CLINICAL ISLET TRANSPLANTATION

A.M..J. Shapiro¹, C. Toso², A. Koh¹, S.R. Calne³, T. Kin⁴, D. O'gorman⁵, A. Malcolm¹, P. Dinyari¹, S. Imes¹, R. Owen¹, N.M. Kneteman⁶, D. Bigam⁶, P. Senior⁷, B. Roep^8
1Surgery, University of Alberta, Edmonton/CANADA, ²Visceral And Transplantation Surgery, Geneva University Hospitals, Geneva/SWITZERLAND, ³Surgery, University of Cambridge, CB2 2AS/UNITED KINGDOM, ⁴Clinical Islet Transplant Program, University of Alberta, Edmonton/CANADA, ⁵Clincal Islet Labroatory, Alberta Helath Sevices, Edmonton/AB/CANADA, ⁶Department Of Surgery, University of Alberta, Edmonton/CANADA, ⁷Clincial Islet Transplant Program, University of Alberta, Edmonton/AB/CANADA, ⁸Dept Immunohaematology And Blood Transfusion, Leiden University Medical Center, NL-233ZA/NETHERLANDS

Body: Introduction: Durability has proven to be a challenge after clinical islet transplantation, with only 18% with the Edmonton Protocol (EP) remaining insulin independent by 5 years. With isletfailure from autoimmune and alloimmune destruction over time, we hypothesized that potent T depletional induction therapy up front with alemtuzumab, and maintainance with tac/MMF would enhance isletprotection, and would be better tolerated than high dose sirolimus.

Methods: n=14 (mean age 49±10) with longstanding T1DM (duration 32±13 years), glycemic lability, recurrent hypos (Clarke score >4) and preserved renal function received mean548,000±223,000 IE intraportal by percutaneous access (8,508±3,123IE/kg). 30mg alemtuzumab iv was given on D-1, with islets maintained in culture. Tac (10ng/ml) was delayed until day 5,and MMF was given up to 2g/d as tolerated.

Results: Of n=14, n=12 had completed transplants, and n=2 await a second infusion, and all are C-peptide positive. Of the n=12 completed, 10/12 (83.3%) remain insulin independent currentlywith good glycemic control, with maximal follow-up 3.9 years; of the remaining 2/12, both lost insulin independent after complete withdrawal from immunosuppression, after aseptic meningitis, andafter nocardial pneumonia with brain abscess; both remain alive and have resolved. In comparing K-M survival curves for alemtuzumab tac/MMF vs EP, for completed transplants on immunosuppression,p=0.029 at 36 months follow-up. In comparing metabolic reserve, 65% of subjects treated with alemtuzumab tac/MMF achieved a normal response vs 12% EP (p=0.01). No subject has become sensitized byPRA. In terms of mechanisms underlying graft protection, we found strong donor Ag specific T regs that did not express FoxP3, with potent IL-10 production in all subjects with the exception of onewithdrawn from immunosuppresssion that showed a strong donor specific alloresponse lacking IL-10). Alloreactivity to islet donor HLA was significantly lower than to third party allo (p=0.034). Interms of autoreactivity by qdot multimer analysis, CD8 islet autoreactivity was markedly reduced after alemtuzumab tac/MMF.



Conclusion: Potent T-depletion with alemtuzumab and tac/MMF maintenance induced a unique donor specific IL-10 regulated immune response, and led to significantly enhanced longterm insulinindependence rates compared to EP. This therapy was extremely well tolerated without side effects and with excellent glycemic control in all but 2 subjects, and this long term data represents asubstantial advance compared to the EP.

Disclosure: All authors have declared no conflicts of interest.