Diabetic Immunotherapy Advances with BCG: Metabolic and Immune Reprogramming

This review describes the cellular and molecular mechanisms underlying multi-dose bacille Calmette-Guérin (BCG) as an investigational immunotherapy for glycemic improvement in autoimmune diabetes. The BCG data is most often human clinical trial data over the last 15 years paired with mechanistic insights. BCG as a vaccine has an excellent safety record with a century-long safety record in tuberculosis prevention worldwide and, for 36 years, has been FDA-approved at higher doses for the treatment of bladder cancer. Our group and others have conducted multiple clinical trials evaluating multi-dose BCG immunotherapy in adults with the two forms of longstanding autoimmune diabetes. In type 1 diabetes (T1D), clinical trials of multi-dose BCG have shown stable repeated reductions in the FDA-recommended biomarker glycated hemoglobin (HbA1c) to near-normal levels (vs placebo) for at least 8 years. This improvement paradoxically occurs without any recovery of pancreatic function from its negligible baseline level. Evidence from long-term trials, together with companion global mechanistic studies, indicates that glycemic improvement is associated with BCG-induced correction of aerobic glycolysis defects in lymphoid and myeloid cells, an outcome also observed in the granuloma of BCG's close relative, tuberculosis. Restoration of energy metabolism to aerobic glycolysis in diabetic lymphoid cells increases glucose utilization, thereby enhancing systemic glucose uptake from the bloodstream, as demonstrated by longitudinal PET/CT imaging. In contrast, latent autoimmune diabetes in adults (LADA), a form of slow autoimmune diabetes that occurs late into adulthood, has minimal or lacks the clinically significant aerobic glycolysis defect. In LADA with multi-dose BCG immunotherapy glycemic improvement in BCG-treated patients does not occur commonly, based on 8 years of data. LADA nevertheless displays other favorable immune and clinical responses suggestive of BCG-induced regulatory T cell (Treg) induction. In LADA, multi-dose BCG decreases inflammation, thus halting pancreatic autoimmunity with insulin rescue and also halts inflammatory driven insulin resistance. BCG's consistent clinical benefits in autoimmune diabetes coincide with the gradual pace of upstream epigenetic reprogramming of genes involved in metabolic and T cell pathways without changing genotype. Understanding the mechanistic chain linking BCG-induced epigenetic changes to clinical efficacy may offer insights into the treatment and potential prevention of autoimmune diabetes.