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]
Bacillus Calmette-Guerin vaccineedit
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 trialsedit
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]
Partial bibliographyedit
Kuhtreiber WM, Washer SL, Hsu E, Zhao M, Reinhold P 3rd, Burger D, Zheng H, Faustman DL, et al. (2015). "Low levels of C-peptide have clinical significance for established Type 1 diabetes". Diabetic Medicine. 32 (10): 1346–53. doi:10.1111/dme.12850. PMC4578991. PMID 26172028.
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. Bibcode:2012PLoSO...741756F. doi:10.1371/journal.pone.0041756. PMC3414482. PMID 22905105.
Wang L, Lovejoy NF, Faustman DL (2012). "Persistence of prolonged C-peptide production in type 1 diabetes as measured with an ultrasensitive C-peptide assay". Diabetes Care. 35 (3): 465–70. doi:10.2337/dc11-1236. PMC3322715. PMID 22355018.
Burger DE, Wang L, Ban L, Okubo Y, Kühtreiber WM, Leichliter AK, Faustman DL (2011). "Novel automated blood separations validate whole cell biomarkers". PLOS ONE. 6 (7): e22430. Bibcode:2011PLoSO...622430B. doi:10.1371/journal.pone.0022430. PMC3142167. PMID 21799852.
Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL (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 (36): 13644–9. Bibcode:2008PNAS..10513644B. doi:10.1073/pnas.0803429105. PMC2533243. PMID 18755894.
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. PMID 16242708.
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. S2CID 22945347.
Kodama S, Faustman DL (2004). "Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes". Pediatr Diabetes. 5 (Suppl 2): 38–44. doi:10.1111/j.1399-543X.2004.00078.x. PMID 15601373. S2CID 43684761.
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. PMC209340. PMID 11435458.
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. Bibcode:2003Sci...302.1223K. doi:10.1126/science.1088949. PMID 14615542. S2CID 897696.
Referencesedit
^"Phase II Clinical Trial: Multi-dosing the BCG Vaccine for Fibromyalgia - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-01-06. Information provided by (Responsible Party): Denise Louise Faustman, MD, Massachusetts General Hospital
^ abc"Biography - Dr. Denise L. Faustman". Changing the Face of Medicine - Physicians. National Library of Medicine. Retrieved 2008-01-16.
^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. S2CID 22945347.
^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. PMC209340. PMID 11435458.
^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. Bibcode:2003Sci...302.1223K. doi:10.1126/science.1088949. PMID 14615542. S2CID 897696.
^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. Bibcode:2006Sci...314.1243F. doi:10.1126/science.1129811. PMID 17124308. S2CID 2314909.
^ ab"BCG vaccine could restore proper immune response in type 1 diabetes". Diabetes.co.uk. Retrieved 2017-06-12.
^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. Bibcode:2006Sci...311.1774C. doi:10.1126/science.1123510. PMID 16556844. S2CID 32144989.
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^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. Bibcode:2006Sci...311.1775N. doi:10.1126/science.1124004. PMID 16556845. S2CID 20631008.
^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. PMC1954678. PMID 17179174.
^"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.
^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.
^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.
^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.
^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. S2CID 25903546.
^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. S2CID 24627549.
^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. S2CID 45958457.
^Karaci M, Aydin M (March 2012). "Tip 1 diabetes mellitustan korunmada BCG aşısının etkisi" [The effect of BCG vaccine from protection of type 1 diabetes mellitus]. Çağdaş Tıp Dergisi / Journal of Contemporary Medicine (in Turkish). 2 (1): 1–8. ISSN 2146-6009.
^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. ISBN 9780127999647.
^ClinicalTrials.gov: Determination of Dosing and Frequency of BCG Administration to Alter T-Lymphocyte Profiles in Type I Diabetics, Last updated: November 4, 2013
^Faustman DL, Wang L, Okubo Y, Burger D, Ban L, et al. (August 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. Bibcode:2012PLoSO...741756F. doi:10.1371/journal.pone.0041756. PMC3414482. PMID 22905105.
^"Joint Statement from JDRF and the American Diabetes Association". JDRF. 2018-06-25. Retrieved 2019-02-11.
External linksedit
Alexandra Sifferlin (2015-06-07). "The Vaccine for Type-1 Diabetes Is Moving Forward". Time. Retrieved 2015-07-30.
Arlene Weintraub (2015-06-07). "Here's How Lee Iacocca Wants To Cure Diabetes". Forbes. Retrieved 2015-07-30.
Shannon Pettypiece (2012-08-09). "Diabetes May Be Reversed by Long-Used Vaccine for TB". Bloomberg News. Retrieved 2012-08-17.
Sharon Begley (2012-08-08). "Human Study Re-ignites Debate Over Controversial Diabetes 'Cure'". Reuters. Retrieved 2012-08-17.
Thomas H. Maugh II (2011-06-25). "Is BCG a cure for diabetes? The long road to acceptance". Los Angeles Times. Retrieved 2011-06-27.
Ron Winslow (2011-06-25). "Drug Offers Hope In Diabetes Study". The Wall Street Journal. Retrieved 2011-06-27.
Michelle Fay Cortez (2011-06-24). "Generic Tuberculosis Medicine Shows Promise for Reversing Type 1 Diabetes". Bloomberg News. Retrieved 2011-06-27.
Arlene Weintraub (2011-06-24). "The Auto Magnate and the Scientist: How Mass General is Working With Lee Iacocca to Find a Diabetes Cure". Xconomy. Retrieved 2011-06-27.
Gina Kolata (2006-03-24). "A Controversial Therapy for Diabetes Is Verified". The New York Times. Retrieved 2007-08-17.
Gina Kolata (2004-11-09). "I Beg To Differ: A Diabetes Researcher Forges Her Own Path to a Cure". The New York Times. Archived from the original on 2007-08-13. Retrieved 2007-08-17.
Sharon Begley (2006-03-24). "After Initial Rejection, Scientists Back Work on Diabetes". The Wall Street Journal. Retrieved 2011-06-23.
Martin Jensen (2005-05-01). "Why Did the JDRF Try to Discredit Cure Research?". Diabetes Health. Retrieved 2011-06-24.
Philip E. Ross (2006-11-12). "Putting Up With Self". Scientific American. Retrieved 2011-06-24.