BCG vaccine may induce reversal of type 1 diabetes
Treatment with bacillus Calmette-Guérin (BCG) appears to reverse advanced type 1 diabetes (T1D) in patients after repeat vaccination, according to a phase II study presented at the 77th Scientific Sessions of the American Diabetes Association in California, USA.
“BCG may induce a permanent increase in expression of genes that restore the beneficial regulatory T cells (Tregs) that prevent the immune system from attacking the body’s own tissue,” researchers said. “Increasing the potency or numbers of [Tregs] is a goal of many clinical trials.”
In the study, T1D patients treated with BCG had statistically significant increases in Treg numbers for 4 to 6 weeks following repeat BCG vaccination; a longer-lasting effect would be optimal and might even steadily reverse diabetic autoreactivity, according to researchers. [ADA 2017, abstract 1816]
"We and other global efforts have known for some time that restoring beneficial Treg cells might halt the abnormal self-reactivity in type 1 diabetes and other autoimmune diseases, but therapies to restore this immune balance have not achieved long-lasting results," Dr Denise Faustman, associate professor of Medicine at Harvard Medical School, director of the Massachusetts General Hospital Immunobiology Laboratory and principal investigator of the trial, said in a press statement.
“The discovery that BCG restores Tregs through epigenetics, a process that modulates whether or not genes are expressed, is exciting. This now provides a better idea of how BCG vaccination appears to work by powerfully modulating Treg induction and resetting the immune system to halt the underlying cause of the disease," she added.
Faustman and her team investigated whether the effect of repeat BCG vaccinations on Tregs could be permanent and driven by host epigenetic modifications to Treg signature genes. They profiled transcriptional start site (TSS) clusters located within the Treg-specific demethylation region in T1D patients before and 8 weeks after in vivo BCG dosing to assess the impact of BCG on methylation at methylation sites on six Treg signature genes, namely FoxP3, TNFRSF18, IL2RA, IKZF2, IKZF4 and CTLA4.
Monitoring via CD4 T cells in blood collected from BCG-treated T1D patients revealed that repeat BCG vaccinations reset the immune system by consistent and rapid demethylation of all six key Treg genes for enhanced mRNA expression.
“This suggests that not only are Treg cell numbers transiently elevated after BCG vaccination, but also that permanent epigenetic expression of Treg genes that control Treg potency is stably re-established by BCG treatment,” researcher said. “BCG vaccination, like tuberculosis, powerfully modulates Treg induction.”
Known for its role in preventing tuberculosis (TB), the BCG vaccine is based on a harmless strain of bacteria associated with the one that causes TB. It is approved by the FDA for vaccination against TB and for the treatment of bladder cancer. According to researchers, there are currently several studies investigating the potential of repeat BCG vaccinations to prevent and reverse autoimmune diseases, including T1D and multiple sclerosis.
"Repeat BCG vaccination appears to permanently turn on signature Treg genes, and the vaccine's beneficial effect on host immune response recapitulates decades of human co-evolution with mycobacteria, a relationship that has been lost with modern eating and living habits,” said Faustman. “It is incredible that a safe and inexpensive vaccine may be the key to stopping these terrible diseases."
An autoimmune disease, T1D is characterized by the destruction of islets by autoreactive T cells, which mistakenly attack islets as if they were an infection. Tregs help prevent these misguided attacks against tissues without diminishing the entire immune system, according to researchers.