ADJUVANT THERAPIES IMPROVING ANTI-REJECTION EFFECTS OF COSTIMULATION BLOCKADE

辅助疗法改善共同刺激封锁的抗排斥效果

• 批准号: 8357527
• 负责人: Allan D. Kirk
• 金额: $ 3.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357527
• 关键词: Adjuvant Therapy; Affinity; Animals; CD8B1 gene; CTLA4-Ig; Cells; Clinical; Data; Flow Cytometry; Funding; Grant; Human; Immunity; In Vitro; Intramuscular Injections; Kidney; Kidney Transplantation; Macaca mulatta; Modified Vaccinia Virus Ankara; National Center for Research Resources; Primates; Principal Investigator; Regimen; Research; Research Infrastructure; Resources; Sirolimus; Source; Specific Pathogen Frees; Steroids; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; United States National Institutes of Health; Vaccination; Viral; Weaning; Withdrawal; alefacept; base; cost; germ free condition; improved; in vivo; prevent; terminally differentiated effector memory (TEM) T cells

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We have initiated the renal transplants planned for this study. In order to develop a clinically translatable regimen our previous regimen (Nat. Med. 2009; 15:746-9) was modified: CTLA-4-Ig was replaced with the higher affinity belatacept. Alefacept was increased from 0.3mg/kg to 1.0mg/kg based on in vitro and in vivo studies, and sirolimus was delivered via intramuscular injection to better approximate clinical levels. Specific pathogen free rhesus monkeys (n=5) underwent MHC mismatched renal allotransplantation. Alefacept (1mg/kg) was given on days -1, 3, 7, and weekly for 8 weeks. Belatacept (10mg/kg) was given on days -1, 3, 7 and weekly (5mg/kg) for 24 weeks. Sirolimus was given daily to maintain a trough of 6-10ng/mL for 16 weeks. The regimen successfully prevented rejection in all 5 animals. Only after both alefacept and sirolimus were weaned did any animal show evidence of rejection. Flow cytometry was used to quantify and characterize T cell subsets. Alefacept induced a transient depletion of memory T cells - most notably CD8+ TEM cells. The proportion of CD2hi T cells dramatically diminished during alefacept treatment and returned to baseline after withdrawal, suggesting that alefacept selectively targeted those cells with the highest CD2 expression. Though this regimen did not produce tolerance, these data support belatacept, alefacept, and sirolimus as a translatable, CNI and steroid-sparing regimen for human kidney transplantation. We now are investigating Modified Vaccinia Virus Ankara strain vaccination as a means of inducing a tractable viral-specific T cell response to assess the effect of this regimen of protective immunity.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 我们已经启动了本研究计划的肾移植。为了开发临床上可转化的方案，我们对之前的方案（Nat. Med. 2009；15:746-9）进行了修改：CTLA-4-Ig 被更高亲和力的belatacept 取代。根据体外和体内研究，阿法西普的剂量从 0.3mg/kg 增加到 1.0mg/kg，西罗莫司通过肌肉注射给药，以更好地接近临床水平。 无特定病原体的恒河猴 (n=5) 接受了 MHC 不匹配的同种异体肾移植。在第-1、3、7天和每周给予阿法西普（1mg/kg），持续8周。贝拉西普 (10mg/kg) 在第 -1、3、7 天给予，每周给予 (5mg/kg)，持续 24 周。每天给予西罗莫司以维持 6-10ng/mL 的谷值，持续 16 周。该方案成功防止了所有 5 只动物的排斥反应。 只有在阿法西普和西罗莫司断奶后，才有动物表现出排斥反应的证据。流式细胞术用于量化和表征 T 细胞亚群。阿法西普诱导记忆 T 细胞短暂耗尽，尤其是 CD8+ TEM 细胞。 CD2hi T 细胞的比例在阿法西普治疗期间显着减少，并在停药后恢复到基线，表明阿法西普选择性地靶向那些具有最高 CD2 表达的细胞。尽管该方案没有产生耐受性，但这些数据支持贝拉西普、阿法西普和西罗莫司作为人类肾移植的可转化、CNI 和类固醇节约方案。我们现在正在研究改良痘苗病毒安卡拉株疫苗接种，作为诱导易处理的病毒特异性 T 细胞反应的一种手段，以评估这种保护性免疫方案的效果。