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-----Original 
Subject: Faustman at Cell.com


BCG Therapy for Type 1 Diabetes: Restoration of Balanced Immunity and Metabolism

Highlights

The BCG vaccine is an attenuated form of mycobacterium originally developed >100 years ago for tuberculosis prevention. Its safety record is unsurpassed. This vaccine is now being investigated as a therapy for type 1 diabetes (T1D) and other autoimmune diseases to restore the immune balance.
Repeated BCG vaccinations in long-term diabetics can restore blood sugars to near normal by resetting the immune system and by increasing glucose utilization through a metabolic shift to aerobic glycolysis, a high-glucose-utilization state.
BCG-treated subjects given at least two vaccines do not experience restoration of blood sugars until about 3 years later, but once the blood sugars return to normal, the therapeutic effect endures beyond 5 years.
T1D subjects prior to BCG treatment have an immune system dominated by oxidative phosphorylation, a low-glucose-utilization state that predominantly utilizes the Krebs cycle for energy. Based on the Hygiene Hypothesis, lifelong underexposure to pathogens could account for the predominance of oxidative phosphorylation in untreated T1D.
Because the BCG-induced restoration of glucose utilization is through regulated cellular utilization of sugar, episodes of hypoglycemia with near-normal blood sugars are rarely reported.
The bacillus Calmette–Guerin (BCG) vaccine is a microorganism developed as a vaccine for tuberculosis 100 years ago and used as therapy for bladder cancer 40 years ago. More recently, BCG has shown therapeutic promise for type 1 diabetes (T1D) and several other autoimmune diseases. In T1D, BCG restored blood sugars to near normal, even in patients with advanced disease of >20 years duration. This clinically important effect may be driven by resetting of the immune system and the shifting of glucose metabolism from overactive oxidative phosphorylation, a state of minimal sugar utilization, to aerobic glycolysis, a state of high glucose utilization, for energy production. The mechanistic findings support the Hygiene Hypothesis and reveal the immune and metabolic synergy of mycobacterial reintroduction in modern humans.

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Glossary

Aerobic glycolysis
a metabolic pathway used by cells to obtain energy and to make purines, which are DNA and RNA building blocks. Aerobic glycolysis is not overly dependent on the mitochondria or the Krebs cycle. This metabolic pathway utilizes lots of sugar on the exterior of the cell as the energy course.
Bacillus Calmette–Guerin (BCG) vaccine
an attenuated Mycobacterium bovisorganism similar to the Mycobacterium tuberculosisorganism. BCG has been used globally as a preventive vaccine for tuberculosis for over 100 years, with over 3 billion people vaccinated.
Cytotoxic T lymphocytes (CTLs)
also known as autoimmune killer cells; pathogenic cells underlying autoimmunity that attack and kill self-organs.
Hygiene Hypothesis
an environment-based proposal to explain the increasing incidence of T1D and other autoimmune diseases. It asserts that diseases appear as a result of a change in environmental factors such as fewer childhood exposures to microorganisms, increased vaccines and thus fewer infections, increased antibiotic usage with fewer infections, cleaner foods without microorganisms, and a lifestyle without occupations with close interactions with soil and animals.
Ketones
substances produced during a late step in oxidative phosphorylation prior to the Krebs cycle; made from acetyl-CoA.
Krebs cycle
a late metabolic step during oxidative phosphorylation that yields energy in the form of ATP. Late stages of the Krebs cycle use the mitochondrial membrane for electron transport.
NOD mouse
a nonobese diabetic mouse that is a common murine model for the study of autoimmunity. Like humans, NOD mice spontaneously develop T1D driven by too many CTLs and too few functional Treg cells.
Oxidative phosphorylation
a metabolic pathway used by cells to obtain energy; dependent on only small amounts of glucose and utilizes the mitochondria and Krebs cycle.
Pentose phosphate shunt
the metabolic pathway for cellular synthesis of purines and pyrimidines; very active in aerobic glycolysis but underactive in oxidative phosphorylation.
Purines
building blocks of the nucleic acids DNA and RNA.
TB
M. tuberculosis, the pathologic version of mycobacteria that causes disease in humans.
Treg-specific demethylation region (TSDR)
the DNA region of the FoxP3 gene critical for Treg generation and stability. This DNA region must to demethylated for the critical CREB protein to bind; CREB must additionally be phosphorylated to bind to the demethylated region.
T regulatory (Treg) cells
suppressive cells that help to quiet the immune response. In autoimmune disease, they are deficient either in numbers or in their suppressive capabilities.
Tumor necrosis factor (TNF)
a naturally made cytokine that helps to mold the immune response. TNF is known to be the ligand for Treg expansion and also the ligand for selective death of cytotoxic lymphocytes.
Type 1 diabetes (T1D)
an autoimmune disease wherein the immune system abnormally attacks the insulin-secreting cells of the pancreas and thus causes life-threatening hyperglycemia.
Type 2 diabetes (T2D)
a disorder where early in the disease insulin is still made by the pancreas but the peripheral tissues where insulin acts are resistant to insulin action. It is generally believed that this insulin resistance eventually drives the massive amounts of pancreatic insulin production to decline.

Article Info

Publication History

Published online: December 29, 2018

Publication stage

In Press Corrected Proof

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© 2018 Elsevier Ltd. All rights reserved.

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