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Postby scoobyjude » Sat Mar 10, 2007 1:55 pm

New Molecular Path To Fight Autoimmune Diseases Discovered By Penn Researchers

Main Category: Multiple Sclerosis News
Article Date: 10 Mar 2007 - 10:00 PST

Multiple sclerosis, diabetes, and arthritis are among a variety of autoimmune diseases that are aggravated when one type of white blood cell, called the immune regulatory cell, malfunctions. In humans, one cause of this malfunction is when a mutation in the FOXP3 gene disables the immune cells' ability to function. In a new study published online in the Proceedings of the National Academy of Sciences, researchers at the University of Pennsylvania School of Medicine have discovered how to modify enzymes that act on the FOXP3 protein, in turn making the regulatory immune cells work better. These findings have important implications for treating autoimmune-related diseases.

"We have uncovered a mechanism by which drugs could be developed to stabilize immune regulatory cells in order to fight autoimmune diseases," says senior author Mark Greene, MD, PhD, the John Eckman Professor of Pathology and Laboratory Medicine. "There's been little understanding about how the FOXP3 protein actually works." First author Bin Li, PhD, a research associate in the Greene lab has been working on elucidating this process since FOXP3's discovery almost five years ago.

Li discovered that the FOXP3 protein works via a complex set of enzymes. One set of those enzymes are called histone deacetylases, or HDACs. These enzymes are linked to the FOXP3 protein in association with another set of enzymes called histone acetyl transferases that modify the FOXP3 proteins.

Li found that when the histone acetyl transferases are turned on, or when the histone deacetylases are turned off, the immune regulatory cells work better and longer. As a consequence of the action of the acetylating enzyme, the FOXP3 protein functions to turn off pathways that would lead to autoimmune diseases.

"I think this simple approach will revolutionize the treatment of autoimmune diseases in humans because we have a new set of enzymatic drug targets as opposed to the non-specific therapies we now use," says Greene. Non-specific therapies include the use of steroids and certain chemotherapy-like drugs that act on many cell types and have significant side effects.

"Before this work, FOXP3 was thought essential for regulatory T-cell function, but how FOXP3 worked was not known," says Li. "Our research identifies a critical mechanism. Based on this mechanism, treatments could be developed to modulate this regulatory cell population."

"In this line of investigation, we have learned how to turn on or off this regulatory immune cell population - which is normally needed to prevent autoimmune diseases - using drugs that are approved for other purposes, but work on these enzymes" notes co-author Sandra Saouaf, PhD, a research associate at Penn.

Li, Greene, Saouaf and Penn colleagues Wayne Hancock and Youhai Chen are now extending this research directly to several mouse models of autoimmune diseases.
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Postby Toyoterry » Sat Mar 10, 2007 3:31 pm

Any ideas on the aformentioned drugs?
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Postby thinkingoutloud86 » Sat Mar 10, 2007 5:17 pm

I may be wrong on this and if someone knows better, please feel free to correct me...but, I think NeuoVax has some relation to the FO3P...

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Postby Lyon » Sat Mar 10, 2007 6:26 pm

I didn't see anything specifically linking it to FOXP3, but in reading about it, it seems like interesting stuff

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Postby dignan » Sat Mar 10, 2007 8:17 pm

TOL, you're right about Neurovax. There are a few postings that refer to it, and here is a fairly recent example:

I also noticed that estrogen has been found to influence FOXP3

A potential role for estrogen in experimental autoimmune encephalomyelitis and multiple sclerosis.

Ann N Y Acad Sci. 2006 Nov;1089:343-72
Offner H, Polanczyk M.
Neuroimmunology Research, Veterans Affairs Medical Center, 3710 SW U.S. Veterans Hospital Rd., Portland, OR 97239, USA.

The extensive literature and the work from our laboratory illustrate the large number of complex processes affected by estrogen that might contribute to the striking ability of 17-beta estradiol (E2) and its derivatives to inhibit clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in mice. These effects require sustained exposure to relatively low doses of exogenous hormone and offer better protection when initiated prior to induction of EAE. The E2 mediates inhibition of encephalitogenic T cells, inhibition of cell migration into central nervous system tissue, and neuroprotective effects that promote axon and myelin survival. E2 effects on EAE are mediated through Esr-1 (alpha receptor for E2) but not Esr-2 (beta receptor for E2), as are its anti-inflammatory and neuroprotective effects. A novel finding is that E2 upregulated the expression of FoxP3 that contributes to the activity of CD4 + CD25 + T regulatory cells (Treg). The protective effects of E2 in EAE suggest its use as a therapy for multiple sclerosis (MS). Possible risks may be minimized by using sub-pregnancy levels of exogenous E2 that produced synergistic effects when used in combination with another immunoregulatory therapy. Alternatively, one might envision using E2 derivatives alone or in combination therapies in both male and female MS patients.

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Last, but not least, some form of t-cell vaccination seemed to help through its influence on FOXP3...

CD4+ regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis.

Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5024-9. Epub 2006 Mar 17.
Hong J, Zang YC, Nie H, Zhang JZ.
Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.

Immunization with irradiated autologous T cells (T cell vaccination) is shown to induce regulatory T cell responses that are poorly understood. In this study, CD4(+) regulatory T cell lines were generated from patients with multiple sclerosis that received immunization with irradiated autologous myelin basic protein-reactive T cells. The resulting CD4(+) regulatory T cell lines had marked inhibition on autologous myelin basic protein-reactive T cells and displayed two distinctive patterns distinguishable by the expression of transcription factor Foxp3 and cytokine profile. The majority of the T cell lines had high Foxp3 expression and secreted both IFN-gamma and IL-10 as compared with the other pattern characteristic of low Foxp3 expression and predominant production of IL-10 but not IFN-gamma. CD4(+) regulatory T cell lines of both patterns expressed CD25 and reacted with activated autologous T cells but not resting T cells, irrespective of antigen specificity of the target T cells. It was evident that they recognized preferentially a synthetic peptide corresponding to residues 61-73 of the IL-2 receptor alpha chain. T cell vaccination correlated with increased Foxp3 expression and T cell reactivity to peptide 61-73...

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