Novel Therapies to Modulate the Inflammatory Alloresponse in Renal Grafts

调节肾移植物炎症同种反应的新疗法

• 批准号: 9306756
• 负责人: Flavio Vincenti
• 金额: $ 237万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306756
• 关键词: Acute; Alloantigen; Allografting; Antibodies; Antigens; Autologous; Biopsy; Blood; Blood Circulation; Calcineurin inhibitor; Cells; Cellular Assay; Cessation of life; Chronic; Clinical; Clinical Research; Clinical Trials; Control Groups; Data; Detection; Deterioration; Deuterium; Development; Effectiveness; Effector Cell; Environment; Equilibrium; Fc Receptor; Functional disorder; Gene Expression; Gene Expression Profiling; Graft Survival; Histologic; Histology; IL6 gene; Immune; Immune response; Immune system; Immunosuppression; Immunosuppressive Agents; In Situ Hybridization; Infiltration; Inflammation; Inflammatory; Infusion procedures; Interleukin 6 Receptor; Kidney; Kidney Transplantation; Label; Lead; Mediating; Medicine; Modeling; Molecular; Molecular Profiling; Mononuclear; Organ; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Protocols documentation; Quality of life; Randomized; Randomized Controlled Trials; Regimen; Regulatory T-Lymphocyte; Renal function; Research Personnel; Resolution; Safety; Signal Transduction; Subcutaneous Injections; T-Lymphocyte; TNFSF10 gene; Testing; Therapeutic; Toxic effect; Transplant Recipients; Treatment Efficacy; Urine; base; cytokine; efficacy testing; follow-up; graft function; improved; inclusion criteria; injured; kidney allograft; migration; nephrotoxicity; novel; novel therapeutics; personalized medicine; premature; prevent; public health relevance; response; safety testing; standard of care; therapeutic target

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.

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异体反应的发展，最终不可逆转地损伤移植物。炎症常见于功能稳定的移植物的方案活检，并与进行性肾功能障碍有关。在稳定的移植物中使用新的药物/方法治疗炎症有几个优点：(1)逆转肾功能的逐渐恶化，防止移植物丢失；(2)为检验新疗法的疗效提供一个实用、安全、更精确的模型。我们提出的基本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异体反应。我们建议通过输注体外扩增的Treg或抑制il - 6通路来扩大Treg网络来增加调节性T细胞（Treg）的数量和/或活性。试验将在移植受者中进行，这些受者在6个月时接受活检。我们提出了两项研究：一项是输注体外扩展Tregs （TASK）的试验，另一项是输注tocilizumab(一种人源抗il - 6受体抗体（TRAIL）的试验。TASK试验的目的是测试输注的安全性和潜在疗效