A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.
A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.
复制标题
一种新型 CD154 单克隆抗体，用于治疗急性和慢性大鼠血管化心脏同种异体移植排斥反应。
DOI：
10.1097/00007890-200206150-00008
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发表时间：
2002
期刊：
影响因子：
6.2
通讯作者：
Chandraker,Anil
中科院分区：
文献类型：
--
作者：
Yuan,Xueli;Dong,VictorM;Coito,AnaJ;Waaga,Ana-Maria;Salama,AlanD;Benjamin,ChristopherD;Sayegh,MohamedH;Chandraker,Anil
背景：CD40-CD154的相互作用在细胞免疫反应中起着至关重要的作用。阻断这一共刺激途径已被证明可以在小鼠和非人类灵长类动物模型中防止急性同种异体移植排斥反应。然而，CD40-CD154通路在慢性排斥反应发生发展中的作用以及CD154靶向对慢性排斥反应进展的影响还没有被评估。F5是一种新的仓鼠抗大鼠CD154的单抗，在完全同种异体急性转化为Lewis[LEW](RT11)和慢性[WF]。1L(Rt1 L)入Lew(Rt1 L)]血管化同种异体心脏移植排斥反应模型。在慢性模型中，对抗体的预防(移植开始日)和阻止进展(移植后第30天或60天开始)进行了评估。结果：在急性排斥模型中，仅抗CD154治疗可预防急性同种异体移植排斥反应，并导致50%的移植物长期存活(>；200天)和供者特异性耐受。在接受抗CD154单抗联合短程环孢素治疗的受者中，同种异体移植物100%长期存活，所有受者均达到供者特异性耐受。在慢性排斥模型中，在预防组和30天阻断组中，使用抗CD154抗体处理的动物同种异体移植物的移植物动脉硬化和纤维化评分均显著低于对照同种异体移植物。结论：新型抗CD154抗体不仅能预防移植肾急性排斥反应，而且能抑制和阻断慢性排斥反应的发生。在急性排斥模型中，环孢素与抗CD154治疗具有协同作用，可延长同种异体移植物存活时间并诱导耐受。在慢性排斥模型中，相对较早的治疗对于防止慢性同种异体移植血管病变和纤维化的进展至关重要。
Background.The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated.Methods.We examined the effect of AH. F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute u) into Lewis [LEW](RT1 1) and chronic [WF. 1L (RT1 l) into LEW (RT1 l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated.Results.In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (> 200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation.Conclusion.A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.