Rigby, Mark R.Harris, Kristina M.Pinckney, AshleyDiMeglio, Linda A.Rendell, Marc S.Felner, Eric I.Dostou, Jean M.Gitelman, Stephen E.Griffin, Kurt J.Tsalikian, EvaGottlieb, Peter A.Greenbaum, Carla J.Sherry, Nicole A.Moore, Wayne V.Monzavi, RoshanakWilli, Steven M.Raskin, PhilipKeyes-Elstein, LynetteLong, S. AliceKanaparthi, SaiLim, NohaPhippard, DeborahSoppe, Carol L.Fitzgibbon, Margret L.McNamara, JamesNepom, Gerald T.Ehlers, Mario R.2016-11-042016-11-042015-08-03Rigby, M. R., Harris, K. M., Pinckney, A., DiMeglio, L. A., Rendell, M. S., Felner, E. I., … the Immune Tolerance Network (ITN) T1DAL Study Group. (2015). Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. The Journal of Clinical Investigation, 125(8), 3285–3296. http://doi.org/10.1172/JCI817221558-8238https://hdl.handle.net/1805/11401BACKGROUND: Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT00965458. FUNDING: NIH and Astellas.en-USIUPUI Open Access PolicyCD4-Positive T-LymphocytesimmunologymetabolismCD8-Positive T-LymphocytesDermatologic Agentsadministration & dosageDiabetes Mellitus, Type 1blooddrug therapyImmunologic Memorydrug effectsRecombinant Fusion ProteinsAlefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patientsArticle