Immunomodulation for Heart Allograft Tolerance

描述(由申请人提供)： 慢性排斥反应是心脏移植物长期存活和功能的主要障碍，无论是在临床上还是在我们的食蟹猴非人类灵长类动物模型中都是如此。这一应用将检验一种假设，即CD28/B7、CD40/CD154和ICOS共刺激通路驱动的致病机制介导CAV，并构成诱导同种异体心脏移植耐受的主要屏障。这一假设得到了我们在这一奖励机制第一任期内的发现的有力支持。当结合钙调神经磷酸酶抑制剂(CNI：环孢素A)或CD154阻断剂时，CD28在移植后三周选择性靶向显著抑制移植后90天的同种异体抗体生成和CAV。同样地，预先用αCD154或CNICD154去除B细胞可显著抑制致病同种免疫。 此应用程序将扩展这些观察，并评估αCD28/B7-和 到目前为止，基于CD40/CD40L的α共刺激通路阻断方案在我们的工作中似乎是最有希望的，它将在停止治疗一年后持续诱导同种异体心脏移植耐受。 具体地说，我们最有希望的方案(抗CD28和其他 CD_(40)/CD_(154)阻断；α_(CD_(28))诱导延迟戒断)将被建立。此外，我们还将对先发制人B细胞耗竭和CD40阻断或耗竭的选择性αCD28替代αCD154的耐受潜力进行系统的评估。我们预测，更有效地控制致病共刺激通路的激活将防止治疗结束后同种异体抗体的产生和CAV的进展，并防止对心脏特异性自身抗原--心肌肌球蛋白失去无反应性。如果是这样的话，我们预测，通过对一组疫苗抗原的反应来衡量，在其他免疫能力强的猴子身上也会观察到移植物的接受性和手术耐受性。 通过测量同种异体免疫和对自身抗原的耐受性丧失是如何被这些候选耐受诱导方案调节的，我们将确定抵抗基于共刺激的耐受诱导的途径，并评估移植物损伤或接受的生物学和分子相关性。

DESCRIPTION (provided by applicant): Chronic rejection is the principal obstacle to long-term survival and function of heart allografts, both clinically and in our cynomolgus monkey non-human primate model. This application will test the hypothesis that pathogenic mechanisms driven by the CD28/B7, CD40/CD154, and ICOS costimulation pathways mediate CAV, and constitute the principal barrier to tolerance induction for a heart allograft. This hypothesis is strongly supported by our findings during the first term of this award mechanism. When combined with either a calcineurin inhibitor (CNI: cyclosporine A) or CD154 blockade, selective targeting of CD28 for three weeks after transplant significantly inhibited alloantibody elaboration and CAV at 90 days after transplant. Similarly, pre-emptive B-cell depletion with αCD154 or CNI significantly inhibited pathogenic alloimmunity. This application will extend these observations and evaluate whether the αCD28/B7- and αCD40/CD40L-based costimulation pathway blocking regimens that appear most promising in our work to date will consistently induce tolerance to a cardiac allograft one year after cessation of treatment. Specifically, the durability and failure mode of our most promising regimens (anti-CD28 with additional CD40/CD154 blockade; αCD28 induction with delayed CNI withdrawal) will be established. In addition, selective αCD28 with preemptive B-cell depletion and CD40 blockade or depletion to replace αCD154 will be systematically evaluated for their tolerogenic potential. We predict that more effective control of pathogenic costimulation pathway activation will prevent alloantibody elaboration and CAV progression after treatment ends, and prevent loss of unresponsiveness to cardiac myosin, a heart-specific autoantigen. If so, we predict that graft acceptance and operational tolerance will also be observed in otherwise immunocompetent monkeys, as gauged by their responses to a panel of vaccine antigens. By measuring how alloimmunity and loss of tolerance to autoantigens are modulated by these candidate tolerance-inducing regimens, we will identify pathways resistant to costimulation-based tolerance induction and assess the biological and molecular correlates of graft injury or acceptance.