Novel Therapies to Modulate the Inflammatory Alloresponse in Renal Grafts

描述(由申请人提供)：晚期移植物丢失的一个重要原因是亚临床同种异体反应的发展，最终对移植物造成不可逆转的损害。炎症通常见于功能稳定的移植物的常规活检，并与进行性肾功能障碍有关。使用新的药物/方法治疗稳定移植物中的炎症具有以下几个优点：(1)逆转肾功能的逐渐恶化，防止移植物丢失；(2)提供一个实用、安全和更精确的模型来测试新疗法的疗效。我们建议的概念是通过利用免疫系统的调节机制来控制移植物中的炎性同种异体反应。我们建议通过输注体外扩增的Tregs或通过抑制IL6途径来扩大Treg网络来增加调节性T细胞(Tregs)的数量和/或活性。这些试验将在移植受者中进行，他们在6个月时接受方案活组织检查。我们提出了两项研究：体外扩张Tregs的输注试验(TASK)和人源化的抗IL6受体抗体(TRAIL)tocilizumab的试验。这项任务试验的目的是测试输液的安全性和潜在疗效。 移植物细胞炎症的体外扩增多克隆(多)或供体(抗原)特异性(DAR)Tregs与对照组(无额外治疗)。氚标记的Tregs可以检测到循环和移植肾中注入的Tregs。其他的机制研究，包括血液和肾脏的基因表达谱，以及尿液细胞因子的分析，可能会提供强有力的疗效信号。这项试验将使我们能够做出三点重要的观察：(1) 确定肾移植受者输注Treg的安全性；(2)确定输注Treg(Polyor DAR)是否能减少移植物中的细胞炎症；以及(3)确定darTregs是否优于PolyTregs(临床或机械方面)。第二项研究建议使用tocilizumab通过减少同种异体反应性T细胞(包括TH17细胞)和增加Tregs的数量和/或活性来控制炎症和Banff标准的临界排斥反应。在为期6个月的活检中出现亚临床临界排斥反应(目前未治疗)的患者将被随机分为两组，一组接受标准治疗(无治疗)，另一组接受为期6个月的两周皮下注射tocilizumab的治疗。这项试验的一个独特和新颖的方面是引入了基于分子的个性化药物：发生交界性排斥反应的患者将根据从肾活检分析得出的分子常见排斥反应模块评分进行分层治疗。后续的肾组织学、肾功能和机制研究将为该方法的安全性和有效性提供数据。这些新疗法可能会更好地了解排斥和耐受的免疫机制，从而引导我们找到新的、毒性较低的方案，以延长患者和移植物的存活时间。

DESCRIPTION (provided by applicant): An important cause of late graft loss is the development of subclinical alloresponses that ultimately injure the graft irreversibly. Inflammation is commonly seen in protocol biopsies of stably functioning grafts and is associated with progressive renal dysfunction. Therapeutic targeting of inflammation in stable grafts with novel agents/approaches has several advantages: (1) reverse the gradual deterioration of renal function and prevent graft loss; (2) provide a practical, safe and more precise model to test the efficacy of new therapies. The concept underlying our proposal is the control the inflammatory alloresponses in the graft through harnessing the regulatory mechanisms of the immune system. We propose to increase the number and/or activity of regulatory T cells (Tregs) by either the infusion of ex vivo expanded Tregs or by inhibiting the IL6 pathway to expand the Treg network. The trials will be performed in transplant recipients who undergo protocol biopsies at 6 months. We propose two studies: a trial of infusions of ex vivo expanded Tregs (TASK) and a trial with tocilizumab, a humanized anti-IL6 receptor antibody (TRAIL). The aim of the TASK trial is to test the safety and potential efficacy of infused ex vivo expanded polyclonal (poly) or donor (antigen) specific (dar) Tregs vs. controls (no additional therapy) in grafts with cellular inflammation. Deuterium-labeled Tregs allow detection of the infused Tregs in both the circulation and the renal allograft. Additional mechanistic studie including gene expression profiling of blood and kidney as well as analysis of urine cytokines may provide robust efficacy signals. This trial will allow us to make 3 important observations: (1) determine the safety of the infusion of Tregs in kidney transplant recipients; (2) determine if infused Treg (poly or dar) reduce cellular inflammation in the graft and (3) determine if darTregs are superior to polyTregs (clinically or mechanistically). The second study proposes the use of tocilizumab to control inflammation and borderline rejection by Banff criteria by decreasing alloreactive T cells (including TH17cells) and increasing the number and/or activity of Tregs. Patients who have subclinical borderline rejection (currently untreated) in the 6-month biopsy will be randomized to either standard of care (no therapy) or treatment with biweekly subcutaneous injection of tocilizumab for 6 months. A unique and novel aspect of this trial is the introduction of molecular-based personalized medicine: patients with borderline rejection will be stratified for therapy based on a molecular common rejection module score derived from analysis of the kidney biopsy. Follow up renal histology, renal function and mechanistic studies will provide data on the safety and efficacy of this approach. These new therapies may provide a better understanding of the immune mechanisms of rejection and tolerance and thereby lead us to novel and less toxic regimens that can prolong patient and graft survival.