Cameron M J, Arreaza G A, Zucker P, Chensue S W, Strieter R M, Chakrabarti S, Delovitch T L
The John P. Robarts Research Institute, University of Western Ontario, London, Canada.
J Immunol. 1997 Nov 15;159(10):4686-92.
Beginning at the time of insulitis, nonobese diabetic (NOD) mice demonstrate a thymocyte and peripheral T cell proliferative hyporesponsiveness induced by TCR cross-linking, which is associated with reduced IL-2 and IL-4 secretion. We previously reported that NOD CD4+ T cell hyporesponsiveness is reversed completely in vitro by exogenous IL-4, and that administration of IL-4 to NOD mice prevents the onset of insulin-dependent diabetes mellitus (IDDM). This result suggested that T cell-mediated destruction of pancreatic islet beta cells may result from a hyporesponsiveness in regulatory Th2 cells favoring a Th1 cell-mediated environment in the pancreas. In the present study, we tested this possibility by analysis of the mechanisms of protection from IDDM afforded by IL-4 treatment in NOD mice. We show that IL-4 protects NOD mice from insulitis and IDDM when administered i.p. three times a week for 10 wk beginning at 2 wk of age. This occurs by the modulation of the homing of autoreactive cells to inflammatory sites and the stabilization of a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Thus, IL-4 treatment favors the expansion of regulatory CD4+ Th2 cells in vivo and prevents the onset of insulitis and IDDM mediated by autoreactive Th1 cells.
从胰岛炎发生时起，非肥胖型糖尿病（NOD）小鼠表现出由TCR交联诱导的胸腺细胞和外周T细胞增殖反应低下，这与IL-2和IL-4分泌减少有关。我们先前报道，外源性IL-4可在体外完全逆转NOD CD4 + T细胞反应低下，并且给NOD小鼠注射IL-4可预防胰岛素依赖型糖尿病（IDDM）的发生。这一结果表明，胰岛β细胞的T细胞介导的破坏可能是由于调节性Th2细胞反应低下，有利于胰腺中Th1细胞介导的环境。在本研究中，我们通过分析IL-4治疗对NOD小鼠IDDM的保护机制来验证这一可能性。我们发现，从2周龄开始，每周腹腔注射3次IL-4，持续10周，可保护NOD小鼠免受胰岛炎和IDDM的侵害。这是通过调节自身反应性细胞向炎症部位的归巢以及在胸腺、脾脏和胰岛中稳定保护性Th2介导的环境来实现的。因此，IL-4治疗有利于体内调节性CD4 + Th2细胞的扩增，并防止自身反应性Th1细胞介导的胰岛炎和IDDM的发生。
