期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 8, 页码 3285-3296出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI81722
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) [NO1-AI-15416, UM1AI109565]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Indiana Clinical and Translational Sciences Institute - NIH, National Center for Advancing Translational Sciences (NCATS) [TR000006]
- National Center for Research Resources (NCRR) [UL1 RR024131, UL1 TR000004]
- NCATS, NIH [UL1 RR024131, UL1 TR000004]
- NCRR [UL1RR024134, UL1TR000003]
- NCATS [UL1RR024134, UL1TR000003]
- Bayer HealthCare LLC, Diabetes Care
BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic beta 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 13 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(+)CD(4+). 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.
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