CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice.
CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice.
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DOI：
10.4049/jimmunol.159.9.4620
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发表时间：
1997-11
影响因子：
4.4
通讯作者：
B. Balasa;T. Krahl;G. Patstone;Jae Lee;R. Tisch;H. O. Mcdevitt;Nora Sarvetnick
中科院分区：
文献类型：
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作者：
B. Balasa;T. Krahl;G. Patstone;Jae Lee;R. Tisch;H. O. Mcdevitt;Nora Sarvetnick
非肥胖糖尿病(NOD)小鼠自发发展为T细胞依赖型自身免疫性糖尿病。在这里，我们研究CD40配体(CD40L)-CD40共刺激在疾病的发生和发展中的作用。抗CD40L单抗治疗3到4周的NOD女性(典型的胰岛素炎开始的年龄)完全预防了胰岛素炎和糖尿病。相比之下，在9周龄时用抗CD40L抗体治疗这些小鼠并没有抑制疾病的进程。这些结果表明，CD40L的共刺激信号是早期所需的，但不是在疾病发展的效应阶段。抗CD40L处理影响体内胰岛抗原特异性T细胞反应的启动。细胞因子分析显示，抗CD40L处理的小鼠T细胞的干扰素-γ和IL-2的释放显著减少，而IL-4的产生却没有随之增加。因此，抗CD40L在体内损害了胰岛抗原特异的Th1细胞反应，并且抗CD40L预防糖尿病与将反应从Th1切换到Th2无关。将抗CD40L抗体处理的小鼠的脾细胞与糖尿病NOD小鼠的脾细胞共转移到NOD/SCID小鼠体内并不能抑制疾病的转移，表明抗CD40L抗体不能通过诱导调节细胞来预防疾病的发生。由于抗CD40L抗体通过抑制病理性Th1细胞向朗格汉斯胰岛的发展和进一步积聚而明显地预防了胰腺炎，我们得出结论，CD40L-CD40共刺激是自发性自身免疫性糖尿病发生发展的早期事件所必需的。
The nonobese diabetic (NOD) mouse spontaneously develops T cell-dependent autoimmune diabetes. Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this disease. Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the age at which insulitis typically begins) completely prevented the insulitis and diabetes. In contrast, treatment of such mice with anti-CD40L at >9 wk of age did not inhibit the disease process. These results suggest that a costimulatory signal by CD40L is required early but not in the effector phase of disease development. Anti-CD40L treatment affected the priming of islet Ag-specific T cell responses in vivo. Cytokine analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from anti-CD40L-treated mice. Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40L was not associated with switching of the response from a Th1 to a Th2 profile. Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly prevented the insulitis by inhibiting the development and further accumulation of pathogenic Th1 cells to islets of Langerhans, we conclude that CD40L-CD40 costimulation is required for early events in the development of spontaneous autoimmune diabetes.