Judge T A, Tang A, Spain L M, Deans-Gratiot J, Sayegh M H, Turka L A
Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
J Immunol. 1996 Mar 15;156(6):2294-9.
A single dose of CTLA4Ig, an inhibitor of CD28-mediated T cell costimulation, given 2 days after transplantation induces specific unresponsiveness to alloantigens in vivo. However, the mechanisms responsible are unknown. Using pigeon cytochrome c as a model Ag, we monitored the effect of CTLA4Ig on the fate of Ag-reactive T cells in normal mice and on pigeon cytochrome c-specific TCR transgenic cells adoptively transferred into congenic mice. CTLA4Ig significantly inhibits immunization with pigeon cytochrome c. In particular, ELISA and ELISPOT assays indicate an 80 to 90% reduction in Th1 (i.e, IL-2 and IFN-gamma) cytokine production and in the numbers of cytokine-producing cells. Interestingly, despite this profound reduction in cytokine-producing cells, Ag-reactive T cells expand in CTLA4Ig-treated animals, although the degree of expansion is reduced by 50% compared with that in control Ig-treated animals. Thus, loss of Th1 cytokine production in CTLA4Ig-treated animals is not fully explained by the decreased expansion of Ag-specific T cells. These results suggest two mechanisms of action for CTLA4Ig in vivo: inhibition of expansion of Ag-reactive cells and induction of anergy in the residual population.
移植后2天给予单剂量CTLA4Ig（一种CD28介导的T细胞共刺激抑制剂）可在体内诱导对同种异体抗原的特异性无反应性。然而，其作用机制尚不清楚。我们以鸽细胞色素c作为模型抗原，监测了CTLA4Ig对正常小鼠体内抗原反应性T细胞命运的影响，以及对过继转移到同基因小鼠体内的鸽细胞色素c特异性TCR转基因细胞的影响。CTLA4Ig显著抑制鸽细胞色素c免疫反应。特别是，ELISA和ELISPOT分析表明，Th1（即IL-2和IFN-γ）细胞因子产生以及产生细胞因子的细胞数量减少了80%至90%。有趣的是，尽管产生细胞因子的细胞数量大幅减少，但在接受CTLA4Ig治疗的动物中，抗原反应性T细胞仍会扩增，不过与接受对照Ig治疗的动物相比，扩增程度降低了50%。因此，在接受CTLA4Ig治疗的动物中，Th1细胞因子产生的减少不能完全由抗原特异性T细胞扩增的减少来解释。这些结果提示CTLA4Ig在体内有两种作用机制：抑制抗原反应性细胞的扩增以及诱导剩余群体的无反应性。
