In vivo BLyS/BAFF neutralization ameliorates islet-directed autoimmunity in nonobese diabetic mice.
In vivo BLyS/BAFF neutralization ameliorates islet-directed autoimmunity in nonobese diabetic mice.
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DOI：
10.4049/jimmunol.181.11.8133
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Noorchashm H
中科院分区：
文献类型：
--
作者：
Zekavat G;Rostami SY;Badkerhanian A;Parsons RF;Koeberlein B;Yu M;Ward CD;Migone TS;Yu L;Eisenbarth GS;Cancro MP;Naji A;Noorchashm H
NOD小鼠自身免疫性糖尿病的发病机制需要b淋巴细胞。先前的研究证实，淋巴减少移行性（TR） b细胞区室减少了新出现的TR b细胞进入脾滤泡（FO）的竞争约束，从而破坏了NOD小鼠的外周阴性选择检查点。因此，开发临床可行的免疫治疗方法来恢复适当的阴性选择对于预防抗胰岛自身免疫至关重要。在这里，我们假设B淋巴细胞刺激剂（BLyS/BAFF）的体内中和可能通过增加TR B细胞进入NOD小鼠滤泡的竞争来增强TR→FO选择的严格性。该研究表明，体内BLyS中和治疗可导致滤泡和边缘区（MZ） b淋巴细胞的耗竭。长期体内BLyS中和导致外周TR:FO b细胞比例增加，表明对卵泡进入具有相对抗性。此外，在体内BLyS中和：1)恢复TR→FO检查点的阴性选择，2)消除血清胰岛素自身抗体（IAA）， 3)降低胰岛炎症的严重程度，4)显著降低自发性糖尿病的发生率，5)阻止胰岛细胞破坏的终末期，6)破坏CD4 t细胞的激活。总的来说，本研究证明了b淋巴细胞定向治疗通过体内BLyS中和预防自身免疫性糖尿病的有效性。
B-lymphocytes are required for the pathogenesis of autoimmune diabetes in NOD mice. Previous studies established that a lymphopenic transitional (TR) B-cell compartment reduces the competitive constraint on the entry of newly emerging TR B-cells into the splenic follicle (FO), thereby disrupting a peripheral negative selection checkpoint in NOD mice. Thus, development of clinically feasible immunotherapeutic approaches for restoration of appropriate negative selection is essential for the prevention of anti-islet autoimmunity. Here we hypothesized that in vivo neutralization of the B lymphocyte stimulator (BLyS/BAFF) may enhance the stringency of TR→FO selection by increasing TR B-cell competition for follicular entry in NOD mice. This study demonstrated that in vivo BLyS neutralization therapy leads to the depletion of follicular and marginal zone (MZ) B-lymphocytes. Long-term in vivo BLyS neutralization caused an increased TR:FO B-cell ratio in the periphery indicating a relative resistance to follicular entry. Moreover, in vivo BLyS neutralization: 1) restored negative selection at the TR→FO checkpoint, 2) abrogated serum insulin autoantibodies (IAA), 3) reduced the severity of islet inflammation, 4) significantly reduced the incidence of spontaneous diabetes, 5) arrested the terminal stages of islet cell destruction and 6) disrupted CD4 T-cell activation in NOD mice. Overall, this study demonstrates the efficacy of B-lymphocyte directed therapy via in vivo BLyS neutralization for the prevention of autoimmune diabetes.
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