Ariyan Charlotte, Salvalaggio Paolo, Fecteau Scott, Deng Songyan, Rogozinski Linda, Mandelbrot Didier, Sharpe Arlene, Sayegh Mohamed H, Basadonna Giacomo P, Rothstein David M
Department of Surgery, Yale Medical School, New Haven, CT 06520, USA.
J Immunol. 2003 Dec 1;171(11):5673-7. doi: 10.4049/jimmunol.171.11.5673.
Knockout and blocking studies have shown a critical role for CTLA-4 in peripheral tolerance, however, it is unknown whether augmenting CTLA-4 expression actually promotes tolerance. Here we demonstrate a specific and requisite role for CTLA-4 and its up-regulation in tolerance through anti-CD45RB. First, long-term murine islet allograft survival induced by anti-CD45RB is prevented by CTLA4-Ig, which interferes with B7:CTLA-4 interactions. Second, anti-CD45RB is ineffective in recipients lacking CTLA-4, B7-1, and B7-2. In contrast, CTLA4-Ig, which targets B7 on allogeneic cells, promotes long-term engraftment in these mice. Moreover, anti-CD45RB was effective in B7-deficient controls expressing CTLA-4. Finally, in wild-type mice, CTLA-4 expression returned to baseline 17 days after receiving anti-CD45RB, and was refractory to further increase. Transplantation and anti-CD45RB therapy at this time could neither augment CTLA-4 nor prolong engraftment. These data demonstrate a specific role for CTLA-4 in anti-CD45RB-mediated tolerance and indicate that CTLA-4 up-regulation can directly promote allograft survival.
基因敲除和阻断研究已表明CTLA-4在外周免疫耐受中起关键作用，然而，增强CTLA-4表达是否真的能促进免疫耐受尚不清楚。在此，我们证明了CTLA-4及其上调在通过抗CD45RB介导的免疫耐受中具有特定且必要的作用。首先，CTLA4-Ig可阻止抗CD45RB诱导的长期小鼠胰岛同种异体移植存活，CTLA4-Ig会干扰B7与CTLA-4的相互作用。其次，抗CD45RB在缺乏CTLA-4、B7-1和B7-2的受体中无效。相反，靶向同种异体细胞上B7的CTLA4-Ig可促进这些小鼠的长期植入。此外，抗CD45RB在表达CTLA-4的B7缺陷对照中有效。最后，在野生型小鼠中，接受抗CD45RB后17天，CTLA-4表达恢复到基线水平，且对进一步增加不再敏感。此时进行移植和抗CD45RB治疗既不能增加CTLA-4表达，也不能延长植入时间。这些数据证明了CTLA-4在抗CD45RB介导的免疫耐受中的特定作用，并表明CTLA-4上调可直接促进同种异体移植存活。
