Sho Masayuki, Sandner Sigrid E, Najafian Nader, Salama Alan D, Dong Victor, Yamada Akira, Kishimoto Koji, Harada Hiroshi, Schmitt Isabela, Sayegh Mohamed H
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Ann Surg. 2002 Nov;236(5):667-75. doi: 10.1097/00000658-200211000-00018.
To determine the precise in vivo interaction between T-cell costimulatory blockade and conventional immunosuppression in transplantation.
Blocking B7 or CD154 T-cell costimulatory activation pathways prevents allograft rejection in small and large animal transplant models and is considered a promising strategy for clinical organ transplantation.
A fully MHC-mismatched vascularized mouse cardiac allograft model was used to test the interactions between anti-CD154 or CTLA4Ig monotherapy and conventional immunosuppressive drugs in promoting long-term graft acceptance. The frequency of alloreactive T cell was measured by ELISPOT. Chronic rejection was examined by histology.
Cyclosporine, tacrolimus, and anti-IL-2R monoclonal antibody therapy abrogated the effect of a single-dose protocol of anti-CD154 therapy. In contrast, rapamycin acted synergistically with anti-CD154 therapy in promoting long-term allograft survival. The addition of calcineurin inhibitors did not abolish this synergistic effect. Intense CD154-CD40 blockade by a multiple-dose schedule of anti-CD154 resulted in long-term graft survival and profound alloreactive T-cell unresponsiveness and overcame the opposite effects of calcineurin inhibitors. CTLA4Ig induced long-term graft survival, and the effect was not affected by the concomitant use of any immunosuppressive drugs.
The widespread view that calcineurin inhibitors abrogate the effects of T-cell costimulatory blockade should be revisited. Sufficient costimulatory blockade and synergy induced by CD154 blockade and rapamycin promote allograft tolerance and prevent chronic rejection.
确定移植中T细胞共刺激阻断与传统免疫抑制之间精确的体内相互作用。
阻断B7或CD154 T细胞共刺激激活途径可防止大小动物移植模型中的同种异体移植排斥反应，被认为是临床器官移植的一种有前景的策略。
使用完全MHC不匹配的血管化小鼠心脏同种异体移植模型来测试抗CD154或CTLA4Ig单一疗法与传统免疫抑制药物在促进长期移植物接受方面的相互作用。通过ELISPOT测量同种异体反应性T细胞的频率。通过组织学检查慢性排斥反应。
环孢素、他克莫司和抗IL-2R单克隆抗体疗法消除了抗CD154疗法单剂量方案的效果。相比之下，雷帕霉素与抗CD154疗法在促进长期同种异体移植存活方面具有协同作用。添加钙调神经磷酸酶抑制剂并未消除这种协同作用。抗CD154多剂量方案强烈阻断CD154-CD40可导致长期移植物存活和深度同种异体反应性T细胞无反应性，并克服了钙调神经磷酸酶抑制剂的相反作用。CTLA4Ig诱导长期移植物存活，且该效果不受任何免疫抑制药物联合使用的影响。
应重新审视钙调神经磷酸酶抑制剂消除T细胞共刺激阻断作用的普遍观点。CD154阻断和雷帕霉素诱导的充分共刺激阻断和协同作用可促进同种异体移植耐受并预防慢性排斥反应。
