Montgomery Sean P, Xu He, Tadaki Douglas K, Celniker Abbie, Burkly Linda C, Berning Justin D, Cruzata Francis, Elster Eric A, Gray Gary, Kampen Robert L, Swanson S John, Harlan David M, Kirk Allan D
The Department of Surgery, Walter Reed Army Medical Center, Washington, DC, USA.
Transplantation. 2002 Nov 27;74(10):1365-9. doi: 10.1097/00007890-200211270-00002.
Antibodies and fusion proteins specific for CD80, CD86, and CD154 have shown promise as agents capable of inducing donor-specific tolerance in rodents. These agents have also been shown to be synergistic with one another in many settings of counter-adaptive immunity. In the nonhuman primate, monoclonal antibodies specific for CD80 and CD86 have prolonged the time to rejection of renal allografts but have not resulted in tolerance. A monoclonal antibody specific for CD154 has resulted in markedly prolonged survival of kidney, islet, cardiac, and skin allografts, but again most animals have eventually developed rejection after prolonged periods of rejection-free survival off therapy.
A combination of monoclonal antibodies specific for CD80, CD86, and CD154 were used in a mismatched nonhuman primate renal-allograft model. Doses used were based on optimized treatment protocols for each agent individually.
Treatment of four rhesus macaques with this combination yielded a mean rejection-free survival of 565 days (311-911 days), significantly greater than untreated controls (mean survival=7.0 days, P=0.001) and animals treated with only a combination of anti-CD80 and CD86 (mean survival=191 days, P=0.01). The survival of animals treated with this combination of monoclonal antibodies was not significantly greater than those treated with anti-CD154 alone, but the production of alloantibody was delayed compared with monotherapy anti-CD154.
These data suggest that a synergy exists between these agents, particularly with regard to T-dependent B-cell responses, but that they fail to induce durable tolerance in nonhuman primates.
针对CD80、CD86和CD154的抗体及融合蛋白已显示出有望作为能够在啮齿动物中诱导供体特异性耐受的药物。这些药物在许多适应性免疫反应的情况下也已显示出彼此协同作用。在非人灵长类动物中，针对CD80和CD86的单克隆抗体延长了肾移植排斥反应的时间，但未导致耐受。针对CD154的单克隆抗体已使肾、胰岛、心脏和皮肤移植的存活时间显著延长，但同样，大多数动物在长时间无排斥存活后最终还是发生了排斥反应。
将针对CD80、CD86和CD154的单克隆抗体组合用于不匹配的非人灵长类动物肾移植模型。所使用的剂量基于每种药物单独的优化治疗方案。
用这种组合治疗4只恒河猴，平均无排斥存活时间为565天（311 - 911天），显著长于未治疗的对照组（平均存活时间 = 7.0天，P = 0.001）和仅用抗CD80和CD86组合治疗的动物（平均存活时间 = 191天，P = 0.01）。用这种单克隆抗体组合治疗的动物的存活时间并不显著长于单独用抗CD154治疗的动物，但与抗CD154单药治疗相比，同种抗体的产生延迟。
这些数据表明这些药物之间存在协同作用，特别是在T细胞依赖性B细胞反应方面，但它们未能在非人灵长类动物中诱导持久的耐受。
