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，用CD154或CNI抢先去除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？CD28/B7-和 到目前为止，基于CD40/CD40L的共刺激通路阻断方案在我们的工作中似乎是最有希望的，它们将在停止治疗一年后持续诱导对同种异体心脏移植物的耐受。 具体地说，我们最有希望的方案(抗CD28和其他 将建立CD40/CD154阻断；？CD28诱导并延迟CNI撤退)。此外，我们还将对选择性CD28和CD40阻断或去除来替代CD154的耐受潜能进行系统评估。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。 公共卫生相关性(由申请人提供)： 该项目将直接评估几种有希望的共刺激阻断策略，以诱导食蟹猴心脏移植受者的耐受性，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。还将确定预测急性或慢性排斥反应或与耐受性相关的生物标记物(免疫抑制停用后的移植物接受性)，并对其有效性进行评估。

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.