Kaneko H, Nakajima A, Azuma M
Department of Rheumatology and Internal Medicine, Juntendo University School of Medicine.
Nihon Rinsho. 1997 Jun;55(6):1531-6.
The past year has seen significant advances in our understanding of the role of costimulatory pathways in antigen-specific T cell activation and maintenance of self-tolerance. It has been suggested that the absence of costimulators on normal tissue cells could serve to induce self-tolerance and that inappropriate expression of costimulators on antigen-presenting cells (APC) could activate self-reactive T cells, resulting in autoimmunity. CD28 on T cells and CD80 and CD86 on APC are key molecules in the maintenance and breakdown of anergy. CTLA-4Ig fusion protein, that binds to both CD80 and CD86 with high affinity and thereby prevents interaction of CD80/CD86 with CD28/CTLA-4, prevents or ameliorates several autoimmune disease in experimental animal models, supporting an importance of this pathway in the development of autoimmune diseases. However, the studies using specific monoclonal antibodies against CD80 and CD86 have shown different outcomes in individual autoimmune models. This suggests that the actual regulatory mechanisms of this pathway in autoimmunity is much more complex, because of the existence of two receptors (CD28 and CTLA-4) and two ligands (CD80 and CD86) and the opposite function of CD28 and CTLA-4 in T cell activation. Further investigation on physiological function of this pathway in vivo may help for developing rational therapeutic approaches manipulating this pathway.
在过去的一年里，我们对于共刺激通路在抗原特异性T细胞活化及自身耐受维持中所起作用的理解取得了重大进展。有人提出，正常组织细胞上缺乏共刺激分子可能有助于诱导自身耐受，而抗原呈递细胞（APC）上不适当表达共刺激分子可能会激活自身反应性T细胞，从而导致自身免疫。T细胞上的CD28以及APC上的CD80和CD86是无反应性维持与破坏的关键分子。CTLA-4Ig融合蛋白能与CD80和CD86高亲和力结合，从而阻止CD80/CD86与CD28/CTLA-4相互作用，在实验动物模型中可预防或改善多种自身免疫性疾病，这支持了该通路在自身免疫性疾病发生中的重要性。然而，使用针对CD80和CD86的特异性单克隆抗体进行的研究在各个自身免疫模型中显示出不同结果。这表明该通路在自身免疫中的实际调控机制要复杂得多，因为存在两种受体（CD28和CTLA-4）和两种配体（CD80和CD86），且CD28和CTLA-4在T细胞活化中具有相反功能。进一步研究该通路在体内的生理功能可能有助于开发合理的治疗方法来调控此通路。
