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Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
- Rigby, Mark R;
- Harris, Kristina M;
- Pinckney, Ashley;
- DiMeglio, Linda A;
- Rendell, Marc S;
- Felner, Eric I;
- Dostou, Jean M;
- Gitelman, Stephen E;
- Griffin, Kurt J;
- Tsalikian, Eva;
- Gottlieb, Peter A;
- Greenbaum, Carla J;
- Sherry, Nicole A;
- Moore, Wayne V;
- Monzavi, Roshanak;
- Willi, Steven M;
- Raskin, Philip;
- Keyes-Elstein, Lynette;
- Long, S Alice;
- Kanaparthi, Sai;
- Lim, Noha;
- Phippard, Deborah;
- Soppe, Carol L;
- Fitzgibbon, Margret L;
- McNamara, James;
- Nepom, Gerald T;
- Ehlers, Mario R
Published Web Location
https://doi.org/10.1172/jci81722Abstract
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.Funding
NIH and Astellas.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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