MS research makes the front page.

MS Research Makes the Front Page

Dr. Stephen Reingold, Society vice president of research and medical programs, in a question and answer format, discusses some of the implications and ramifications of this important research.

I.

Q. What exactly did the research consist of?

A. Dr. Lawrence Steinman and colleagues at Stanford University, in work partially supported by the National Multiple Sclerosis Society (NMSS), studied brain tissue from three people who had died with MS and compared it to tissue from three healthy individuals. Searching for evidence of immune cells called T-lymphocytes in the brain tissue, they expected to find as many as 18-20 different types of cells that might be related to the disease. Instead, they discovered a small number of T-cell types in the MS brains sample--only four--and none of these was seen in healthy control tissue.

Using a different approach, the NMSS-supported team from Harvard Medical School, headed by Drs. DAvid Hafler and Howard Weiner, explored the blood of five people with early relapsing-remitting MS and compared it to the blood of five heatlhy control subjects. Also, looking for the presence of MS-specific immune T-cells, they found increased numbers of one T-cell type which was reacting to brain myelin--the presumed target of attack in the disease--in people with MS as compared with controls.

These two findings allow us, for the first time, to consider homing in on specific immune system problems which might be related to the disease.

II.

Q. Are these T-cells the whole story in the MAS response, or are there other components of immune response that are important as well?

A. T-cells are clearly necessary for the MS immune reponse, but they are by no means the only important players in this disease process. Individual T-cells in MS are highly selective and responsive only to a single triggering agent--called an antigen--that can activate them and participate in the MS response. The specific triggering antigen for MS has been unknown. One of the new findings in the Harvard paper suggests that one important antigen or trigger is a component of myelin, actually a small peptide fragment of a major myelin protein called myelin basic protein. However, there may be other myelin peptides which can also trigger an MS response. These need to be discovered. Myelin is a normal part of our bodies where it serves to insulate nerve fibers in the brain and spinal cord, and it should not be the target of immune attack. It seems that there is an additional factor present in some people--most likely a genetic factor--which allows their immune system to misidentify normal myelin as "foreign" and to mount an inappropriate immue attack against that important insulating material.

It appears that a combination of factors is necessary before someone develops MS. Three of these are: 1. Specific T-Cells, capable of reacting to a myelin antigen; 2. The specific portion of myelin that acts to trigger the T-cells; and 3. A genetic factor that enables the T-cells to initiate an inappropriate immune response. Each of these elements is likely a necessary part of the MS disease process, but none of them alone may be sufficient to cause MS.

The key question for developing a specific therapy for MS is which element(s) of this complex can be targeted safely and effectively.

III.

Q. These findings seem to have clear implications for helping us understand the immune response in MS. What are the implications for treatment?

A. Most current experimental therapies for MS that relate to immune function are fairly non-specifi: that is, they may alter significant aspects of immune function, in addition to those related to the MS process. Moreover, many have significant detrimental side effects. For years it has been hoped that we could identify a specific MS problem that could be selectively targeted for new therapies. In mice with the MS-like disease, experimental allergic encephalomyelitis (EAE), we have known the details of the disease-specific immune response for some time and a variety of drugs including monoclonal antibodies and synthetic peptides, which block those responses in a highly specific fashion, have been extremely successful in treating this animal disease. Once we're certain about the details of the MS response, such therapies become more feasible for the human disorder as well.

IV.

Q. This work was done on humans with MS. Does this mean that animal research related to MS is no longer needed?

A. Absolutely not. All of the important concepts leading up to the work were based on research with mice susceptible to EAE, the MS-like disease in animals. In addition, the first successful specific immune therapies have been tested on the same animal disease. In the future, animal studies will help push forward our knowledge of the immune nature of MS and will continue to provide the essential first data on safety and effectiveness of any new therapy.

In truth, there is no computer model or tissue culture system which can come even close to reproducing the complexity of the immune system and the brain and spinal cord. Humane animal research remains an essential aspect of the struggle for an answer to MS.

V.

Q. These studies seem to have "sewed up" the problem. Are there unanswered questions?

A. Yes, there are. First, in each study, the number of people with MS was extremely small, and they clearly did not represent the spectrum of disease type and duration and severity that must be studied to make firm conclusions. In addition, many people with MS have at some point taken experimental treatments which alter immune responses: we don't know the treatment status of those in these experiments, or how their treatments might affect these findings, and this needs to be considered. Finally, it's not clear how specific these findings are for MS: healthy control subjects are important; but people with other neurological and immunological diseases must be studied also.

Additional studies including more subjects with MS, covering a greater spectrum of MS disease-types, as well as appropriate controls, must be made by these and other investigators to confirm the initial findings.

VI.

Q. On a larger scale, what are the implications for future investigation?

A. One of the results noted from the experimental treatment work with rodents was that neurological symptoms were reversed. Dr. Steinman and others have stated that new therapies based on these latest findings could be ready for the first stage of clinical trials within two years. Other investigators will certainly be looking to confirm the findings of this study--and perhaps to advance them. The unraveling of the MS process--and what has taken place has been a major step in that process--is leading researchers closer and closer to an ability to develop safe and sensible therapies specifically for MS.

VII.

Q. What role has the Society played in bringing us to this point?

A. THe National Multiple Sclerosis Society has provided significant research and training support to all of the laboratories which have participated in this work. More and more, joint efforts among varieties of funding agencies are the key to providing the level of support needed to undertake these complex studies; the National Multiple Sclerosis Society is core to this effort and will continue to be so.