Browsing by Author "Russell, William E"

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    Targeting effector memory T cells with alefacept in new onset type 1 diabetes: 12 month results from the T1DAL study
    (Elsevier, 2013-12) Rigby, Mark R; DiMeglio, Linda A; Rendell, Marc S; Felner, Eric I; Dostou, Jean M; Gitelman, Stephen E; Patel, Chetanbabu M; Griffin, Kurt J; Tsalikian, Eva; Gottlieb, Peter A; Greenbaum, Carla J; Sherry, Nicole A; Moore, Wayne V; Monzavi, Roshanak; Willi, Steven M; Raskin, Philip; Moran, Antoinette; Russell, William E; Pinckney, Ashley; Keyes-Elstein, Lynette; Howell, Michael; Aggarwal, Sudeepta; Lim, Noha; Phippard, Deborah; Nepom, Gerald T; McNamara, James; Ehlers, Mario R; Department of Pediatrics, IU School of Medicine
    Background Type 1 diabetes (T1D) results from autoimmune targeting of the pancreatic beta cells, likely mediated by effector memory T cells (Tems). CD2, a T cell surface protein highly expressed on Tems, is targeted by the fusion protein alefacept, depleting Tems and central memory T cells (Tcms). We hypothesized that alefacept would arrest autoimmunity and preserve residual beta cells in newly diagnosed T1D. Methods The T1DAL study is a phase II, double-blind, placebo-controlled trial that randomised T1D patients 12-35 years old within 100 days of diagnosis, 33 to alefacept (two 12-week courses of 15 mg IM per week, separated by a 12-week pause) and 16 to placebo, at 14 US sites. The primary endpoint was the change from baseline in mean 2-hour C-peptide area under the curve (AUC) at 12 months. This trial is registered with ClinicalTrials.gov, number NCT00965458. Findings The mean 2-hour C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110 nmol/L) in the alefacept group and decreased by 0.115 nmol/L (95% CI -0.278 to 0.047) in the placebo group, which was not significant (p=0.065). However, key secondary endpoints were met: the mean 4-hour C-peptide AUC was significantly higher (p=0.019), and daily insulin use and the rate of hypoglycemic events were significantly lower (p=0.02 and p<0.001, respectively) at 12 months in the alefacept vs. placebo groups. Safety and tolerability were comparable between groups. There was targeted depletion of Tems and Tcms, with sparing of naïve and regulatory T cells (Tregs). Interpretation At 12 months, alefacept preserved the 4-hour C-peptide AUC, lowered insulin use, and reduced hypoglycemic events, suggesting a signal of efficacy. Depletion of memory T cells with sparing of Tregs may be a useful strategy to preserve beta cell function in new-onset T1D.