More MS news articles for September 2002

Gender Research Collaboration Yields 6 New Multiple Sclerosis-Related Research Projects

http://www.nationalmssociety.org/Research-2002Sept16.asp

September 16, 2002

Six new research projects on sex-based differences in immune system responses have begun as a result of a first-ever collaboration between the National MS Society and the National Institute of Allergy and Infectious Disease. The joint venture brings $7.3 million of new funding to support projects with direct relevance to multiple sclerosis, an immune-based disease that shows marked differences between men and women.

“Gender differences in MS have been underexplored, so in 1998 the National MS Society targeted this area for special research emphasis,” according to Stephen C. Reingold, PhD, the Society’s Vice President of Research Programs. “So far we’ve committed some $8.7 for research in this area.” To leverage additional support, the Society forged a collaborative agreement with the NIAID, an institute of the federal NIH.

As part of that agreement, in 2001 the NIAID invited the scientific community to submit research proposals on “Sex-based Differences in the Immune Response.” Of 60 proposals reviewed by a specially convened peer-review panel, 14 were approved for funding. The National MS Society has committed to co-funding six, for a total of $3.2 million, because of their relevance to MS. NIH’s funding share for these six projects is $4.1 million.

The six new projects focus on how sex hormones influence the behavior of immune cells; how pregnancy changes immune responses, for clues to improved strategies for treating autoimmune diseases; how the sex hormone estrogen protects mice from MS-like disease; and how a gene related to immune function is different in men and women and how it may contribute to MS susceptibility.

A list of grantees and their projects follows.

Other efforts supported by the National MS Society’s gender research initiative have included a pilot clinical trial of the sex hormone estriol to treat women with MS, a pilot clinical trial of the sex hormone testosterone to treat men with MS, and grant supplements to induce scientists to add gender questions to their current MS research projects.  The National MS Society is the largest private funder of MS research in the world, and this year alone will spend over $32 million to fund over 300 research studies.

NEW GENDER PROJECTS RESULTING FROM NMSS/NIAID COLLABORATION



Michele M. Kosiewicz, PhD
Health Sciences Center
University of Louisville
Louisville, KY
NMSS Chapter Area: Kentucky/SE Indiana
7/1/02-6/30/05; Total Award: $569,250
NMSS Funding Share: $247,500

“Sex-based differences in regulatory T cell responses”  Exploring whether sex hormones alter the activity of regulatory cells that can naturally dampen destructive immune responses.

Multiple sclerosis occurs more frequently in women than in men, and this is also the case for other autoimmune diseases such as lupus. Preliminary research in mice suggests that one key difference in the immune systems of males and females is the activity of naturally occurring regulatory cells capable of switching off immune attacks. Before adolescence, there appears to be no difference between the sexes regarding these regulatory cells, referred to as CD4+CD25+ regulatory T cells. After adolescence, the numbers and function of these cells appears to be reduced in females, perhaps contributing to increased vulnerability to autoimmune disease. Michele Kosiewicz, PhD, and colleagues are investigating whether sex hormones are at the root of this difference.

In a series of innovative experiments, the team is analyzing the activity of regulatory T cells in male and female mice in different life stages, including post-adolescence and during estrous cycles. The investigators are tracking whether there are differences in the way these regulatory cells interact with other immune cells, and manipulating levels of sex hormones to determine whether these alterations change the behavior of the regulatory cells.

Gaining an in-depth understanding of how regulatory T cells behave and change over time, and how they differ between the sexes, may ultimately offer new treatment opportunities for individuals with multiple sclerosis.



Timothy R. Mosmann, PhD
Center for Vaccine Biology & Immunology
University of Rochester
Rochester, NY
NMSS Chapter Area: Upstate New York
7/1/02-6/30/06; Total Award: $1,347,500
NMSS Funding Share: $550,000

“Bi-directional interactions between immunity and pregnancy”  How the immune system is inhibited during pregnancy to allow the mother to carry a “foreign” fetus, and how this mechanism may be applied to treating autoimmune disease.

Pregnancy presents a mystery to scientists because the fetus contains half of the father’s genes, and therefore should be rejected by the mother’s immune system as being “foreign,” just as would a foreign tissue graft. But by a little-understood process, in most cases the mother’s immune system adjusts to the fetus. Tim R. Mosmann, PhD, is testing the idea that the mother’s strong immune responses led by T cells (the same T cells involved in the attack in MS) are inhibited during pregnancy, and that weak immune responses are allowed to occur. His team is using a mouse model to track T cell functions and interactions during pregnancy, with particular focus on how their responses are inhibited.

This innovative research should provide new information on under-explored immune mechanisms during pregnancy, and may ultimately provide new leads for turning off immune attacks in autoimmune diseases such as MS.


Halina Offner, PhD
Portland VA Medical Center
Oregon Health & Science University
Portland, OR
NMSS Chapter Area: Oregon
8/1/02-7/31/06; Total Award: $1,521,560
NMSS Funding Share: $641,268

“Immunoregulatory effects of estrogen in EAE”  Determining how the female sex hormone estrogen inhibits immune-system responses in an MS-like disease in mice.

In people with MS, there is a distinct gender bias – women develop the disease two or three times as often as men. Sex hormones may contribute to MS susceptibility by influencing the immune attack on brain and spinal cord tissues. In previous studies, Halina Offner, PhD, found that treatment with the female sex hormone estrogen reduced severity of EAE, an MS-like disease in mice. Specifically, estrogen greatly reduced production of TNF-alpha, an immune messenger protein known to incite inflammation.

Now, Dr. Offner and her colleagues are investigating the influence of estrogen on immune responses even further. The team is exploring the hormone’s influence on genes that control various cells and proteins of the immune system.

In one series of experiments, the team is examining whether estrogen can still protect against EAE in mice whose immune cells are lacking specific docking sites, or receptors, for estrogen. Dr. Offner also is undertaking screening of numerous genes that have been found to be important in EAE, in order to determine whether they are influenced by estrogen.

The studies should add greatly to our knowledge of how estrogen influences the immune system, and provide fundamental information that will be required if estrogen is to be developed as a potential treatment for MS.



Howard R. Petty, PhD
College of Science
Wayne State University
Detroit, MI
NMSS Chapter Area: Michigan
7/1/02-6/30/06; Total Award: $1,116,500
NMSS Funding Share: $495,000

“Mechanisms regulating neutrophil activation in pregnancy”  Tracking specific immune cells during pregnancy, to improve understanding of factors that may be capable of turning off inflammation such as that involved in MS.

In women with certain autoimmune diseases, including MS, pregnancy can actually improve symptoms,  especially in the second and third trimesters, possibly as a consequence of hormone changes. Researchers are exploring immune functions during pregnancy to better understand this process.

Howard R. Petty, PhD, and colleagues are comparing the activity of immune cells called neutrophils in pregnant women, non-pregnant women, and men. Neutrophils are part of the body’s first line of defense against foreign invaders, such as bacteria. They also play a role in inflammation, and are capable of damaging tissues.

Dr. Petty’s team is measuring differences in the function of neutrophils, and is exploring new information suggesting that cells of the developing fetus may produce a factor that can neutralize the activity of the mother’s harmful neutrophils. If so, and if this factor can be understood and harnessed, it could lead to the development of a drug that would turn off inflammation.

This project should increase our fundamental understanding of immune factors at work during pregnancy, a time when MS disease activity tends to lessen. This may provide the key to new treatment approaches.


Rhonda R. Voskuhl, MD
Reed Neurological Research Center
University of California at Los Angeles
Los Angeles, CA
NMSS Chapter Area: Southern California
8/1/02-7/31/06; Total Award: $1,183,500
NMSS Funding Share: $495,000

“Mechanisms underlying the protective effect of pregnancy doses of estrogens in EAE”  Studying the effects of the sex hormone estrogen on immune-system responses in mice with MS-like disease for clues to its potential use to treat human MS.

Many women with MS who become pregnant experience a “holiday” from symptoms, especially during the second and third trimesters. One possible reason for this is the changes in hormone levels during pregnancy.

Rhonda R. Voskuhl, MD, has experimentally treated mice with the MS-like disease EAE, and also a small number of women with MS, with the sex hormone estrogen at levels mimicking those in later stages of pregnancy. She found benefit in EAE and evidence of safety and hints that estrogen was beneficial in women with MS (which is being pursued in further clinical trials). She is now focusing on how estrogen alters immune responses. This is vital if estrogen is to be exploited as a possible treatment for MS.

One aim of this study is to determine which of two cell-surface docking sites (receptors) for estrogen facilitates the hormone’s beneficial effects. Dr. Voskuhl’s team is also exploring how estrogen increases the production of an inflammation-fighting messenger chemical called IL-10.

Understanding the basic biological mechanisms through which estrogen alters immune responses may lead to a new treatment for individuals with MS.


Brian Weinshenker, MD
Mayo Clinic and Foundation
Rochester, MN
NMSS Chapter Area: Minnesota
9/1/02-8/31/05; Total Award: $ 1,568,556
NMSS Funding Share: $749,820
Paid in part by Thomas Maren Foundation

“Interferon gamma polymorphisms and gender bias in MS”  Studying genetic variations related to an interferon and their possible connection to gender differences in susceptiblity to MS.

MS occurs in individuals whose genetic makeup makes them susceptible to developing the disease, and the disease occurs more frequently in women than in men. Brian Weinshenker, MD, and an international team of collaborators are approaching the question of gender difference in MS by investigating differences in the genetic makeup of men and women.

Researchers around the world are searching for MS susceptibility genes using a variety of methods, including tracing gene variations, called polymorphisms, which occur more frequently in persons who have the disease. One area of possible interest is on chromosome 12, which contains genes that control a powerful immune messenger chemical called interferon  (IFN) gamma. Unlike interferon betas, which are used to treat MS, IFN gamma has been linked to immune attacks in MS, and recent evidence suggests that it is more active in women who have MS than in men.

In this project, Dr. Weinshenker’s team is aiming to fine-tune the location of IFN gamma gene and to examine variations that occur in the gene that may account for differences in MS and MS susceptibility seen between males and females.

Ultimately, this highly focused research will help us understand gender differences in MS and may add pieces to the puzzle of immune causes of MS, and the importance of interferons in both causation and treatment.
 

© 2002 The National Multiple Sclerosis Society