Costimulation Blockade-Based Strategies for Tolerance Induction

共刺激阻断代表了一种新的免疫抑制，伴随着更特定的靶点 毒性较小。Belatacept是FDA批准的第一种用于肾脏的共刺激阻滞剂 移植受者。尽管肾功能优越，心血管风险状况有所改善，但显著 更好的患者和移植物存活7年，高排斥率以及其他后勤挑战 限制了其临床应用的广度。我们现在拥有世界上最大的使用belatacept的体验 肾移植受者，近1000名患者。我们在肾功能方面也观察到了类似的益处， 但我们在临床范围外使用它时观察到的高排斥率让他们感到惊讶 审判，几乎是之前报道的两倍。有趣的是，大约有一半的患者 经历了排斥，而另一半没有，这引发了一个问题，为什么有些患者会 对共刺激阻断疗法敏感，而对其他人耐受。我们早期对小鼠和非小鼠的研究 人类灵长类动物(NHP)认为共刺激作用、阻断抵抗排斥反应是 他强调了制定一项成功的容忍战略的潜在好处。其中一个 在实验模型中提高耐受性的最有效方法是瞬时干扰 供体抗原导入过程中的CD28和CD40通路。我们已经评估了下一代 共刺激阻断试剂(针对CD28和CD154的区域抗体)，并表明它们都是 安全有效。尽管取得了这些进展，但仍有一部分动物和患者在服药期间拒绝 心理治疗。在比较这些排斥受体和稳定受体的过程中，我们发现了一种记忆T细胞生物标记物 在NHP和人类中，都与协同刺激作用阻滞性排斥反应风险增加有关。我们假设 使用这种预测性生物标记物可能会让我们确定协同刺激-阻断-的最佳候选者- 基于耐受诱导疗法，并建议纵向评估这种疗法的稳定性和可塑性 生物标志物，并在接受双重共刺激的动物中以前瞻性的方式测试其预测能力 封锁疗法。共刺激非依赖性记忆T细胞利用的关键途径的进一步探索 包括间充质基质细胞(MSCs)在内的下一代细胞疗法的开发将 提供强有力的策略来降低排斥风险，特别是促进耐受性诱导 容易被拒绝的接受者。基于免疫状态的耐受诱导方案的研究进展 个别受者将促进个性化的移植耐受策略，以最大限度地减少围术期 移植免疫抑制和保护免疫。

Costimulation blockade represents a new class of immunosuppression with more specific targets accompanied by less toxicity. Belatacept is the first FDA approved costimulation blockade reagent for use in kidney transplant recipients. Despite superior renal function, improved cardiovascular risk profile, and significantly better patient and graft survival at 7 years, the high rates of rejection as well as other logistical challenges have limited the breadth of its clinical adoption. We now have the world's largest experience using belatacept in kidney transplant recipients, approaching 1000 patients. We have observed similar benefits in renal function, but were surprised by the high rates of rejection we observed when using it outside the context of a clinical trial, nearly double what was previously reported. It is interesting to note that approximately half of the patients experienced rejection while the other half did not, provoking the question as to why some patients are susceptible while others are resistant to costimulation blockade therapy. Our early studies in mice and non- human primates (NHP) identified costimulation blockade resistant rejection as an important area for investigation and emphasized the potential benefits of developing a successful tolerance strategy. One of the most effective methods to promote tolerance in experimental models has been the transient disruption of the CD28 and CD40 pathways during the introduction of donor antigens. We have evaluated the next generation of costimulation blockade reagents (domain antibodies targeting CD28 and CD154) and shown that they are both safe and efficacious. Despite these advances there is still a subset of animals and patients who reject while on therapy. In comparing these rejecting vs. stable recipients, we have identified a memory T cell biomarker that correlated with increased risk of costimulation blockade-resistant rejection in both NHP and humans. We posit that the use of this predictive biomarker may allow us to identify optimal candidates for costimulation-blockade- based tolerance induction therapies, and propose to longitudinally assess the stability and plasticity of this biomarker and test its predictive power in a prospective fashion in animals receiving dual costimulation blockade therapy. Further exploration of critical pathways utilized by costimulation-independent memory T cells and development of next-generation cellular therapies including mesenchymal stromal cells (MSCs) will provide powerful strategies to mitigate the risk of rejection and promote tolerance induction in particularly rejection-prone recipients. The development of tolerance induction protocols based on the immune status of individual recipients will facilitate personalized strategies for transplantation tolerance, to minimize peri- transplant immunosuppression and preserve protective immunity.