by Kevin C. Ma (Harvard College, 2017)
During most of the New England Symposium, our attention was focused on how metabolism and its pathways converge with and impact tuberculosis, on the scale of molecular genetics to epidemiology. These talks highlighted important new areas of potential interdisciplinary research efforts and suggested metabolism-related therapeutics for continuing the fight against infectious diseases. But it was in the last presentation with Denise Faustman, Associate Professor at MGH, that we saw that the flow of ideas can go both ways: the results of efforts in understanding and treating tuberculosis can provide new therapeutic avenues for the treatment of autoimmune and metabolic disorders, like Type 1 Diabetes.
In 2001, Professor Faustman and colleagues reported in the Journal of Clinical Investigation that the treatment of non-obese diabetic mice with Complete Freund’s Adjuvant (CFA) coupled with islet transplantation or splenocyte injection appeared to cure Type 1 Diabetes (1). CFA is an adjuvant which contains oils and killed Mycobacterium tuberculosis, and has been shown to induce immune response and production of TNFα, an inflammatory signaling protein (2). This work extended earlier research done which implicated TNFα as a potent tool to counter the autoimmune attack (3).
The result of these and numerous other studies implicated TNFα as a protein that is able to induce cellular death specifically in autoimmune T cells (7). Because TNFα cannot be safely administered into humans at high doses, Faustman employed an alternative approach: administration of the BCG vaccine. The BCG vaccine, originally used to combat tuberculosis, had been known to induce TNF for several decades (5). In 2012, Faustman published the results of an initial, proof of concept clinical trial using the BCG vaccine to treat late stage diabetic patients. Her results showed markedly improved insulin secretion in BCG patients; however, these results were transient and not permanent reversals (6).
Further work will be needed to better understand whether or not BCG can be an effective and long-lasting treatment. Professor Faustman is currently raising funds for a Phase II clinical trial, and offers extensive background information as well as a page for frequently asked questions on her lab page (8). We note that her findings are not without controversy: follow up research done by the Benoist-Mathis lab at Harvard questioned some initial findings, including whether or not the infusion of spleen cells was necessary for reversing Type 1 Diabetes, and criticized Faustman’s work for not including a control (9). This follow up study, Faustman’s reply (10) and other technical comments will give the interested reader a more balanced view of this approach. Finally, it is important to note that TNFα is not, by any means, a panacea for all autoimmune related diseases. In fact, as one audience member noted following Faustman’s presentation, elevated levels of TNFα are actually implicated in the pathogenesis of systemic lupus erythematosus (11).
While further research will be needed to determine if BCG is truly an effective therapeutic agent, it is clear that researchers working to tackle metabolic, autoimmune, and infectious diseases have much to benefit in collaborations with one another.
1. Ryu et al., Reversal of established autoimmune diabetes by restoration of endogenous β cell function. J Clin Invest. 2001;108(1):63–72.
2. Rabinovitch, A, Suarez-Pinzon, WL, Lapchak, PH, Meager, A, Power, RF. Tumor necrosis factor mediates the protective effect of Freund’s adjuvant against autoimmune diabetes in BB rats. J Autoimmun 1995. 8:357-366.
3. Ulaeto, D, Lacy, PE, Kipnis, DM, Kanagawa, O, Unanue, ER. A T-cell dormant state in the autoimmune process of nonobese diabetic mice treated with complete Freund’s adjuvant. Proc Natl Acad Sci USA 1992. 89:3927-3931.
4. S. Kodama, W. Kühtreiber, S. Fujimura, E. A. Dale, D. Faustman, Science 302, 1223 (2003).
5. Rahman MM, McFadden G (2006) Modulation of tumor necrosis factor by
microbial pathogens. PLoS Pathog 2: e4.
6. 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 7, e41756 (2012).
7. Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, et al. (2008) Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci U S A 105: 13644–13649.
9. J. Nishio et al., Science 311, 1775 (2006).
10. Faustman DL. Permanent reversal of diabetes in NOD mice. Science 2007; 317:196.
11. D. Kollias et al. Current Directions in Autoimmunity, vol. 5, pp. 30–50, 2002.