TY - JOUR
T1 - Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
AU - Immune Tolerance Network (ITN) T1DAL Study Group
AU - Rigby, Mark R.
AU - Harris, Kristina M.
AU - Pinckney, Ashley
AU - DiMeglio, Linda A.
AU - Rendell, Marc S.
AU - Felner, Eric I.
AU - Dostou, Jean M.
AU - Gitelman, Stephen E.
AU - Griffin, Kurt J.
AU - Tsalikian, Eva
AU - Gottlieb, Peter A.
AU - Greenbaum, Carla J.
AU - Sherry, Nicole A.
AU - Moore, Wayne V.
AU - Monzavi, Roshanak
AU - Willi, Steven M.
AU - Raskin, Philip
AU - Keyes-Elstein, Lynette
AU - Long, S. Alice
AU - Kanaparthi, Sai
AU - Lim, Noha
AU - Phippard, Deborah
AU - Soppe, Carol L.
AU - Fitzgibbon, Margret L.
AU - McNamara, James
AU - Nepom, Gerald T.
AU - Ehlers, Mario R.
N1 - Publisher Copyright:
© 2015, American Society for Clinical Investigation. All rights reserved.
PY - 2015/8/3
Y1 - 2015/8/3
N2 - BACKGROUND. 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.
AB - BACKGROUND. 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.
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U2 - 10.1172/JCI81722
DO - 10.1172/JCI81722
M3 - Article
C2 - 26193635
AN - SCOPUS:84939218518
SN - 0021-9738
VL - 125
SP - 3285
EP - 3296
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -