Denise Faustman

Denise L. Faustman, (born 1958[1]) is a U.S. physician and medical researcher. An Associate Professor of Medicine at Harvard University and Director of the Immunobiology Laboratory at Massachusetts General Hospital, her work specializes in diabetes mellitus type 1 (formerly called juvenile diabetes) and other autoimmune diseases.[2] She has worked at Massachusetts General Hospital in Boston since 1985.[1]

Education and career

Faustman was born in Royal Oak, Michigan in 1958. In 1978, she received her BS in zoology and chemistry from the University of Michigan. She earned a Ph.D. in transplantation immunology in 1982 and an MD in 1985 from the Washington University School of Medicine in St. Louis, Missouri. She did her internship and residency in medicine at Massachusetts General Hospital.[1]

Research

Faustman's current research is based on the observation that autoreactive T cells, that is, T cells programmed to attack the body's own cells and tissues, are more sensitive than normal T cells to the effects of TNF-alpha (TNF-α), a cytokine that influences the immune system. Under some conditions, TNF-α causes T cells to undergo apoptosis, or programmed cell death. Faustman's hypothesis, contrary to conventional thinking, is that blocking TNF-α actually promotes the survival of undesirable autoreactive T cells, and that certain autoimmune diseases can be treated by stimulating TNF-α to trigger apoptosis in autoimmune T cells.[3] TNF-α is a strong promoter of inflammation, and several treatments have been developed to block the effects of TNF-α in chronic and autoimmune diseases, including adalimumab, infliximab, and etanercept. However, side effects of these drugs can include new-onset autoimmunity and flare-ups of autoimmune symptoms.

Faustman's approach was tested in non-obese diabetic mice (NOD mice), a strain of mice that spontaneously develops type 1 diabetes. Injecting the mice with a common inflammatory agent that increases the production of TNF-α, called complete Freund's adjuvant (CFA), and a preparation of spleen cells reversed type 1 diabetes in mice with end-stage disease and allowed the beta islet cells to regenerate.[4][5]

Faustman hypothesized that this regeneration may be attributed in part to the re-differentiation of the spleen cells - that although the splenic stem cells they identified were not obligatory for regeneration to occur, these cells could hasten regeneration.[6] The source of islet cell regeneration is debated. Researchers from three laboratories funded by the Juvenile Diabetes Research Foundation confirmed that Dr. Faustman's protocol can successfully reverse type 1 diabetes in end-stage mice;[7][8][9] however, they did not find that the splenic cells played a role and suggested that the source of islet cell regeneration was proliferation of existing pancreatic islet cells.

A research group led by a researcher from the U.S. National Institutes of Health (NIH) has also replicated Faustman's work in mice with type 1 diabetes.[10] This group found that adult stem cells from the spleen did play a role in regeneration and also that Faustman's protocol could be used to reverse a second autoimmune disease, called Sjögren's syndrome, in mice.

Bacillus Calmette-Guerin vaccine

Former Chrysler chairman Lee Iacocca, whose wife died of type 1 diabetes complications and who has declared a desire to see the disease cured in his lifetime,[11] is a patron of her work. The Iacocca Foundation helped raise the $11.5 million needed to support a Phase I human clinical trial at Massachusetts General Hospital to test whether vaccination with Bacillus Calmette-Guerin (BCG), a weakened strain of bacteria that is used in the prevention of tuberculosis and in the treatment of bladder tumors and bladder cancer, as a treatment for advanced type 1 diabetes. Like CFA in the mouse, BCG induces TNF-α production in humans (CFA is not approved for use in humans). In previous human trials, BCG has not generally been shown to have a benefit in the prevention of type 1 diabetes or remission of the disease in those who are newly diagnosed,[12][13][14][15][16] although one study from Israel did show a benefit (disease remission) in newly diagnosed type 1 diabetes.[17] Faustman hypothesizes that the optimal dosing of BCG has not been utilized in previous trials.[2]

Clinical trials

Safety results from the Phase I human clinical trial were announced in June 2010.[18] BCG was found to be safe as administered in this trial to participants with advanced type 1 diabetes. No serious adverse events were reported, only expected mild inflammation at the injection site.

Additional Phase I data were presented at the American Diabetes Association's 71st Scientific Sessions in June 2011[19] and published in August 2012.[20] In the 20-week, double-blind, placebo-controlled study, participants with long-term type 1 diabetes (a mean duration of disease of 15 years) were randomized to repeated BCG vaccinations (n=3) or placebo (n=3). The participants were matched to control subjects without diabetes (n=6) and also compared to reference subjects with and without the disease. Two of the three BCG-treated participants experienced a transient but statistically significant rise in C-peptide levels compared to reference subjects. Participants who received BCG vaccination also experienced a transient increase in the number of circulating dead autoreactive T cells against insulin. One participant who was randomized to the placebo arm also had similar rises in C-peptide and dead autoreactive T cells after unexpectedly developing an acute infection with the Epstein-Barr virus, which, similar to BCG vaccination, is known to induce TNF. Faustman et al. concluded that BCG treatment or EBV infection transiently modified the autoimmunity that underlies advanced type 1 diabetes.[19]

Partial bibliography

References

  1. ↑ 1.0 1.1 1.2 "Biography - Dr. Denise L. Faustman". Changing the Face of Medicine - Physicians. National Library of Medicine. Retrieved 2008-01-16.
  2. ↑ 2.0 2.1 "Faustman Lab Website". Retrieved 2011-06-24.
  3. ↑ Kodama S, Davis M, Faustman DL (2005). "The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis". Cell Mol Life Sci 62 (16): 1850–62. doi:10.1007/s00018-005-5022-6. PMID 15968469.
  4. ↑ Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL (2001). "Reversal of established autoimmune diabetes by restoration of endogenous beta cell function". J Clin Invest 108 (1): 63–72. doi:10.1172/JCI12335. PMC 209340. PMID 11435458.
  5. ↑ Kodama S, Kuhtreiber W, Fujimura S, Dale EA, Faustman DL (2003). "Islet regeneration during the reversal of autoimmune diabetes in NOD mice". Science 302 (5648): 1223–7. doi:10.1126/science.1088949. PMID 14615542.
  6. ↑ Faustman DL, Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Toth ZE, Mezey E (2006). "Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice". Science 314 (5803): 1243. doi:10.1126/science.1129811. PMID 17124308.
  7. ↑ Chong AS, Shen J, Tao J, Yin D, Kuznetsov A, Hara M, Philipson LH (2006). "Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration". Science 311 (5768): 1774–5. doi:10.1126/science.1123510. PMID 16556844.
  8. ↑ Suri A, Calderon B, Esparza TJ, Frederick K, Bittner P, Unanue ER (2006). "Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells". Science 311 (5768): 1778–80. doi:10.1126/science.1123500. PMID 16556846.
  9. ↑ Nishio J, Gaglia JL, Turvey SE, Campbell C, Benoist C, Mathis D (2006). "Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution". Science 311 (5768): 1775–8. doi:10.1126/science.1124004. PMID 16556845.
  10. ↑ Tran SD, Kodama S, Lodde BM, Szalayova I, Key S, Khalili S, Faustman DL, Mezey E (2007). "Reversal of Sjogren's-like syndrome in non-obese diabetic mice". Ann Rheum Dis 66 (6): 812–4. doi:10.1136/ard.2006.064030. PMC 1954678. PMID 17179174.
  11. ↑ "BCG Vaccination Appears Promising as a Treatment for People With Existing Type 1 Diabetes, Phase I Trial Results Show". ScienceDaily - Science News. ScienceDaily LLC. Retrieved 2011-06-24.
  12. ↑ Dahlquist G, Gothefors L (1996). "The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination". Diabetologia 38 (7): 500–2. doi:10.1007/BF03035306. PMID 7556994.
  13. ↑ Allen HF, Klingensmith GJ, Jensen P, Simoes E, Hayward A, Chase HP (1999). "Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study". Diabetes Care. 22 (10): 1703–7. doi:10.2337/diacare.22.10.1703. PMID 10526739.
  14. ↑ Huppmann M, Baumgarten A, Ziegler AG, Bonifacio E (2005). "Neonatal Bacille Calmette-Guerin vaccination and type 1 diabetes". Diabetes Care 28 (5): 1204–6. doi:10.2337/diacare.28.5.1204. PMID 15855590.
  15. ↑ Parent ME, Siemiatycki J, Menzies R, Fritschi L, Colle E (1997). "Bacille Calmette-Guérin vaccination and incidence of IDDM in Montreal, Canada". Diabetes Care 20 (5): 767–72. doi:10.2337/diacare.20.5.767. PMID 9135940.
  16. ↑ Elliott JF, Marlin KL, Couch RM (1998). "Effect of bacille Calmette-Guérin vaccination on C-peptide secretion in children newly diagnosed with IDDM". Diabetes Care 21 (10): 1691–3. doi:10.2337/diacare.21.10.1691. PMID 9773732.
  17. ↑ Shehadeh N, Calcinaro F, Bradley BJ, Bruchim I, Vardi P, Lafferty KJ (1994). "Effect of adjuvant therapy on development of diabetes in mouse and man". Lancet 343 (8899): 706–7. doi:10.1016/S0140-6736(94)91583-0. PMID 7907682.
  18. ↑ "Mass. General Hospital, Iacocca Foundation announce completion of Phase I diabetes trial". Press Release. EurekAlert!. Retrieved 2011-06-24.
  19. ↑ 19.0 19.1 Faustman DL, Wang L, Yoshiaki O, Burger DE, Ban L, Man G, Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan DM. "BCG Treatment of Long-Term Type 1 Diabetics". Abstract 2240-PO. American Diabetes Association. Retrieved 2011-06-24.
  20. ↑ Faustman DL, Wang L, Okubo Y, Burger D, Ban L et al. (2012). "Proof-of-concept, randomized, controlled clinical trial of bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes". PLoS ONE 7 (8): e41756. doi:10.1371/journal.pone.0041756. PMC 3414482. PMID 22905105.

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