Journal Article

Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

Burger, Douglas, Man, Guotong, Wang, Limei, Zheng, Hui, Ban, Liqin, Faustman, Denise L., Nathan, David M., Okubo, Yoshiaki, Pompei, Richard, Avruch, Joseph, Schoenfeld, David

2012

Overview

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. 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. 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. ClinicalTrials.gov NCT00607230.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Adults / Antibodies / Apoptosis / Autoantibodies / Autoantibodies - chemistry / Autoimmune diseases / Autoimmunity / Bacillus Calmette-Guerin vaccine / BCG / BCG Vaccine - immunology / Beta cells / Biology / Biomarkers / Biomarkers - metabolism / C-Peptide - chemistry / Case-Control Studies / Clinical trials / Cytotoxicity / Diabetes / Diabetes mellitus / Diabetes mellitus (insulin dependent) / Diabetes Mellitus, Type 1 - therapy / Double-Blind Method / Epstein-Barr virus / FDA approval / Female / Gene expression / Glutamate / Glutamate decarboxylase / Glutamate Decarboxylase - metabolism / Glutamic acid / Health aspects / Herpesvirus 4, Human - metabolism / HIV / Hospitals / Human immunodeficiency virus / Humans / Immune response / Immune system / Immunity / Immunology / Immunoregulation / Immunotherapy / Infections / Innate immunity / Insulin / Insulin secretion / Insulin-Secreting Cells - cytology / Laboratories / Lymphocytes / Lymphocytes T / Male / Medical schools / Medicine / Middle Aged / Multiple sclerosis / Pancreas / Peptides / Placebos / Regeneration / Stimulators / T cells / T-Lymphocytes - cytology / Tuberculosis / Tumor necrosis factor / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / Type 1 diabetes / Vaccines / Virus diseases / Viruses