Denise Faustman

From Wikipedia, the free encyclopedia

Dr. Denise Faustman

Denise Faustman, is a U.S. physician and medical researcher. An associate Professor of Medicine at Harvard University, her work specializes in Diabetes mellitus type 1 (formerly called juvenile diabetes). She has worked at Massachusetts General Hospital in Boston since 1985.

1 Research
2 Recent Controversy
- 2.1 Research
- 2.2 The Debate
3 Partial bibliography
4 External links

[edit] Research

Faustman's 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 to the effects of TNF-alpha (TNF-α), a cytokine that influences the immune system. 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 include flare-ups of autoimmune symptoms.

Under some conditions, TNF-α causes T cells to undergo apoptosis, or programmed cell death. Autoimmune T cells are more sensitive to TNF-α and undergo apoptosis more readily than normal T cells when exposed to TNF-α. Faustman's hypothesis, somewhat contrary to conventional thinking, is that blocking TNF-α actually promotes the survival of undersirable autoreactive T cells, and that autoimmune diseases should be treated by stimulating TNF-α to trigger apoptosis in self-destructive autoimmune T cells. [1]

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, is a patron of her work. After Faustman was denied funding by the JDRF, The Iacocca Foundation provided an $11.5 million dollar grant which both supported Faustman's work, and is being used for a clinical trial to be conducted by Harvard researcher David Nathan. This trial will not use spleen cells but only 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. BCG induces TNF-α. In previous human trials, it has not been shown to have a therapeutic effect in type 1 diabetics. Faustman hypothesizes that the correct dosing of BCG for diabetics has not been utilized in previous trials. As part of her research, she is seeking to define a dose that might have a therapeutic effect in the clinical trial to be led by Dr. Nathan.

Faustman's research has been profiled in the New York Times on November 9, 2004 and March 24, 2006, and in the Wall Street Journal on March 24, 2006.

[edit] Recent Controversy

[edit] Research

This approach was recently 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 (Freund's adjuvant) and a preparation of spleen cells allowed the beta islet cells to regenerate. [2]

The adjuvant increased the production of TNF-α , which reduced the number of autoreactive T cells and allowed for islet cell regrowth. Faustman hypothesizes that this regeneration may be attributed in part to the re-differentiation of the spleen cells, a position that continues to be debated.

[edit] The Debate

Faustman's protocol of Freund's adjuvant, along with the spleen cells, was effective in curing even mice with end-stage diabetes.

However, a debate continues over the source of the islet cell regeneration. An article in Diabetes Health details the backstory of the controversy.[3]

Researchers from three laboratories funded by the Juvenile Diabetes Research Foundation confirmed her success with mice and published paper in the March 24, 2006 issue of Science, but suggest that the proliferation of existing pancreatic stem cells may have been responsible for the success of the treatment. They did not find that adult spleen cells played a role in the regeneration of islets. Faustman responded in the Wall Street Journal that "The pancreas is too smart to cure itself in only one way," and stated "I think there will be many sources of regeneration, and we're only at the beginning of understanding what they are."

Coverage of the debate has also varied. The New York Times, in a March 24, 2006 article titled "A Controversial Therapy for Diabetes Is Verified," states that "Three groups of scientists report today that they independently replicated a controversial finding." [4] Similarly, The Wall Street Journal's article ran with the headline, "After Initial Rejection, Scientists Back Work on Cure for Diabetes."

A newspiece that ran in Science on that same day, however, says ""Three separate attempts have failed to replicate promising results that electrified the diabetes community 2 years ago." [5] In addition, the piece reported that ""because the three groups could not detect spleen-derived beta cells, and because treatment with CFA and islets alone yielded the same results as when spleen cells were added to the mix, the groups attribute these cures to CFA and temporary islets," and that "using CFA to cure mice is probably not relevant to humans." But nobody has ever measured BCG dosage and autoreactive cell death in repeated dosages as Faustman plans to. A grassroots campaign to raise money through Joinleenow.org from the Iacocca Foundation plans to bring Faustman's work to human trials.

Since then, a group from the National Institutes of Health has replicated her work in mice who have type 1 diabetes and Sjogren's disease. This laboratory was also able to confirm a role for a splenic stem cell in regeneration. The results are part of a poster presentation by Tran et al. (Abstract # 1202-P) at the June 2006 American Diabetes Association (ADA) Meeting [6]. Similarly, a Japanese group also presented corroboratory findings at the ADA meeting, presented by Okubo et al (Abstract # 1193-P).

[edit] Partial bibliography

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. 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. PMID 15968469.

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. PMID 15601373.

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. 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. PMID 14615542.

Begley, S. After Initial Rejection, Scientists Back Work On Cure for Diabetes. Wall Street Journal. (Eastern edition). New York, N.Y.: Mar 24, 2006. pg. B.1