Costimulation Blockade-Based Strategies for Tolerance Induction

基于共刺激封锁的耐受诱导策略

• 批准号: 10609611
• 负责人: Andrew B Adams
• 金额: $ 66.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609611
• 关键词: Achievement; Address; Adoption; Animals; Antibodies; Antigens; Area; Biological Markers; CD28 gene; CD8B1 gene; Cell Survival; Cell Therapy; Cells; Clinical; Clinical Trials; Critical Pathways; Development; Experimental Models; FDA approved; Frequencies; Graft Survival; Grant; Health; Human; IL7 gene; Immune; Immunity; Immunologic Markers; Immunophenotyping; Immunosuppression; Individual; Interleukin-15; Investigation; Kidney; Kidney Transplantation; Life; Logistics; Mediating; Methods; Mus; Neoadjuvant Therapy; OX40; Outcome; Pathway interactions; Patients; Phenotype; Protocols documentation; Reagent; Regimen; Renal function; Reporting; Resistance; Risk; Savings; Signal Transduction; T memory cell; T-Cell Development; TNFRSF5 gene; TNFSF5 gene; Testing; Toxic effect; Transplant Recipients; Transplantation; Transplantation Tolerance; Work; base; cardiovascular risk factor; clinical translation; end-stage organ failure; experience; high risk; immunological status; improved; mesenchymal stromal cell; next generation; nonhuman primate; personalized strategies; predictive marker; preservation; prospective; translational study

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.

共刺激阻断剂代表了一类新的免疫抑制剂，具有更特异的靶点 伴随着更少的毒性。贝拉西普是FDA批准使用的第一种共刺激阻断试剂 在肾移植受者中。尽管具有上级肾功能，改善了心血管风险特征， 7年时患者和移植物存活率显著提高，排斥反应率高， 挑战限制了其临床应用的广度。我们在肾移植中也观察到了类似的获益。 功能，但我们惊讶于我们在上下文之外使用它时观察到的高拒绝率。 一项临床试验，几乎是之前报道的两倍。值得注意的是，大约一半的 这些患者经历了排斥反应，而另一半则没有，这就引发了一个问题，为什么有些人 患者对共刺激阻断疗法敏感，而其他患者对共刺激阻断疗法有抗性。我们早期的研究 小鼠和非人灵长类动物（NHP）将共刺激阻断抵抗性排斥反应确定为重要的 他强调了制定一项成功的容忍战略的潜在好处。 在实验模型中促进耐受性的最有效方法之一是瞬时 在引入供体抗原期间破坏CD 28和CD 40途径。我们已经评估 下一代共刺激阻断试剂（靶向CD 28和CD 154的结构域抗体） 证明了它们既安全又有效。尽管有了这些进步， 以及在治疗过程中产生排斥反应的患者在比较这些拒绝与稳定的受体时，我们有 确定了一种记忆T细胞生物标志物，与共刺激阻断抵抗的风险增加相关 NHP和人类的排斥反应。我们认为，使用这种预测性生物标志物可能使我们能够 确定基于共刺激-阻断疗法的最佳候选者，并建议纵向 评估这种生物标志物的稳定性和可塑性，并以前瞻性的方式测试其预测能力， 接受双重共刺激阻断治疗的动物。进一步探索关键途径， 共刺激非依赖性记忆T细胞和下一代细胞疗法的开发，包括 间充质基质细胞（MSC）将提供强有力的策略，以减轻排斥反应的风险， 促进特别是排斥倾向接受者的耐受诱导。建立宽容 基于个体受体免疫状态的诱导方案将促进个性化策略 耐受性，以尽量减少移植免疫抑制和保护性免疫。