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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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，我们修改了先前的方案（Nat.Med.2009; 15：746-9）：用更高亲和力的贝拉西普代替CTLA-4-IG。基于体外和体内研究，阿法塞从0.3mg/kg增加至1.0mg/kg，西罗莫司通过肌内注射递送至更接近临床水平。 无特定病原体的恒河猴（n=5）进行MHC不匹配的同种异体肾移植。阿法塞（1 mg/kg）于第-1、3、7天给药，每周给药一次，共8周。贝拉西普（10 mg/kg）在第-1、3、7天给药，每周一次（5 mg/kg）给药，共24周。西罗莫司每日给药，以维持6- 10 ng/mL的谷值，持续16周。该方案成功地防止了所有5只动物的排斥反应。 只有在阿法西普和西罗莫司断奶后，任何动物才显示出排斥反应的证据。流式细胞术用于定量和表征T细胞亚群。Alefacept诱导记忆T细胞的瞬时消耗-最明显的是CD 8 + TEM细胞。在alefacept治疗期间，CD 2 hi T细胞的比例急剧下降，并在停药后恢复到基线水平，这表明alefacept选择性地靶向具有最高CD 2表达的那些细胞。尽管该方案未产生耐受性，但这些数据支持贝拉西普、阿法西普和西罗莫司作为可翻译的CNI和类固醇保留方案用于人肾移植。我们现在正在研究改良的牛痘病毒安卡拉株疫苗接种作为诱导易处理的病毒特异性T细胞应答的手段，以评估这种保护性免疫方案的效果。