TRIAL OF ANTI-TNF ALPHA IN ISLET TRANSPLANTATION

抗 TNF α 在胰岛移植中的试验

• 批准号: 6381978
• 负责人: ANDREW M SHAPIRO
• 金额: $ 55.2万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381978
• 关键词: artificial immunosuppression; clinical research; clinical trials; genetic transcription; human genetic material tag; human subject; human therapy evaluation; insulin dependent diabetes mellitus; monoclonal antibody; outcomes research; pancreatic islet transplantation; polymerase chain reaction; postoperative complications; postoperative state; prognosis; transplant rejection; transplantation immunology; tumor necrosis factor alpha

DESCRIPTION (adapted from the application) Objective and study aim: A novel steroid-free immunosuppression protocol has resulted in unprecedented success after islet transplantation alone at our center. While this experience has clearly established clinical islet transplantation as an effective and safe therapy for selected patients, a major draw-back has been the requirement of two cadaveric donor pancreata to achieve a stable insulin-free state. The objective of the current study is to evaluate in a rigorously controlled clinical study, the efficacy of anti-TNFalpha (Infliximab) mAb therapy to provide protection against injury-mediated islet graft loss in the immediate post-transplant period. The hypothesis is that the addition of anti-TNFalpha mAb will result in insulin-independence after single-donor transplantation. Reliable attainment of insulin-independence after single-donor islet transplantation will represent a major advance to the field, placing the procedure on a par with whole-pancreas transplantation in regards to donor utilization, but without the associated risk of major morbidity. Basis/rationale: Immediate loss of a substantial proportion of isolated islets occurs following embolization to an intrahepatic site, presumably resulting from non-immune injury incurred during pancreas procurement, isolation and purification, and exacerbated by cytokine-mediated activation of apoptotic pathways following islet deprivation of surrounding acinar and ductal elements. Many of these early inflammatory pathways implicate TNFalpha. Pre-treatment of the recipient with an anti-TNFalpha mAb (Infliximab) should minimize activation of these pathways, promoting islet engraftment, and thereby offering the possibility of insulin-independence after transplantation of islets derived from a single-donor. Protocol summary: A prospective randomized placebo-controlled trial will compare outcomes in type 1 diabetic patients undergoing solitary islet transplantation under the cover of Infliximab anti-TNFalpha mAb (5 mg/kg delivered via the portal vein immediately pre-transplant) (n=10 per group, 1:1 randomization), The primary end-point comparison will be the proportion of patients achieving insulin-independence after single-donor transplantation in each group. Secondary end-points will address a) evidence of improvement in islet engraftment (basal, stimulated insulin and C-peptide response, acute insulin response to arginine, correction of HbA1c), and b) comparison of peripheral TNFalpha and other cytokine, granzyme B and perforin activity in the Infliximab vs placebo treatment groups.

说明(改编自应用程序) 目的和研究目的：一种新的非类固醇免疫抑制方案 仅在我们的胰岛移植后就取得了前所未有的成功 中间。虽然这一经历清楚地确立了临床胰岛 移植作为一种有效和安全的治疗方法，适用于选定的患者，是一种主要的 回缩一直是两具身体供体胰腺实现的要求 稳定的无胰岛素状态。当前研究的目标是评估 在一项严格控制的临床研究中，抗肿瘤坏死因子α的疗效 (英夫利昔单抗)单抗治疗对损伤介导的胰岛的保护作用 移植后即刻移植物丢失。我们的假设是 加入抗肿瘤坏死因子α单抗后将导致胰岛素独立 单一供者移植。在治疗后可靠地实现胰岛素独立 单一供体胰岛移植将是该领域的重大进步， 在以下方面使该手术与全胰腺移植相提并论 对捐赠者的利用，但没有相关的重大发病率风险。 依据/理由：立即丧失相当大比例的孤立小岛 发生在肝内部位的栓塞术后，可能导致 免受胰腺获取、隔离和处理过程中的非免疫性损伤 纯化，并通过细胞因子介导的凋亡激活而加剧 胰岛剥夺周围腺泡和导管成分后的通路。 这些早期炎症途径中的许多都与肿瘤坏死因子α有关。前置处理 具有抗肿瘤坏死因子α单抗(Infliximab)的接受者应尽量减少激活 在这些途径中，促进胰岛植入，从而提供 胰岛来源移植后胰岛素非依赖性的可能性 来自单一捐赠者。 方案概述：一项前瞻性随机安慰剂对照试验将 1型糖尿病患者接受孤立性胰岛治疗的结果比较 英利昔单抗抗肿瘤坏死因子α单抗(5 mg/kg)覆盖下移植 移植前立即经门静脉给药)(每组10例，1：1 随机化)，主要的终点比较将是 年单供者移植后实现胰岛素独立的患者 每组。次要终点将处理a)改善的证据 胰岛植入(基础、刺激的胰岛素和C-肽反应，急性 精氨酸对胰岛素的反应，糖化血红蛋白的校正)，以及b)比较 外周血中肿瘤坏死因子α及其他细胞因子、颗粒酶B和穿孔素的活性 英夫利昔单抗与安慰剂治疗组比较。