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TRIAL OF ANTI-TNF ALPHA IN ISLET TRANSPLANTATION

抗 TNF α 在胰岛移植中的试验

基本信息

批准号：
6524384
负责人：
ANDREW M SHAPIRO
金额：
$ 56.85万
依托单位：
UNIVERSITY OF ALBERTA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2006-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6524384
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

项目摘要

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（改编自应用程序）目的和研究目的：一种新的无类固醇免疫抑制方案，在我们的研究中，中心虽然这一经验已明确建立了临床胰岛移植作为一种有效和安全的治疗选择的患者，一个主要的回缩一直是两个尸体供体胰腺的要求，稳定的无胰岛素状态本研究的目的是评估在一项严格对照的临床研究中，（英夫利西单抗）mAb治疗可提供针对损伤介导的胰岛移植后即刻移植物丢失。假设是，添加抗TNF α mAb将导致胰岛素依赖性，单供体移植胰岛素依赖性的可靠实现单供体胰岛移植将代表该领域的主要进展，将该手术与全胰腺移植术相提并论，供体利用率，但没有相关的重大发病率的风险。依据/原理：大部分孤立胰岛立即丧失发生在肝内部位栓塞后，可能导致在胰腺获取、隔离和纯化，并加剧了马槟榔介导的激活凋亡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涉及TNF α。预处理使用抗TNF α mAb（英夫利昔单抗）受体应尽量减少激活这些途径，促进胰岛移植，从而提供胰岛移植后胰岛素依赖性的可能性来自一个捐赠者方案总结：一项前瞻性随机安慰剂对照试验将比较1型糖尿病患者接受单独胰岛移植的结局在英夫利昔单抗抗-TNF α mAb（5 mg/kg）覆盖下移植在移植前立即通过门静脉递送）（每组n=10，1：1 主要终点比较将是单供体移植后达到胰岛素依赖的患者每组次要终点将涉及a）改善的证据，胰岛移植（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，HbA 1c）的校正，和B）比较外周TNF α和其他细胞因子、颗粒酶B和穿孔素活性英夫利西单抗vs安慰剂治疗组。