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，无论是临床还是在我们的食蟹猴非人灵长类动物模型中。本申请将检验由CD 28/B7、CD 40/CD 154和ICOS共刺激通路驱动的致病机制介导CAV并构成心脏同种异体移植物耐受诱导的主要障碍的假设。这一假设得到了我们在这一奖励机制第一个任期内的研究结果的有力支持。当与钙调磷酸酶抑制剂（CNI：环孢素A）或CD 154阻断剂结合时，移植后3周选择性靶向CD 28显著抑制同种抗体的产生和移植后90天的CAV。同样，先发制人的B细胞耗竭与？CD 154或CNI显著抑制致病性同种免疫。 本申请将扩大这些意见，并评估是否？CD 28/B7-和 ?基于CD 40/CD 40 L的共刺激通路阻断方案在我们的工作中最有前途，在停止治疗一年后，它将持续诱导对心脏同种异体移植物的耐受。 具体而言，我们最有希望的方案（抗CD 28与额外的 CD 40/CD 154阻断; CD 28诱导延迟CNI停药）。此外，选择性？CD 28与先发制人的B细胞耗竭和CD 40阻断或耗竭，以取代？将系统评价CD 154的致耐受性潜力。我们预测，更有效地控制致病性共刺激通路的激活将防止同种抗体的制定和治疗结束后CAV的进展，并防止心脏肌球蛋白，心脏特异性自身抗原的无反应性的损失。如果是这样的话，我们预测，移植物的接受和操作的耐受性也将观察到在其他免疫功能正常的猴子，作为衡量他们的反应，一组疫苗抗原。 通过测量这些候选耐受诱导方案如何调节同种异体免疫和对自身抗原的耐受性丧失，我们将确定对基于共刺激的耐受诱导具有抗性的途径，并评估移植物损伤或接受的生物学和分子相关性。 公共卫生相关性（由申请人提供）： 该项目将直接评估几种有前途的共刺激阻断策略，以诱导食蟹猴心脏同种异体移植受体的耐受性，并将提高我们对与这些方案相关的移植物接受或损伤机制的理解。还将鉴定预测急性或慢性排斥反应或与耐受性（免疫抑制剂撤药后的移植物接受）相关的生物标志物，并评估其效用。

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 ?CD154 or CNI significantly inhibited pathogenic alloimmunity. This application will extend these observations and evaluate whether the ?CD28/B7- and ?CD40/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; ?CD28 induction with delayed CNI withdrawal) will be established. In addition, selective ?CD28 with preemptive B-cell depletion and CD40 blockade or depletion to replace ?CD154 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. PUBLIC HEALTH RELEVANCE (provided by applicant): This Project will directly evaluate several promising costimulation blockade strategies to induce tolerance in cynomolgus monkey heart allograft recipients, and will improve our understanding of mechanisms of graft acceptance or injury that are associated with these regimens. Biomarkers predictive of acute or chronic rejection or associated with tolerance (graft acceptance after withdrawal of immunosuppression) will also be identified and their utility assessed.