Meyers C M, Kelly C J
Renal-Electrolyte Division, University of Pennsylvania School of Medicine, Philadelphia 19104.
J Clin Invest. 1994 Nov;94(5):2093-104. doi: 10.1172/JCI117564.
We have used a murine model of organ-specific autoimmunity to characterize therapeutic modalities capable of down-regulating the cellular limb of the autoimmune response. Murine interstitial nephritis is an autoimmune disease mediated by tubular antigen-specific CD8+ nephritogenic effector T cells which are delayed-type hypersensitivity (DTH) reactive and cytotoxic to renal epithelial cells. Previous studies have demonstrated that disease can be suppressed with experimentally induced populations of T cells (Ts1 and Ts2 cells) obtained after injection of tubular antigen-coupled splenocytes into syngeneic mice. As the target of Ts2 is the CD8+ effector T cell, we have evaluated its effects on nephritogenic effector T cell clones isolated from diseased animals. Our studies demonstrate that soluble proteins expressed by Ts2 cells (TsF2) specifically abrogate the DTH, cytotoxic, and nephritogenic potential of M52 cells, although T cell receptor and IL-2 receptor expression are unchanged in these unresponsive M52 clones. TsF2-induced inhibition is dependent on new mRNA and protein synthesis. In a cytotoxic clone, M52.26, exposure to TsF2 induces expression of TGF-beta 1 which is, in turn, required for inhibition of cytotoxicity and nephritogenicity. Our studies are consistent with TGF-beta 1 behaving, at least in some T cells, as a nonspecific final effector of clone-specific suppression.
我们利用器官特异性自身免疫的小鼠模型来表征能够下调自身免疫反应细胞分支的治疗方式。小鼠间质性肾炎是一种由肾小管抗原特异性CD8 +致肾炎效应T细胞介导的自身免疫性疾病，这些细胞具有迟发型超敏反应（DTH）活性，对肾上皮细胞具有细胞毒性。先前的研究表明，将肾小管抗原偶联的脾细胞注射到同基因小鼠中后获得的实验诱导T细胞群体（Ts1和Ts2细胞）可以抑制疾病。由于Ts2的靶标是CD8 +效应T细胞，我们评估了其对从患病动物中分离出的致肾炎效应T细胞克隆的影响。我们的研究表明，Ts2细胞表达的可溶性蛋白（TsF2）特异性消除了M52细胞的DTH、细胞毒性和致肾炎潜力，尽管这些无反应的M52克隆中的T细胞受体和IL-2受体表达没有变化。TsF2诱导的抑制作用依赖于新的mRNA和蛋白质合成。在细胞毒性克隆M52.26中，暴露于TsF2会诱导TGF-β1的表达，而TGF-β1又是抑制细胞毒性和致肾炎性所必需的。我们的研究结果与TGF-β1至少在某些T细胞中作为克隆特异性抑制的非特异性最终效应物的作用一致。
