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

American Diabetes Association

Ashley Pinckney

Carla J. Greenbaum

Carol L. Soppe

Clifford

Cook

Deborah Phippard

Eric I. Felner

Eva Tsalikian

Feutren

Gerald T. Nepom

James McNamara

Jean M. Dostou

Kristina M. Harris

Kurt J. Griffin

Linda A. DiMeglio

Lynette Keyes-Elstein

Marc S. Rendell

Margret L. Fitzgibbon

Mario R. Ehlers

Mark R. Rigby

Nicole A. Sherry

Noha Lim

Peter A. Gottlieb

Philip Raskin

Roshanak Monzavi

S. Alice Long

Sai Kanaparthi

Stephen E. Gitelman

Steven M. Willi

Wayne V. Moore

Journal of Clinical Investigation

PubMed

null null

Crossref

English

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

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

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.

IUPUIScholarWorks

Carolina Digital Repository

BackgroundType 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.MethodsIn 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.ResultsA 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 &lt; 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 &lt; 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P &lt; 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P &lt; 0.01).ConclusionsIn 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 registrationhttps://clinicaltrials.gov/ NCT00965458.FundingNIH and Astellas

Rigby, Mark R

Harris, Kristina M

DiMeglio, Linda A

Rendell, Marc S

Felner, Eric I

Dostou, Jean M

Gitelman, Stephen E

Griffin, Kurt J

Gottlieb, Peter A

Greenbaum, Carla J

Sherry, Nicole A

Moore, Wayne V

Willi, Steven M

Long, S Alice

Soppe, Carol L

Fitzgibbon, Margret L

Nepom, Gerald T

Ehlers, Mario R

eScholarship - University of California

https://scholarworks.iupui.edu/bitstream/handle/1805/11401/JCI81722.pdf?sequence=1&isAllowed=y

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Abstract

Similar works

Full text

Available Versions

Crossref

IUPUIScholarWorks

Carolina Digital Repository

eScholarship - University of California

IUPUIScholarWorks