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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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References

  • Comas I.
  • et al.
Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans.
Nat. Genet. 2013; 45: 1176-1182
  • Barnes I.
  • et al.
Ancient urbanization predicts genetic resistance to tuberculosis.
Evolution. 2011; 65: 842-848
  • Strachan D.P.
Hay-fever, hygiene, and household size.
BMJ. 1989; 299: 1259-1260
View in Article
  • Goodridge H.S.
  • et al.
Harnessing the beneficial heterologous effects of vaccination.
Nat. Rev. Immunol. 2016; 16: 392-400
  • Jensen K.J. 
  • et al.
Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial.
J. Infect. Dis. 2015; 211: 956-967
  • Netea M.G.
  • van Crevel R.
BCG-induced protection: effects on innate immune memory.
Semin. Immunol. 2014; 26: 512-517
  • Arts R.J.
  • et al.
Immunometabolic pathways in BCG-induced trained immunity.
Cell Rep. 2016; 17: 2562-2571
  • Kleinijenhuis J.
  • et al.
Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity.
J. Innate Immun. 2014; 6: 152-158
  • Kleinnijenhuis J. 
  • et al.
Bacille Calmette–Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes.
Proc. Natl. Acad. Sci. U. S. A. 2012; 109: 17537-17542
  • Kuhtreiber W.M. 
  • et al.
Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations.
NPJ Vaccines. 2018; 3: 23
  • Okubo Y.
  • et al.
Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2.
Sci. Rep. 2013; 3: 3153
  • Okubo Y. 
  • et al.
Treg activation defect in type 1 diabetes: correction with TNFR2 agonism.
Clin. Transl. Immunol. 2016; 5: e56
View in Article
  • Faustman D.L.
  • et al.
Proof-of-concept, randomized, controlled clinical trial of Bacillus–Calmette–Guerin for treatment of long-term type 1 diabetes.
PLoS One. 2012; 7: e41756
  • Ban L.
  • et al.
Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism.
Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 13644-13649
  • Morikawa H.
  • et al.
Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation.
Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 5289-5294
  • Scott-Browne J.P.
  • et al.
Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis.
J. Exp. Med. 2007; 204: 2159-2169
  • Yadav V.
  • et al.
Understanding the host epigenetics in Mycobacterium tuberculos infection.
J. Genet. Genome Res. 2015; 2: 016
View in Article
  • Yaseen I.
  • et al.
Mycobacteria modulate host epigenetic machinery by Rv1988 methylation of a non-tail arginine of histone H3.
Nat. Commun. 2015; 68922
View in Article
  • Bettini M.L.
  • et al.
Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency.
Immunity. 2012; 36: 717-730
  • Liu Y.
  • et al.
Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function.
Mol. Cell. Biol. 2014; 34: 3993-4007
  • Bai G.
  • et al.
Cyclic AMP signalling in mycobacteria: redirecting the conversation with a common currency.
Cell. Microbiol. 2011; 13: 349-358
  • Rehren G. 
  • et al.
Differential gene expression between Mycobacterium bovis and Mycobacterium tuberculosis.
Tuberculosis (Edinb.). 2007; 87: 347-359
  • Shi L.
  • et al.
Immunometabolism in tuberculosis.
Front. Immunol. 2016; 7: 150
  • Gleeson L.E.
  • et al.
Cutting edge: Mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication.
J. Immunol. 2016; 196: 2444-2449
View in Article
  • Cheng S.C.
  • et al.
mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity.
Science. 2014; 3451250684
  • Ryu S.
  • et al.
Reversal of established autoimmune diabetes by restoration of endogenous beta cell function.
J. Clin. Invest. 2001; 108: 63-72
View in Article
  • Kodama S. 
  • et al.
Islet regeneration during the reversal of autoimmune diabetes in NOD mice.
Science. 2003; 302: 1223-1227
  • Faustman D.L.
TNF, BCG, and the proteasome in autoimmunity: an overview of the pathways & results of a Phase I study in type 1 diabetes.
in: Faustman D. (Ed.) The Value of BCG and TNF in Autoimmunity. 1st edn.  Academic Press, ; 2014: 81-104
  • Ristori G.
  • et al.
Effects of bacille Calmette–Guerin after the first demyelinating event in the CNS.
Neurology. 2014; 82: 41-48
  • Arnoldussen D.L.
  • et al.
BCG vaccination and allergy: a systematic review and meta-analysis.
J. Allergy Clin. Immunol. 2011; 127(246–253.e21)
  • Shann F.
The nonspecific effects of vaccines and the expanded program on immunization.
J. Infect. Dis. 2011; 204: 182-184
  • Kristensen I.
  • et al.
Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa.
BMJ. 2000; 321: 1435-1438
View in Article
  • Karaci M.
The protective effect of the BCG vaccine on the development of type 1 diabetes in humans.
in: Faustman D. (Ed.) The Value of BCG and TNF in Autoimmunity. 1st edn.  Academic Press, ; 2014: 52-62
  • Kiraly N.
  • et al.
BCG for the prevention of food allergy – exploring a new use for an old vaccine.
Med. J. Aust. 2015; 202: 565-566
  • Higgins J.P.
  • et al.
Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review.
BMJ. 2016; 355: i5170
  • Biering-Sørensen S.
  • et al.
Early BCG-Denmark and neonatal mortality among infants weighing <2500g: a randomized controlled trial.
Clin. Infect. Dis. 2017; 65: 1183-1190
  • Rieckmann A.
  • et al.
Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010.
Int. J. Epidemiol. 2017; 46: 695-705
View in Article
  • Pollard A.J.
  • et al.
Non-specific effects of vaccines: plausible and potentially important, but implications uncertain.
Arch. Dis. Child. 2017; 102: 1077-1081
  • McInerney M.F.
  • et al.
Prevention of insulitis and diabetes onset by treatment with complete Freund’s adjuvant in NOD mice.
Diabetes. 1991; 40: 715-725
View in Article
  • Sadelain M.W.J.
  • et al.
Prevention of type I diabetes in NOD mice by adjuvant immunotherapy.
Diabetes. 1990; 39: 583-589
View in Article
  • McDevitt H.
  • et al.
Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunity.
Arthritis Res. 2002; 4: S141-S152
View in Article
  • Huppmann M.
  • et al.
Neonatal bacille Calmette–Guerin vaccination and type 1 diabetes.
Diabetes Care. 2005; 28: 1204-1206
  • Karaci M.
  • Aydin M.
The effect of BCG vaccine from protection of type 1 diabetes mellitus.
J. Contemp. Med. 2012; 2: 1-8
View in Article
  • Shehadeh N.
  • et al.
Effect of adjuvant therapy on development of diabetes in mouse and man.
Lancet. 1994; 343 (see comments): 706-707
  • Allen H.F.
  • et al.
Effect of bacillus Calmette–Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study.
Diabetes Care. 1999; 22: 1703-1707
  • Hayashi D.
  • et al.
Comparable studies of immunostimulating activities in vitro among Mycobacterium bovis Bacillus Calmette-Guérin (BCG) substrains.
FEMS Immunology and Medical Microbiology. 2009; 56: 116-128
  • Drouin P.
  • et al.
Diagnosis and classification of diabetes mellitus.
Diabetes Care. 2009; 32: S62-S67
  • van Dam A.D.
  • et al.
BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice.
Atherosclerosis. 2016; 251: 6-14
  • Inafuku M.
  • et al.
Intravenous Mycobacterium bovis bacillus Calmette–Guerin ameliorates nonalcoholic fatty liver disease in obese, diabetic ob/ob mice.
PLoS One. 2015; 10e0128676
  • Kuhtreiber W.M.
  • et al.
Impact of blood sugar control on metabolites and carbohydrate metabolism in type 1 diabetes.
Diabetes. 2018; 67: A473
View in Article

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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