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.

描述（根据应用程序改编） 目标和研究目的：一种新型的无类固醇免疫抑制方案具有 仅在我们的胰岛移植后，导致了前所未有的成功 中心。虽然这种经验清楚地建立了临床胰岛 移植作为选定患者的有效且安全的治疗，这是主要的 拖拉是两个尸体供体pancreata的要求 稳定的无胰岛素状态。当前研究的目的是评估 在严格控制的临床研究中，抗TNFALPHA的功效 （英夫利昔单抗）mAb治疗可提供防止损伤介导的胰岛的保护 移植后期移植期的损失。假设是 抗TNFALPHA mAb的添加将导致胰岛素独立之后 单位移植。可靠地达到胰岛素独立之后 单次胰岛移植将代表该领域的重大进步， 将程序放在全胰腺移植的标准范围内 供体利用，但没有主要发病率的相关风险。 基础/理由：立即丢失大量孤立的胰岛 发生在栓塞到肝内部位后发生，大概是导致的 在胰腺采购，隔离和 纯化，并因细胞因子介导的凋亡激活而加剧 沿周围腺泡和导管元素胰岛剥夺的途径。 这些早期炎症途径中有许多暗示TNFALPHA。预处理 具有抗TNFALPHA MAB（英夫利昔单抗）的接受者应最大程度地减少激活 在这些途径中，促进胰岛植入，从而提供 衍生的胰岛移植后独立胰岛素独立的可能性 来自单张子。 协议摘要：一项前瞻性随机安慰剂对照试验将 比较1型糖尿病患者接受孤立胰岛的结局 英夫利昔单抗抗Tnfalpha mAb的覆盖（5 mg/kg）的移植 通过门户静脉立即进行移植）（每组n = 10，1：1 随机化），主要终点比较将是 单位移植后实现胰岛素独立的患者 每个组。次要终点将解决a）改进的证据 胰岛植入（基础，刺激的胰岛素和C肽反应，急性 胰岛素对精氨酸的反应，HBA1C的校正）和b）比较 周围TNFALPHA和其他细胞因子，颗粒酶B和穿孔素活性 英夫利昔单抗与安慰剂治疗组。