abstract


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Posted by JoeC on 21:44:16 2012/08/08

In Reply to: BCG Faustman posted by Mark


Denise L. Faustman1*, Limei Wang1, Yoshiaki Okubo1, Douglas Burger1, Liqin Ban1, Guotong Man1, Hui Zheng2, David Schoenfeld2, Richard Pompei3, Joseph Avruch3, David M. Nathan3

1 The Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Biostatistics, Massachusetts General Hospital, Boston, Massachusetts, United States of America, 3 Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America

Abstract
Background
No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.

Methodology/Principal Findings
Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95 3.8], 2.57 [95% CI 1.65 3.49]) and the EBV-infected subject (3.16 [95% CI 2.54 3.69]) vs.1.65 [95% CI 1.55 3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.

Conclusions/Significance
We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.

Trial Registration
ClinicalTrials.gov NCT00607230
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0041756


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