Denise Faustman

Last updated
Denise Louise Faustman
Born1958 (age 64–65)
Royal Oak, Michigan
NationalityAmerican
Alma mater University of Michigan
Washington University in St. Louis
Known forType 1 diabetes reversal trials, mainly
Medical career
FieldImmunology
Institutions Harvard University
Massachusetts General Hospital
Website https://www.faustmanlab.org/

Denise Louise Faustman [1] (born 1958 [2] ) is an American 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. [3] She has worked at Massachusetts General Hospital in Boston since 1985. [2]

Contents

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 PhD 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. [2]

Research

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 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, [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]

Partial bibliography

Related Research Articles

<span class="mw-page-title-main">BCG vaccine</span> Vaccine primarily used against tuberculosis

Bacillus Calmette–Guérin (BCG) vaccine is a vaccine primarily used against tuberculosis (TB). It is named after its inventors Albert Calmette and Camille Guérin. In countries where tuberculosis or leprosy is common, one dose is recommended in healthy babies as soon after birth as possible. In areas where tuberculosis is not common, only children at high risk are typically immunized, while suspected cases of tuberculosis are individually tested for and treated. Adults who do not have tuberculosis and have not been previously immunized, but are frequently exposed, may be immunized, as well. BCG also has some effectiveness against Buruli ulcer infection and other nontuberculous mycobacterial infections. Additionally, it is sometimes used as part of the treatment of bladder cancer.

Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are diminished, leading to insufficient insulin secretion and hyperglycemia.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, post-infectious IBS, diabetes mellitus type 1, Henoch–Schönlein purpura (HSP) sarcoidosis, systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

<span class="mw-page-title-main">Albert Calmette</span> French physician and immunologist

Léon Charles Albert Calmette ForMemRS was a French physician, bacteriologist and immunologist, and an important officer of the Pasteur Institute. He discovered the Bacillus Calmette-Guérin, an attenuated form of Mycobacterium bovis used in the BCG vaccine against tuberculosis. He also developed the first antivenom for snake venom, the Calmette's serum.

<span class="mw-page-title-main">Amylin</span> Peptide hormone that plays a role in glycemic regulation

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D), and is sometimes referred to as type 1.5 diabetes. It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D. Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients.

Non-obese diabetic or NOD mice, like biobreeding rats, are used as an animal model for type 1 diabetes. Diabetes develops in NOD mice as a result of insulitis, a leukocytic infiltrate of the pancreatic islets. The onset of diabetes is associated with a moderate glycosuria and a non-fasting hyperglycemia. It is recommended to monitor for development of glycosuria from 10 weeks of age; this can be carried out using urine glucose dipsticks. NOD mice will develop spontaneous diabetes when left in a sterile environment. The incidence of spontaneous diabetes in the NOD mouse is 60–80% in females and 20–30% in males. Onset of diabetes also varies between males and females: commonly, onset is delayed in males by several weeks. The mice are known to carry IgG2c allele.

rBCG30 is a prospective vaccine against tuberculosis created by a team headed by Marcus A. Horwitz at UCLA. It is a live vaccine, consisting of BCG genetically modified to produce abundant amounts of a 30kDa antigen that has been shown to produce a strong immune response in animals and humans. The vaccine completed a Phase I double-blind randomized controlled clinical trial that demonstrated that rBCG30 was safe and immunogenic; during nine months of follow-up, rBCG30, but not BCG, induced significantly increased Antigen 85B-specific immune responses in eight immunological assays.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Mitumomab (BEC-2) is a mouse anti-BEC-2 monoclonal antibody investigated for the treatment of small cell lung carcinoma in combination with BCG vaccination. Mitumomab attacks tumour cells, while the vaccine is thought to activate the immune system. It was developed by ImClone and Merck.

Interferon-gamma release assays (IGRAs) are diagnostic tools for latent tuberculosis infection (LTBI). They are surrogate markers of Mycobacterium tuberculosis infection and indicate a cellular immune response to M. tuberculosis if the latter is present.

<span class="mw-page-title-main">PTPRN</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase-like N, also called "IA-2", is an enzyme that in humans is encoded by the PTPRN gene.

<span class="mw-page-title-main">Autoimmune disease</span> Abnormal immune response to a normal body part

An autoimmune disease is a condition that results from an anomalous response of the immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that there are more than 80 recognized autoimmune diseases, with recent scientific evidence suggesting the existence of potentially more than 100 distinct conditions. Nearly any body part can be involved.

Freund's adjuvant is a solution of antigen emulsified in mineral oil and used as an immunopotentiator (booster). The complete form, Freund's Complete Adjuvant is composed of inactivated and dried mycobacteria, whereas the incomplete form lacks the mycobacterial components. It is named after Jules T. Freund.

Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases. It must provide absence of specific antibodies for exactly that antigenes.

<span class="mw-page-title-main">Non-specific effect of vaccines</span> Unintended side effects of vaccines which may be beneficial or bad

Non-specific effects of vaccines are effects which go beyond the specific protective effects against the targeted diseases. Non-specific effects can be strongly beneficial by increasing protection against non-targeted infections. This has been shown with two live attenuated vaccines, BCG vaccine and measles vaccine, through multiple randomized controlled trials. Theoretically, non-specific effects of vaccines may be detrimental, increasing overall mortality despite providing protection against the target diseases. Although observational studies suggest that diphtheria-tetanus-pertussis vaccine (DTP) may be detrimental, these studies are at high risk of bias and have failed to replicate when conducted by independent groups.

<span class="mw-page-title-main">Pancreatic islet macrophage</span>

Islet resident macrophages are the predominant myeloid cell of the pancreatic islets of langerhans.

Trained immunity is a long-term functional modification of cells in the innate immune system which leads to an altered response to a second unrelated challenge. For example, the BCG vaccine leads to a reduction in childhood mortality caused by unrelated infectious agents. The term "innate immune memory" is sometimes used as a synonym for the term trained immunity which was first coined by Mihai Netea in 2011. The term "trained immunity" is relatively new – immunological memory has previously been considered only as a part of adaptive immunity – and refers only to changes in innate immune memory of vertebrates. This type of immunity is thought to be largely mediated by epigenetic modifications. The changes to the innate immune response may last up to several months, in contrast to the classical immunological memory, and is usually unspecific because there is no production of specific antibodies/receptors. Trained immunity has been suggested to possess a transgenerational effect, for example the children of mothers who had also received vaccination against BCG had a lower mortality rate than children of unvaccinated mothers. The BRACE trial is currently assessing if BCG vaccination can reduce the impact of COVID-19 in healthcare workers. Other vaccines are also thought to induce immune training such as the DTPw vaccine.

References

  1. ↑ "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
  2. 1 2 3 "Biography - Dr. Denise L. Faustman". Changing the Face of Medicine - Physicians. National Library of Medicine. Retrieved 2008-01-16.
  3. 1 2 "Faustman Lab Website" . Retrieved 2011-06-24.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. 1 2 "BCG vaccine could restore proper immune response in type 1 diabetes". Diabetes.co.uk. Retrieved 2017-06-12.
  9. ↑ 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.
  10. ↑ 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. Bibcode:2006Sci...311.1778S. doi:10.1126/science.1123500. PMID   16556846. S2CID   42150301.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ "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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ ClinicalTrials.gov: Determination of Dosing and Frequency of BCG Administration to Alter T-Lymphocyte Profiles in Type I Diabetics, Last updated: November 4, 2013
  23. ↑ 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 . PMC   3414482 . PMID   22905105.
  24. ↑ "Joint Statement from JDRF and the American Diabetes Association". JDRF. 2018-06-25. Retrieved 2019-02-11.
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