Cameron M J, Arreaza G A, Delovitch T L
John P. Robarts Research Institute, University of Western Ontario, London, Canada.
Crit Rev Immunol. 1997;17(5-6):537-44.
T cells from NOD mice display an age-dependent, TCR-inducible proliferative hyporesponsiveness that may be causal to IDDM. Exogenous IL-4 completely restores this hyporesponsiveness in vitro and prevents IDDM in vivo when administered to NOD mice. We therefore tested the hypothesis that stimulation of a Th2 response by either IL-4 or CD28 costimulation may block progression to IDDM. Low-dose IL-4 treatment beginning at 2 weeks of age (pre-insulitis) protects NOD mice from insulitis, sialitis, and thyroiditis, indicating that IL-4 modulates T cell migration to these inflammatory sites. Cytokine secretion profiles of stimulated T cells and assays of intrapancreatic cytokine concentrations revealed that IL-4 treatment prevents IDDM by stabilizing a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Whereas treatment of NOD mice with an anti-CD28 mAb between 2 to 4 weeks of age inhibits destructive insulitis and protects against IDDM by enhancing IL-4 production by T cells, anti-CD28 treatment between 5 to 7 weeks of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the protective effect conferred by anti-CD28 treatment. Our data demonstrate that stimulation of a Th2-cell-enriched environment in the pancreas during the inductive phase of disease development blocks progression to IDDM in NOD mice.
非肥胖型糖尿病（NOD）小鼠的T细胞表现出一种年龄依赖性、T细胞受体（TCR）诱导的增殖低反应性，这可能是导致胰岛素依赖型糖尿病（IDDM）的原因。外源性白细胞介素-4（IL-4）在体外能完全恢复这种低反应性，并且在给予NOD小鼠时能在体内预防IDDM。因此，我们检验了这样一个假说，即通过IL-4或CD28共刺激来刺激Th2反应可能会阻断IDDM的进展。从2周龄（胰岛炎前期）开始的低剂量IL-4治疗可保护NOD小鼠免受胰岛炎、涎腺炎和甲状腺炎的侵害，这表明IL-4可调节T细胞向这些炎症部位的迁移。受刺激T细胞的细胞因子分泌谱以及胰腺内细胞因子浓度的测定结果显示，IL-4治疗通过在胸腺、脾脏和胰岛中稳定保护性的Th2介导环境来预防IDDM。在2至4周龄之间用抗CD28单克隆抗体（mAb）治疗NOD小鼠可抑制破坏性胰岛炎，并通过增强T细胞产生IL-4来预防IDDM，而在5至7周龄之间进行抗CD28治疗则不能预防IDDM。同时进行抗IL-4治疗可消除抗CD28治疗所赋予的保护作用。我们的数据表明，在疾病发展的诱导阶段，在胰腺中刺激富含Th2细胞的环境可阻断NOD小鼠IDDM的进展。
