Woodward J E, Bayer A L, Chavin K D, Blue M L, Baliga P
Department of Surgery, Medical University of South Carolina, Charleston 29425, USA.
Transplantation. 1998 Jul 15;66(1):14-20. doi: 10.1097/00007890-199807150-00003.
T-cell activation requires engagement of the T cell receptor with the antigen-MHC and simultaneous ligation of the coreceptor CD28. CD28 binds both the CD80 (B7-1) and CD86 (B7-2) ligands on antigen-presenting cells. The functional role of these costimulatory pathways in transplantation is not completely understood. We tested the hypothesis that in vivo blockade of the CD28 pathway via the anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) would prolong allograft survival.
Neonatal C57BL/6J (H2b) hearts were transplanted to CBA/J (H2k) recipients in a heterotopic nonvascularized model, with anti-CD80 and/or anti-CD86 mAbs being administered intravenously at the time of allografting (day 0) and on the following day (day 1).
Anti-CD80 mAb (29.8+/-1.5 days) and anti-CD86 mAb (30.8+/-0.5 days) alone significantly prolonged allograft survival compared with the isotype control (10.7+/-0.4 days, P < 0.01, Wilcoxon rank sum). The concurrent (days 0 and 1) and sequential administration of anti-CD86 mAb on days 0 and 1 plus anti-CD80 mAb on days 2 and 3 prolonged allograft survival to >80 days. Simultaneous administration of anti-CD80 and anti-CD86 mAbs significantly suppressed donor-specific cytotoxic T lymphocyte responses to alloantigen. Anti-CD86 mAb suppressed intragraft interleukin (IL)-4, IL-10, IL-12 p40, and IL-15 mRNA expression.
Anti-CD80 and/or anti-CD86 mAbs are potent immunosuppressants in prolonging allograft survival. Combined blockade of the B7 (CD80 and CD86) ligands seems to be the most effective in prolonging allograft survival and suppressing donor-specific allogeneic cytotoxic T lymphocyte responses. In vivo blockade of CD86, in comparison to CD80, had the greatest immunosuppressive effect on day 7 intragraft cytokines, suggesting its role on early allogeneic immune responses.
T细胞活化需要T细胞受体与抗原-MHC结合，同时共刺激分子CD28被激活。CD28可与抗原呈递细胞上的CD80（B7-1）和CD86（B7-2）配体结合。这些共刺激通路在移植中的功能作用尚未完全明确。我们验证了通过抗CD80和抗CD86单克隆抗体（mAb）在体内阻断CD28通路可延长同种异体移植物存活时间的假说。
在异位非血管化模型中，将新生C57BL/6J（H2b）小鼠心脏移植到CBA/J（H2k）受体小鼠体内，在移植时（第0天）和次日（第1天）静脉注射抗CD80和/或抗CD86 mAb。
与同型对照（10.7±0.4天，P<0.01，Wilcoxon秩和检验）相比，单独使用抗CD80 mAb（29.8±1.5天）和抗CD86 mAb（30.8±0.5天）可显著延长同种异体移植物存活时间。在第0天和第1天同时给予抗CD86 mAb，以及在第0天和第1天给予抗CD86 mAb、第2天和第3天给予抗CD80 mAb可使同种异体移植物存活时间延长至>80天。同时给予抗CD80和抗CD86 mAb可显著抑制供体特异性细胞毒性T淋巴细胞对同种异体抗原的反应。抗CD86 mAb可抑制移植物内白细胞介素（IL）-4、IL-10、IL-12 p40和IL-15 mRNA表达。
抗CD80和/或抗CD86 mAb是延长同种异体移植物存活时间的有效免疫抑制剂。联合阻断B7（CD80和CD86）配体似乎是延长同种异体移植物存活时间和抑制供体特异性同种异体细胞毒性T淋巴细胞反应最有效的方法。与CD80相比，在体内阻断CD86对第7天移植物内细胞因子具有最大的免疫抑制作用，提示其在早期同种异体免疫反应中的作用。
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