Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes.
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.


RESULTS
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 95(th) percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov NCT00607230.
The Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America. faustman@helix.mgh.harvard.edu
Denise L
DL
Faustman
Limei
L
Wang
Yoshiaki
Y
Okubo
Douglas
D
Burger
Liqin
L
Ban
Guotong
G
Man
Hui
H
Zheng
David
D
Schoenfeld
Richard
R
Pompei
Joseph
J
Avruch
David M
DM
Nathan
D000328:Adult; D001323:Autoantibodies / Q000737:chemistry; D015551:Autoimmunity; D001500:BCG Vaccine / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D002096:C-Peptide / Q000737:chemistry; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D004311:Double-Blind Method; D005260:Female; D005968:Glutamate Decarboxylase / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology; D008297:Male; D008875:Middle Aged; D010919:Placebos; D013601:T-Lymphocytes / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001323:Autoantibodies; D001500:BCG Vaccine; D015415:Biomarkers; D002096:C-Peptide; D010919:Placebos; D014409:Tumor Necrosis Factor-alpha; D005968:Glutamate Decarboxylase