗原的自发T细胞应答，并成为糖尿病。我们推测，在T1 DM的自然过程中以及随后的基于抗原的免疫治疗中，B细胞是T细胞自身免疫向β细胞抗原决定性扩散的必要组成部分。 在这项建议中，我们将研究B细胞在T1 DM自发发展过程中以及在基于抗原的免疫治疗后在TB NOD/SCID和T NOD/SCID小鼠以及Ig Mu-/-BMB NOD和Ig Mu-/-BM NOD小鼠中在Th1和Th2免疫决定性扩散中的作用。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，并可能为开发干预人类IDDM的新的免疫疗法提供基础。

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.