title: Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients.
abstract: 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.
  
  
  BACKGROUND
  https://clinicaltrials.gov/ NCT00965458.
  
  
  BACKGROUND
  NIH and Astellas.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Rigby
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Harris
authors.forename: Ashley
authors.initials: A
authors.lastname: Pinckney
authors.forename: Linda A
authors.initials: LA
authors.lastname: DiMeglio
authors.forename: Marc S
authors.initials: MS
authors.lastname: Rendell
authors.forename: Eric I
authors.initials: EI
authors.lastname: Felner
authors.forename: Jean M
authors.initials: JM
authors.lastname: Dostou
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gitelman
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: Eva
authors.initials: E
authors.lastname: Tsalikian
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Greenbaum
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Sherry
authors.forename: Wayne V
authors.initials: WV
authors.lastname: Moore
authors.forename: Roshanak
authors.initials: R
authors.lastname: Monzavi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Willi
authors.forename: Philip
authors.initials: P
authors.lastname: Raskin
authors.forename: Lynette
authors.initials: L
authors.lastname: Keyes-Elstein
authors.forename: S Alice
authors.initials: SA
authors.lastname: Long
authors.forename: Sai
authors.initials: S
authors.lastname: Kanaparthi
authors.forename: Noha
authors.initials: N
authors.lastname: Lim
authors.forename: Deborah
authors.initials: D
authors.lastname: Phippard
authors.forename: Carol L
authors.initials: CL
authors.lastname: Soppe
authors.forename: Margret L
authors.initials: ML
authors.lastname: Fitzgibbon
authors.forename: James
authors.initials: J
authors.lastname: McNamara
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ehlers
mesh_terms: D000293:Adolescent; D000328:Adult; D000077944:Alefacept; D002096:C-Peptide / Q000097:blood; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002648:Child; D003879:Dermatologic Agents / Q000008:administration & dosage*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects*; D008297:Male; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D002096:C-Peptide; D003879:Dermatologic Agents; D011993:Recombinant Fusion Proteins; D000077944:Alefacept