Am J Transplant 2012;12:1576C1583 [PMC free of charge article] [PubMed] 7. harmful impact of growing alloantibody and auto- titers upon islet transplant survival. Application of a range of autoantibody markers including zinc transporter 8 antigen (ZnT8A), which includes previously been proven to become of importance in recurrent autoimmunity after pancreas transplantation (17), IA-2A and GADA, and high-resolution single-bead antigen alloantibody monitoring with intensive serial monitoring over time, were essential to the analysis. Perturbations in titer rather than absolute values Granisetron Hydrochloride now appear to be the keys to understanding how to better protect islets posttransplant. Piemonti et al. analyzed the outcomes of 59 islet recipients in this manner and found a surprisingly high presence of donor-specific antibody (DSA) pretransplant in almost half of the cases. The finding of improved islet survival in cases with Rabbit polyclonal to PDK4 pretransplant DSA seems anomalous. Autoantibody riseespecially epitopic spreading to additional autoantigenswas a poor prognostic marker and occurred early posttransplant (detectable by day 16 posttransplant, and almost 70% of the subjects developed autoantibodies within 3 months). Rising autoantibodies were associated with a 5.2 times increased risk of graft failure, which occurred at a median of 304 days posttransplant. A rise of both DSA and autoantibody was an especially poor prognostic marker of graft endurance. The finding by Piemonti et al. that antithymocyte Granisetron Hydrochloride globulin (ATG) induction was associated with the greater risk of antibody formation and poorer long-term graft survival is inconsistent with the finding by Bellin et al. (6) of 50% islet transplant success with Granisetron Hydrochloride T-cell depletional induction. One may surmise that the omission of tumor necrosis factor- blockade at induction and the omission of therapeutic calcineurin inhibition in the maintenance regimen of Piemonti et al. may have contributed to this finding rather than the specific use of ATG per se. Drawbacks to this study include the fact that it was conducted over an 8-year period with evolving collagenase enzymes and islet isolation techniques and with changing induction and maintenance approaches over this time. The data were collected prospectively, but analyzed retrospectively. Patients were not managed based on their antibody responses, so it remains to be seen whether rising antibody responses would be reversible with more intensified, preemptive immunosuppression, and thus whether this would indeed be protective to the graft. A future study now begs for a prospective, controlled intervention arm based upon simultaneous state-of-the-art antibody and T-cellCbased assays to direct immunotherapy. The contributions by Piemonti et al. have certainly laid the foundation for such a study. If immunosuppression could be tailored to meet these immunological perturbations, and especially be minimized in patients with optimal profiles, islet transplantation could be more broadly and safely applied to a much greater cohort of patients with type 1 diabetes. ACKNOWLEDGMENTS No potential conflicts of interest relevant to this article were reported. Footnotes See accompanying original article, p. 1656. REFERENCES 1. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999C2010. Diabetes Care 2012;35:1436C1445 [PMC free article] [PubMed] [Google Scholar] 2. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 Granisetron Hydrochloride diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230C238 [PubMed] [Google Scholar] 3. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91:373C378 [PubMed] [Google Scholar] 4. Seventh Annual Report Collaborative Islet Transplant Registry [Internet], 2011. Available from Accessed 9 February 2013 5. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after.