Enhanced early islet engraftment offers the potential for improved graft function after islet allotransplantation (IT). Nine patients underwent IT under a fully completed prospective research protocol using double cytokine blockade with anti TNFα (ethanercept day 0, 3,7,10) and IL-1β (anakinra, day 0-7) at the time of each islet infusion, with anticoagulation. Mean islet infusion dose was 8,967 islet equivalents (IEq)/kg body weight (range 3582-6395), for a total dose per patient of 12,999 IEq/kg (range: 6842-24892) in 1 or 2 preparations (5 and 4 patients, respectively). Immunosuppression was achieved with tacrolimus, MMF, and induction with anti thymocyte globulin (7 patients) or alemtuzumab (2 patients). Islet damage markers (measured by microRNA375) were low. Peak liver enzymes (as a marker of inflammation/ischemia) were only 95+60 IU/ml for AST and 128+78 IU/ml for ALT by day 3-4 post IT. There were no thrombotic events and no infectious complications associated with combined IL1-β and TNF-α blockade. 6 patients became insulin independent, 2 had partial function, and one had primary non function (PNF). Two patients had a severe drop in serum C-peptide with new antiGAD65 antibody formation from day 28, followed by complete graft loss (one with preexisting antibody had PNF, the other developed de novo antibody and lost C-peptide at month 3); they were not retransplanted. Another patient died at home 16 months after IT, for unclear reasons, while being insulin independent. Upon completion of 24 months of follow-up, 6/9 patients have excellent glycemic control (fasting blood glucose, IVGGT, C-peptide), HbA1c < 6%, and no episodes of hypoglycemia unawareness. Eight patients developed HLA alloantibodies at various time points (class 1 – 5, class 2 – 6) with enhanced T cell alloreactivity. One patient retained good graft function despite having anti GAD65 antibodies. The use of double cytokine blockade is safe, with reduction of inflammation at transplantation and presumably with better engraftment. However, it does not influence later islet loss from T-cell mediated auto- and alloimmunity, which require different strategies in order to maintain long term islet function.

CITATION INFORMATION: Onaca N, Takita M, Levy M, Naziruddin B. Safety and Decreased Inflammation of Early Double Cytokine Blockade (IL-1β and TNF-α) Facilitates Engraftment in Islet Allotransplantation. Am J Transplant. 2017;17 (suppl 3).

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