Denise Faustman
Encyclopedia
Denise L. Faustman, 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. She has worked at Massachusetts General Hospital
in Boston since 1985.
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.
, 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. 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.
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. 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; 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. 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.
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, is a patron of her work. The Iacocca Foundation helped raise the $11.5 million dollars 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, although one study from Israel did show a benefit (disease remission) in newly diagnosed type 1 diabetes. Faustman hypothesizes that the optimal dosing of BCG has not been utilized in previous trials.
Additional Phase I data were presented at the American Diabetes Association's
71st Scientific Sessions in June 2011. 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.
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
and medical researcher. An Associate Professor of Medicine at Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
and Director of the Immunobiology Laboratory at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
, her work specializes in diabetes mellitus type 1
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
(formerly called juvenile diabetes) and other autoimmune diseases. She has worked at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
in Boston since 1985.
Education and career
Faustman was born in Royal Oak, MichiganRoyal Oak, Michigan
Royal Oak is a city in Oakland County of the U.S. state of Michigan. It is a suburb of Detroit. As of the 2010 census, the city had a total population of 57,236. It should not be confused with Royal Oak Charter Township, a separate community located nearby....
in 1958. In 1978, she received her BS in zoology
Zoology
Zoology |zoölogy]]), is the branch of biology that relates to the animal kingdom, including the structure, embryology, evolution, classification, habits, and distribution of all animals, both living and extinct...
and chemistry
Chemistry
Chemistry is the science of matter, especially its chemical reactions, but also its composition, structure and properties. Chemistry is concerned with atoms and their interactions with other atoms, and particularly with the properties of chemical bonds....
from the University of Michigan
University of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
. She earned a Ph.D.
Ph.D.
A Ph.D. is a Doctor of Philosophy, an academic degree.Ph.D. may also refer to:* Ph.D. , a 1980s British group*Piled Higher and Deeper, a web comic strip*PhD: Phantasy Degree, a Korean comic series* PhD Docbook renderer, an XML renderer...
in transplantation immunology in 1982 and an MD
Doctor of Medicine
Doctor of Medicine is a doctoral degree for physicians. The degree is granted by medical schools...
in 1985 from the Washington University School of Medicine
Washington University School of Medicine
Washington University School of Medicine , located in St. Louis, Missouri, is one of the graduate schools of Washington University in St. Louis. One of the top medical schools in the United States, it is currently ranked 4th for research according to U.S. News and World Report and has been listed...
in St. Louis, Missouri
St. Louis, Missouri
St. Louis is an independent city on the eastern border of Missouri, United States. With a population of 319,294, it was the 58th-largest U.S. city at the 2010 U.S. Census. The Greater St...
. She did her internship and residency in medicine at Massachusetts General Hospital.
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 apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, 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. 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
Adalimumab
Adalimumab is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab was constructed from a fully human monoclonal antibody, while infliximab...
, infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
, and etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
. 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
NOD mice
Non-obese diabetic or NOD mice, like the Biobreeding rat, are used as an animal model for type 1 diabetes.- History :Non-obese diabetic mice exhibit a susceptibility to spontaneous development of autoimmune insulin dependent diabetes mellitus...
), a strain of mice that spontaneously develops type 1 diabetes
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
. Injecting the mice with a common inflammatory agent that increases the production of TNF-α, called complete Freund's adjuvant
Freund's adjuvant
Freund's adjuvant is a solution of antigen emulsified in mineral oil and used as an immunopotentiator . The complete form, Freund's Complete Adjuvant, is composed of inactivated and dried mycobacteria , whereas the incomplete form lacks the mycobacterial components...
(CFA), and a preparation of spleen cells reversed type 1 diabetes in mice with end-stage disease and allowed the beta islet
Beta cell
Beta cells are a type of cell in the pancreas located in the so-called islets of Langerhans. They make up 65-80% of the cells in the islets.-Function:...
cells to regenerate.
Faustman hypothesized that this regeneration may be attributed in part to the re-differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
of the spleen cells - that although the splenic stem cells they identified were not obligatory for regeneration to occur, these cells could hasten regeneration. The source of islet cell regeneration is debated. Researchers from three laboratories funded by the Juvenile Diabetes Research Foundation
Juvenile Diabetes Research Foundation
JDRF is the leading global organization focused on type 1 diabetes research. Driven by volunteers connected to children, adolescents, and adults with this disease, JDRF is the largest charitable supporter of T1D research...
confirmed that Dr. Faustman's protocol can successfully reverse type 1 diabetes in end-stage mice; 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
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
islet cells.
A research group led by a researcher from the U.S. National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) has also replicated Faustman's work in mice with type 1 diabetes. 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 ChryslerChrysler
Chrysler Group LLC is a multinational automaker headquartered in Auburn Hills, Michigan, USA. Chrysler was first organized as the Chrysler Corporation in 1925....
chairman Lee Iacocca
Lee Iacocca
Lido Anthony "Lee" Iacocca is an American businessman known for engineering the Mustang, the unsuccessful Ford Pinto, being fired from Ford Motor Company, and his revival of the Chrysler Corporation in the 1980s...
, whose wife died of type 1 diabetes complications and who has declared a desire to see the disease cured in his lifetime, is a patron of her work. The Iacocca Foundation helped raise the $11.5 million dollars needed to support a Phase I human clinical trial at Massachusetts General Hospital to test whether vaccination with Bacillus Calmette-Guerin
Bacillus Calmette-Guérin
Bacillus Calmette-Guérin is a vaccine against tuberculosis that is prepared from a strain of the attenuated live bovine tuberculosis bacillus, Mycobacterium bovis, that has lost its virulence in humans by being specially subcultured in an artificial medium for 13 years, and also prepared from...
(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, although one study from Israel did show a benefit (disease remission) in newly diagnosed type 1 diabetes. Faustman hypothesizes that the optimal dosing of BCG has not been utilized in previous trials.
Clinical trials
Safety results from the Phase I human clinical trial were announced in June 2010. 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
American Diabetes Association
The American Diabetes Association is a United States-based association working to fight the consequences of diabetes, and to help those affected by diabetes...
71st Scientific Sessions in June 2011. 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
C-peptide
C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...
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
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
, 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.