Costimulation Blockade-Based Strategies for Tolerance Induction

共刺激阻断代表了一种具有更特定靶点的新的免疫抑制 伴随着较小的毒性。Belatacept是FDA批准的第一种用于共刺激阻断的试剂 在肾移植受者身上。尽管肾功能优越，心血管风险状况有所改善，但 显著提高患者和移植物的7年存活率、高排斥率以及其他后勤保障 挑战限制了其临床应用的广度。我们在肾脏方面观察到了类似的益处。 函数，但对在上下文之外使用它时观察到的高拒绝率感到惊讶 一项临床试验，几乎是之前报道的两倍。有趣的是，大约有一半的人 患者经历了排斥反应，而另一半则没有，这引发了一个问题，为什么有些人 患者易受影响，而其他患者对共刺激阻断疗法有抵抗力。我们的早期研究在 小鼠和非人灵长类动物(NHP)发现共刺激抑制抵抗排斥是一种重要的 他强调了制定一项成功的容忍战略的潜在好处。 在实验模型中，提高耐受性的最有效方法之一是瞬变 在引入供体抗原的过程中，CD28和CD40通路的中断。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) 并证明了它们都是安全有效的。尽管取得了这些进展，但仍有一小部分动物 以及在治疗期间拒绝接受治疗的患者。在比较这些拒绝和稳定的收件人时，我们有 发现一个记忆T细胞生物标记物，与共刺激拮抗的风险增加相关 在NHP和人类中都存在排斥反应。我们假设，使用这种预测性生物标记物可能会允许我们 确定共刺激-阻断疗法的最佳候选者，并纵向建议 评估该生物标志物的稳定性和可塑性，并以预期的方式测试其预测能力 接受双重共刺激阻断治疗的动物。进一步探索中国利用的关键途径 共刺激非依赖性记忆T细胞与下一代细胞疗法的发展 间充质基质细胞(MSCs)将提供强大的策略来降低排斥反应的风险和 促进对特别容易被排斥的受者的耐受性诱导。宽容的发展 基于单个接受者免疫状态的诱导方案将促进个性化策略 对于耐受性，尽量减少移植围术期的免疫抑制，并保持保护性免疫。

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 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 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 tolerance, to minimize peri- transplant immunosuppression and preserve protective immunity.