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Successful Initiative on Gender Differences in MS

The initiative on Gender Differences in MS was launched in 1998 to increase research attention on the question of why more women than men have multiple sclerosis, why it seems to affect women differently than men and what the biological differences between the sexes can tell us about the cause and course of MS.  Attention to gender research in MS has been raised such that this area is now a part of our other research goals and no longer a targeted initiative. The information below traces progress made in this field.

Understanding the gender differences in MS that is, the increased incidence and prevalence of MS in women compared to men, along with differences in disease course and manifestations can provide new information about MS, its cause and even its treatment. In 1996, the Society convened a special task force to review the available literature in the field; this group recommended that the Society invest in sex-based research related to MS. By the time the concept of “targeted research” was developed at the Society, a plan for supporting “gender research” was in place, and this became the first targeted research area.

The Society issued a series of “requests for applications” for full grant and training support in gender research, and offered funding supplements to investigators who would add gender-based analyses to their already funded, ongoing projects.

Funding Results
Prior to 1998, the Society supported fewer than 5 research and training grants with a “gender” focus. By 2003, such projects accounted for some $6.6 million in total expenditures, a 10-fold increase over pre-targeted funding. Topping this portfolio are six projects funded through a first-ever cooperative research program in gender and immunity research between the Society and the NIH’s National Institute of Allergy and Infectious Diseases. The Society committed to co-funding six projects, 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.

Since 1998, the Society’s gender initiative has resulted in the support of 27 research projects, including the 6 major projects jointly supported with the NIH, and 20 grant supplements, with a total commitment since 1998 of $9.8 million. Eleven of the investigators attracted by this initiative had never before conducted gender-related research, and 9 of the investigators had never before been grantees of the Society.

Scientific Progress
The Society’s gender initiative generated new information on sex differences in disease course, the immune system, brain tissues, hormonal influences, and response to infection, and significantly increased the body scientists pursuing these questions in MS. Here is a sample of these results:

Rhonda Voskuhl, MD (University of California at Los Angeles) found that, in a small-scale, early-phase trial of the hormone estriol (a form of estrogen), women with relapsing-remitting MS showed decreases in MRI-detected brain lesion activity and immune responses during treatment; additional study of estriol is called for and planned to determine longer-term efficacy and safety.

Bruce Bebo, PhD (Oregon Health Sciences University) created a special mouse strain whose immune cells lack the receptor, or docking protein, for testosterone. Male mice of this strain indeed develop a more severe form of the MS-like disease EAE (and more similar to female disease) than males with intact receptors. In a related project, Dr. Rhonda Voskuhl is now conducting a preliminary clinical trial of testosterone gel in 12 men who have relapsing MS.

Halina Offner, PhD (Oregon Health Sciences University) explored the potential of sex hormones as a supplement to use of therapeutic T cell receptor (TCR) peptide vaccines an experimental approach currently being tested in persons with MS. Supplementing vaccination with estrogen dramatically increased the number of protective T cells in mice and prevented EAE, suggesting that a combination therapy of TCR vaccination and estrogen may be most effective against MS.

Carol Lee Koski, MD (University of Maryland, Baltimore) found that those animals with an MS-like disease treated with the hormone progesterone showed significant nerve cell loss, while those treated with either estrogen or both estrogen and progesterone were protected from nerve cell loss. This suggests that estrogen has a neuroprotective effect.

Cory Teuscher, PhD (University of Vermont, Burlington) found that in an MS-like disease in mice  that occurs after a viral infection, certain genes seem to control disease severity in males, while others appear to influence severity in females.

Scott Barnum, PhD (University of Alabama at Birmingham) showed that introducing high levels of a protein (C-reactive protein or CRP, which is regulated by testosterone) in female mice can delay the onset of EAE, indicating that sex hormones might in part through this path, control immune function and diseasea potential link between hormones, immune function and MS disease course.

Pamela McCombe, MBBS, PhD (University of Queensland, Australia) identified a pregnancy hormone, termed early pregnancy factor, which in lab rats reduced the severity of EAE, and could inhibit immune responses to a myelin protein. Further studies of this potentially important hormone and its possible implications for future MS therapy are under way.

Robert P. Skoff, PhD (Wayne State University, Detroit) is examining differences between men and women in development of myelin the nerve fiber insulation that is destroyed in MS and the cells that make myelin (oligodendrocytes), and made the surprising finding that the number of oligodendrocytes is 20% to 40% higher in female mice than males, and that the death and growth of these cells occurs at a higher rate in females as well.

Gender Research Mainstreamed
In 2003, the Research Programs Advisory Committee reviewed the Society’s involvement with gender research. The initiative was declared to be a success in attracting investigators into this previously underserved area, in generating new data and in resulting in the expenditure of nearly $10 million in new research and training focused on sex-based issues that impact. The study of gender differences is no longer an under-explored area, and is a self-sustaining area of research interest. Our interest in and support for gender research in MS continues, and projects in this area will be supported on a fully competitive basis in our investigator-initiated research programs.

Recent News: Gender Grantees Find Clue to Why Women Get MS More Often Than Men

An international team of researchers funded in part by the National MS Society has uncovered a genetic clue which, if confirmed, may help explain why women develop MS about twice as often as men. Read more

Recent News: Gender Grantees Meet to Share Findings 

Perhaps the single most powerful force in advancing science is the sharing of ideas that is why investigators studying sex-based differences in immune responses were brought together for a September 2004 meeting in Bethesda. The researchers had won funding in 2002 through a collaboration between the National Institutes of Health and the National MS Society and other agencies.

Fourteen grantees presented their findings related to sex influences not only in MS and its animal models but also in other autoimmune diseases and models, including lupus, myocarditis and arthritis, and in non-disease states such as pregnancy. The informal setting allowed for spontaneous exchanges among the investigators who work in parallel fields that rarely intersect.

“This was a terrifically informative meeting,” commented Patricia O’Looney, PhD, Director of Biomedical Research at the National MS Society. “I must have witnessed the beginnings of at least three new collaborations. That’s the whole point of meetings like this!” she added.

Six of the 14 grantees whose work relates specifically to MS are being supported by the Society. Among these, Drs. Halina Offner (Oregon Health Sciences University) and Michele Kosiewicz (University of Louisville) presented results of their experiments that examine how sex hormones influence immune cells and activity. Dr. Rhonda Voskuhl (UCLA) talked about the protective impact of estrogen on brain cells as well as its role in fighting inflammation, and described her team’s development of a unique mouse model that will help tease out the influence of sex hormones versus genes on immune responses.

In an end-of-meeting summary, Dr. Caroline Whitacre (Ohio State University), who chaired the original National MS Society Task Force that recommended that gender differences be targeted for more research, noted the enormous volume of data being amassed on the different ways that male and female immune systems act in health, during pregnancy, and within the context of different immune-related diseases including MS. This exchange of ideas among investigatos should go a long way toward increasing progress in this important area.

Last updated August 3, 2005