Denise Faustman

File:Denise Faustman.jpgDr. Denise Faustman

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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.

## Contents

* 1 Research
* 2 Recent Controversy
* 2.1 Research
* 3 Partial bibliography
* 4 External links

## Research

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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 entanercept. 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.

## Recent Controversy

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### Research

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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.

Type 1 Autoimmune Diabetes is caused by rogue T cells that attack healthy tissue. In the case of Type 1 Autoimmune Diabetes, the healthy tissue under attack are the beta cells that regulate and produce insulin. Faustman's protocol of Freund's adjuvant, along with the spleen cells, was effective in curing even mice with end-stage diabetes. In her human trial, scheduled for early 2008, she plans to use BCG to kill the rogue T-cells that maintain the diseased state of autoimmunity. CFA and BCG affect rogue T-cells in a peculiar way, they induce cell apoptosis, a kind of cell suicide. Normal T-cells remain unaffected. The research is promising because it is hoped that once the bad T-cells are gone, regeneration of the beta cells will ensue. However, a debate continues over the source of the islet cell regeneration.

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. The JDRF funded researchers did not find that adult spleen cells played a role in the regeneration of islets. However, they did find that regeneration occurred once the rogue T-cells were removed; it just wasn't obvious where the regeneration was coming from. Faustman has stated in the Wall Street Journal regarding the debated source of islet regeneration, "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."

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." [3] 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." [4] 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 [5]. Similarly, a Japanese group also presented corroboratory findings at the ADA meeting, presented by Okubo et al (Abstract # 1193-P).

## Partial bibliography

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* 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.CS1 maint: Multiple names: authors list (link)

* 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.CS1 maint: Multiple names: authors list (link)

* 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.CS1 maint: Multiple names: authors list (link)

* 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.CS1 maint: Multiple names: authors list (link)

* 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

* Jensen, Martin. "Why Did the JDRF Try to Discredit Cure Research?". Diabetes Health. San Francisco, CA: May 2005.

## External links

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* Gina Kolata (March 24, 2006). "A Controversial Therapy for Diabetes Is Verified". The New York Times. Retrieved 2007-08-17.

* Gina Kolata (November 9, 2004). "I Beg To Differ: A Diabetes Researcher Forges Her Own Path to a Cure". The New York Times. Retrieved 2007-08-17.

* [6] Massachussetts General Hospital Diabetes Update Page

* [7] Wall Street Journal article, "After Initial Rejection, Scientists Back Work on Diabetes

* [8] Faustmanlab.org - home page regarding this research with updates and new information

* Join Lee Now

* [9] "Putting Up With Self" from Scientific American

* [10]Diabetes Health article on Dr. Faustman

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