All About Multiple Sclerosis

More MS news articles for March 2004

Making sense of basic research studies in MS: Part I of II

http://www.veritasmedicine.com/d_home.cfm?type=WU&did=121&cid=72576&rfr=vpt

April 9th, 2004
Amit Bar-Or, M.D.
Veritas Medicine

The following two Viewpoints are aimed at helping readers sort out the wealth of information that is being transmitted in both the popular media and the scientific literature. In this first Viewpoint, we will start by considering why such information is important and identify the challenges that we face in trying to make sense of everything that is published. To do this, we will review some basic concepts of how the immune system works, and what might go wrong in patients with MS.  In the next Viewpoint, we will discuss how the approved immune modulators in MS appear to work.

Although insights from basic research are no substitute for the results of well-designed clinical trials in MS, understanding how existing therapies work plays an important role in the development of new and improved treatments. Such an understanding can also help to optimize the use of current therapies, and then added information may help patients and their care teams.

However, it is not always easy to interpret the rapidly growing, and at times inconsistent, information that comes from studies of how MS drugs work. One challenge relates to how easily one can translate studies that take place in a laboratory dish to the actual ways a given medication works in people afflicted with MS. Studying drug effects in animal models has become an important part of the process of drug development and approval in MS. But it is now appreciated that observations from these models do not always predict effects—or toxicities—in patients.

The challenge can be addressed by distinguishing between results of how drugs work that are based on animal and laboratory studies, and those that are drawn from direct observations of clinical trials in patients with MS. To do this, let’s consider the ways in which the four approved immune modulators in MS (Avonex®, Betaseron®, Copaxone® and Rebif®) are thought to work. We’ll learn that it has become apparent recently that some of the ways we thought these medicines work may be more relevant than others.

MS as an autoimmune disease

The following explanation is slightly technical, but essential to understanding MS treatment. One of the main purposes of the normal immune system is to protect us from foreign elements, such as bacteria or viruses. In order to do that effectively and safely, the immune system must be very good at distinguishing what is ‘foreign’ and what is ‘self.’ When the immune system does not make a clear distinction, it can reacts to a component of ‘self’ (referred to as a ‘self-antigen’ or an ‘auto-antigen’) as though it were a foreign element (‘foreign-antigen’). The immune system may then attack the ‘auto-antigen,’ resulting in injury to the person’s own organs. These autoimmune diseases tend to target certain organs selectively. In the case of MS, the central nervous system is the target. The exact cause that triggers this autoimmune attack remains elusive. Most experts believe that MS manifests in persons with a pre-existing genetic susceptibility, combined with an environmental exposure during a critical period—probably early adolescence (1). Why the brain is the target of the attack in MS remains unknown.

The cells in the immune system responsible for making the distinction between foreign antigens and self-antigens are the T cells and the B cells. T-helper (Th) cells can be thought of as the ‘conductors’ of the immune response. Once these cells are activated, they direct the functions of many other immune system components. Every T cell is unique, distinguished by a unique receptor on its surface called the ‘T cell receptor,’ or TCR. The TCR allows its particular T cell to recognize only a few foreign antigens. The enormous number of T cells in the body--billions and billions—enables a person to respond to just about every conceivable foreign antigen.

T cells get activated when their particular, unique TCR comes in direct contact with the antigen fragment that it can recognize. (Almost always, this happens with the help of another cell type, called an ‘antigen presenting cell.’)  When a T cell recognizes foreign antigens through its TCR and receives additional appropriate signals, it becomes activated. At that point, it can release a variety of molecules that can direct the functions of other immune cells.

There is one final critical feature to the T cell response. When a T cell becomes activated, it can develop down one of two different pathways, called ‘Th1 responses’ and ‘Th2 responses.’ Whether an activated T cell has a Th1 response or a Th2 response depends on the local signals during the activation process. The presence of a molecule known as interleukin-12 (IL-12) generates Th1 responses; in the presence of a different molecule, IL-4, Th2 responses are promoted. This is the normal way the immune system works to create T cells that can respond in different ways, depending on the circumstance. For example, the body needs both Th1 responses to fight viral infections, and Th2 responses to combat parasites. Normally, a balance is maintained between the body’s Th1 and Th2 responses. If this balance is shifted inappropriately, disease can occur. For example, it is thought that too much of a Th2 response can lead to asthma.

There is growing evidence to suggest that in MS there may be too much of a Th1 response, and that Th1 T cells may contribute to damage in the CNS that can eventually lead to neurological disability (1-3). Part of this evidence comes from studies in animal models of MS, particularly in a model in mice known as EAE (experimental autoimmune encephalomyelitis). In the EAE model, introducing Th1 cells that recognize CNS antigens into a healthy animal will lead to a disease similar to MS. Giving the animal Th2 cells that recognize the same CNS antigens does not trigger disease. Moreover, giving the Th2 cells will protect the animal from getting disease when the Th1 cells are introduced. These observations have suggested that in MS, Th1 responses may be ‘pro-inflammatory’ and cause damage, whereas Th2 responses may be ‘anti-inflammatory’ and protective (4,5). While this is likely to be an over-simplification, it does make the important point that in MS, cells of the immune system are not all 'bad' or all 'good.'

In the next Viewpoint, we will use the information above to review the current thinking about how the approved immune modulators work in MS.

References:

1. Compston A, Coles A. Multiple sclerosis. Lancet 2002; 359:1221-1231

2. Hemmer B, Archelos JJ, Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nature Rev Neurosci 2002; 3:291-201.

3. Steinman L, Martin R, Bernard C, et al. Multiple sclerosis: deeper understanding of its pathogenesis reveals new targets for therapy. Annu Rev Neurosci 2002; 25:491-505.

4. Kieseier BC, Bernd C.; Hartung, Hans-Peter. Multiple paradigm shifts in multiple sclerosis. Curr Opin in Neurol 2003; 16(3):247-252.

5. Antel JP and Bar-Or A. Multiple Sclerosis: Therapy. In: Myelin Biology and Disorders. Robert Lazzarini, Ed. Elsevier Academic Press. 2004; pp 791-806.
 

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