Faustman's current research is based on the observation that autoreactive T cells (T cells that mistakenly 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 is that certain autoimmune diseases can be treated by stimulating TNF-α to trigger apoptosis in autoimmune T cells.[4]
Prior to entering human clinical trials, 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.[5][6]
Faustman hypothesized that this regeneration may be attributed in part to the re-differentiation of the spleen cells – that although the splenic stem cells were not obligatory for regeneration to occur, these cells could hasten regeneration.[7] The source of islet cell regeneration is debated. Faustman's team was the first to document type 1 diabetes reversal in mice and in a subsequent phase I trial demonstrated successful human clinical results who had received the BCG vaccination.[8] 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;[9][10][11] 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) replicated Faustman's work in mice with type 1 diabetes.[12]
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,[13] is a patron of her work. The Iacocca Foundation helped raise the $11.5 million needed to support a Phase I human clinical trial (for safety) at Massachusetts General Hospital to test 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 potential treatment for advanced type 1 diabetes. Like CFA in the mouse (not approved for use in humans), BCG induces TNF-α production in humans. In some human trials, BCG was not found to prevent type 1 diabetes, or lead to type 1 diabetes remission in those who are newly diagnosed,[14][15][16][17][18] although one study from Israel showed disease remission in newly diagnosed type 1 diabetes,[19] and an observational study from Turkey suggested that multiple doses of the BCG vaccine in childhood may protect against the development of type 1 diabetes.[20][21] Faustman hypothesizes that the optimal dose of BCG was not utilized in previous trials.[3] Faustman hypothesizes that BCG could induce a permanent gene expression that restores regulatory T cells (Tregs), helping to prevent the immune system attack which characterizes type 1 diabetes.[8]
Clinical trials
Faustman and co-workers published efficacy data from the Phase I trial NCT00607230[22] in 2012.[23] In the double-blind, placebo-controlled proof-of-concept study, six participants with long-term (mean duration of disease 15 years) type 1 diabetes 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. Blood samples were monitored weekly for 20 weeks. 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; it, like the 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. The data from the Phase I trial has sparked some controversy regarding the scientific rigor of the study, and the JDRF and the ADA made a joint statement listing concerns with the trial.[24]
Kuhtreiber WM, Kodama S, Burger DE, Dale EA, Faustman DL (2005). "Methods to characterize lymphoid apoptosis in a murine model of autoreactivity". J Immunol Methods. 306 (1–2): 137–50. doi:10.1016/j.jim.2005.08.008. PMID16242708.
^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. PMID10526739.
^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. PMID9135940. S2CID25903546.
^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. PMID9773732. S2CID24627549.
^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. PMID7907682. S2CID45958457.
^Karaci, Mehmet (March 18, 2014). "The Protective Effect of the BCG Vaccine on the Development of Type 1 Diabetes in Humans". In Faustman, Denise (ed.). The Value of BCG and TNF in Autoimmunity. Academic Press. ISBN9780127999647.
