No targeted immunotherapies exist for reversing advanced type 1 diabetes. Bacillus-Calmette-Guerin (BCG), which induces release of tumor necrosis factor (TNF), has been used successfully in rodent models to reverse disease by specifically removing autoreactive T cells and unleashing pancreas regeneration to restore long-term normoglycemia. In murine models of type 1 diabetes, this therapeutic intervention is unique in removing beta-cell autoimmunity and improving glycemia even in animals with near complete eradication of beta-cell function, and not just in new onset diabetes.
In this proof-of-principle, phase I trial, we treated adult patients with long-term type 1 diabetics with BCG, a non-virulent genetic vaccine, to determine whether BCG depletes the disease-causing autoimmune cells and identify any pancreatic beta-cell responses. We randomly assigned patients with long-term type 1 diabetes (mean 15-years duration) to repeated BCG vaccinations (n=3) or placebo (n=3) in this 20-week double-blinded placebo-controlled trial and compared them to subjects without diabetes (n=6). We measured blood samples for autoreactive T cells, TREG cells, GAD autoantibodies, and C-peptide, a marker of insulin secretion. Another group of patients with type 1 diabetes (n=58) and nondiabetic (n=17) subjects served as reference subjects for the T cell and other assays. BCG-treated patients and one placebo-treated patient who unexpectedly developed an acute Epstein-Barr virus infection, another known inducer of TNF, exclusively showed transient increases in the number of circulating dead autoreactive T cells against insulin. In two of the BCG subjects and the EBV-infected subject, C-peptide levels rose transiently above baseline levels to a statistically significant extent in comparison to longitudinally followed C-peptide in reference subjects.
BCG-treatment or EBV-infection transiently modified the autoimmunity that underlies even advanced type 1 diabetes, suggesting that similar therapy may have value in the treatment and even reversal of advanced type 1 diabetes. Larger trials are necessary to extend these results and identify the most effective doses and frequency of BCG treatment.