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.
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