Costimulation Blockade-Based Strategies for Tolerance Induction

基于共刺激封锁的耐受诱导策略

基本信息

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
项目类别：
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

项目摘要

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.

共刺激封锁代表了一类新的免疫抑制，具有更具体的目标伴随着较小的毒性。 Belatacept是FDA批准的CORTIMATURATY BLOCKADE封锁试剂在肾脏移植接受者中。尽管肾功能卓越，心血管风险概况提高，并且 7年时的患者和移植物生存更高，拒绝率和其他后勤率很高挑战限制了其临床采用的广度。我们观察到肾脏的类似好处功能，但对我们在使用之外使用时观察到的高拒绝率感到惊讶一项临床试验，几乎是先前报道的两倍。有趣的是，大约一半患者遭到拒绝，另一半没有被拒绝，这引起了为什么某些问题的问题患者易感性，而其他患者则耐心刺激性阻滞治疗。我们的早期研究小鼠和非人类灵长类动物（NHP）确定了抗抑制作用的抗抑制作用是重要的调查领域，并强调制定成功的宽容策略的潜在好处。在实验模型中促进公差的最有效方法之一就是瞬态引入供体抗原期间，CD28和CD40途径的破坏。我们已经评估了下一代的共刺激阻滞试剂（靶向CD28和CD154的域抗体）并表明它们既安全有效又有效。尽管有这些进步，仍然有一部分动物和治疗期间拒绝的患者。在比较这些拒绝与稳定接收者时，我们有鉴定出一种记忆T细胞生物标志物，该标志物与抗cont刺激性封锁的风险增加相关 NHP和人类的拒绝。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结构阻滞的疗法的最佳候选者，并提议纵向评估该生物标志物的稳定性和可塑性，并以前瞻性方式测试其预测能力接受双重共刺激封锁治疗的动物。进一步探索由与共刺激无关的记忆T细胞和下一代细胞疗法的发展，包括间充质基质细胞（MSC）将提供有力的策略，以减轻拒绝风险和促进特别容易受到拒绝的接受者的耐受性诱导。宽容的发展基于个人接收者的免疫状态的归纳协议将促进个性化策略为了耐受性，以最大程度地减少移植免疫抑制并保持保护性免疫。