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，最终不可逆地损伤移植物。炎症通常见于功能稳定移植物的方案活检，并与进行性肾功能不全相关。用新型药物/方法治疗稳定移植物中的炎症具有几个优点：（1）逆转肾功能的逐渐恶化并防止移植物损失;（2）提供实用、安全和更精确的模型来测试新疗法的功效。我们提出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症反应。我们提出通过输注离体扩增的调节性T细胞（TCLs）或通过抑制IL 6途径以扩增Treg网络来增加调节性T细胞（TCLs）的数量和/或活性。这些试验将在6个月时接受方案活检的移植受者中进行。我们提出两项研究：离体扩增的Tcl 3（ASK）的输注试验和使用人源化抗IL 6受体抗体（TRAIL）托珠单抗（tocilizumab）的试验。ASK试验的目的是测试输注的安全性和潜在疗效。 在具有细胞炎症的移植物中，离体扩增的多克隆（poly）或供体（抗原）特异性（dar）TdR与对照（无额外治疗）。氘标记的TdR允许检测循环和肾移植物中注入的TdR。其他机制研究，包括血液和肾脏的基因表达谱分析以及尿液细胞因子分析，可提供稳健的疗效信号。这次试验将使我们能够做出3个重要的观察：（1） 确定在肾移植受者中输注Treg的安全性;（2）确定输注的Treg（聚或dar）是否减少移植物中的细胞炎症;和（3）确定darTreg是否上级聚Treg（临床上或机制上）。第二项研究提出使用托珠单抗通过减少同种异体反应性T细胞（包括TH 17细胞）和增加Tcl 3的数量和/或活性来控制炎症和Banff标准的临界排斥反应。在6个月活检中具有亚临床临界排斥反应（目前未治疗）的患者将被随机分配至标准治疗（无治疗）或托珠单抗皮下注射治疗，每两周一次，持续6个月。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医学：临界排斥反应患者将根据来自肾活检分析的分子常见排斥模块评分进行分层治疗。随访肾组织学、肾功能和机制研究将提供该方法的安全性和有效性数据。这些新的治疗方法可以更好地理解排斥和耐受的免疫机制，从而使我们能够找到新的、毒性更小的治疗方案，延长患者和移植物的生存期。

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.