David-Axel Laplaud, MD, PhD
Neurology Department and Inserm UMR643,
University Hospital, Nantes, France
From a clinical point of view, multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, characterised by demyelinated lesions of white matter. Usually, the lesions are located around the ventricles in the deep white matter of the brain, and they can easily be detected on T2 weighted sequences in brain magnetic resonance imaging (MRI) scans. More recently, the presence of lesions close to, or within, the cortex has been underlined, these lesions outnumbering the others particularly in ‘old’ MS.
The disease is considered the most frequent of the rare diseases, as the prevalence in the EU and the USA is around 1–2 per 1,000 people, mainly affecting young adults. Women are more commonly diagnosed with MS, with a sex ratio of 3 to 1; this female predisposition is not fully understood, but stresses the importance of sex hormones in the context of MS.
From a clinical point of view, several types of MS have been described based on disability progression and the frequency of relapse. The most frequent type, affecting 85% of the patient’s, is relapsing remitting MS, characterised by relapses separated by periods of remission. The second type of the disease is primary progressive MS (with or without relapses), which is characterised by a progressive disability of the disease from the onset. Approximately 15% of the patients suffer from this type of MS, mostly affecting men around 40 years.
After a period of around 20 years, the relapsing remitting phase will gradually become secondary progressive. Relapses may be superimposed on the disability progressing, but usually they are less frequent than in the relapsing phase of the disease.
Immunopathology
The etiology of MS is still largely unknown but is considered multifactorial with the implication of different genes and environmental triggers. To date, approximately 20 different genes are known as risk factors for the disease, mostly affecting the immune system. Environmental factors with suspected implications for MS include Epstein-Barr virus and vitamin D status.
Examination of MS lesions is vital in understanding the disease. Under a microscope, the lesions are well defined, with a light grey or brown colour surrounding the ventricles in the white matter, particularly presented in the chronic plaques. When using specific stains on the myelin sheaths (for example, Luxol Fast Blue), these lesions are characterised by the loss of myelin with a relative preservation of axons; a hallmark of the disease. In most cases, the lesions consist of a central microvessel, possibly surrounded by a cell infiltrate. The border between the normal tissue and the lesion is sharp in the chronic MS plaques.
The acute MS lesion is characterised by a demyelination with cell infiltrate surrounding the vessels: mainly composed of CD4 and CD8 T-cells, and occasionally B-cells and plasmocytes.
The most frequently occurring infiltrating cells are the macrophages, which outnumber the T-cells with a ratio of 10 to 1. In the lesions, the macrophages are loaded with myelin debris as evidenced with specific immunostaining, thereby suggesting that the cells are digesting
the myelin sheaths.
MS can be transferred into an animal subject by immunisation with a myelin peptide. This triggers an autoimmune response against the central nervous system, with autoreactive T-cells committed against myelin determinants. This model is named Experimental Autoimmune Encephalomyelitis (EAE) and can clinically mimic the human disease. Several animal models exist, in different species, with different triggering antigens, and also in humanised/transgenic animals. This model allows studies on relapses and disability progression, and contributes to the overall understanding of the disease process.
Indeed, this model is useful to better understand the physiopathological mechanisms underlying the disease, and also to test therapeutic molecules. For example, natalizumab, a monoclonal antibody directed against the specific integrin VLA4, which is a reference treatment for MS, was first used in experimental autoimmune encephalmyelitis (EAE) as a ‘proof of concept’.
Moreover, from a neuropathological point of view, EAE can also mimic the human disease and usually a cellular infiltrate can be found in the lesions as presented in MS, with patches of demyelination close to the meninges. Furthermore, axonal loss is also usually found in the lesions, exactly as in the human disease. The use of the different EAE models, particularly with transgenic animals, allowed advances in the general understanding of the mechanisms underlying inflammation in the central nervous system.
Based on these findings, a complex model of the physiopatholoy of the lesions of MS has been devised. To summarise this, in the blood of the patient are naïve circulating, potentially autoreactive T-cells committed to myelin determinants that would be activated by an unknown antigen in secondary lymphoid organs. Upon activation, these T-cells express chemokine receptors and adhesion molecules needed for attraction and adhesion to brain endothelia, and then acquire the ability to cross the blood
brain barrier (BBB) and have access to the brain parenchyma. Within the brain, the T-cells are activated by local antigen presenting cells or by perivascular macrophages. These produce proinflammatory cytokines, leading to
the production of interleukins, antibodies, chemokines, matrix metalloproteinases, reactive oxygen species and glutamate, which damage neurons and oligodendrocytes, and breach the BBB provoking an afflux of immunocompetenT-cells into the brain. All of these cells will then contribute to the lesion process.
Treatment: where do we stand?
Based on these findings on the immunopathology of MS, several types of treatments have been developed. Due to
the altered immune system of the patient, the treatments are centred on immunomodulatory or immunosuppressive drugs. More recently, selective intervention on the immune system has been achieved with the use of monoclonal antibodies directed against a specific cell population. In the case of MS patients, B-cell depletion or a more general T- and B-cell depletion has been studied in several clinical trials. Recent treatments for MS act on the migratory patterns of the immune cells to the central nervous system (CNS) using natalizumab, and with the recent drug fingolimod. Unfortunately, to date we have no agents able to locally inactivate the infiltrating cells or act on the microglia and macrophages.
The most common drugs used in the treatment of MS are the immunomodulatory molecules beta interferon and glatiramer acetate. Beta interferon probably acts on T-cell activation, inducing a decreased activation pattern, proliferation and survival of the T-cells. The molecule also reduces crossing of the BBB by the T-cells.5 Glatiramer acetate is thought to mimic myelin antigens and to drive an anti-inflammatory Th2 cytokine bias, but it is also considered to act directly on the antigen presenting cells.
All these molecules have a proven efficacy concluded in several pivotal trials, and reduce the risk of relapse in multiple sclerosis patients by 30%. The advantage of these treatments is their weak toxicity, but a disadvantage is their low efficacy.
Other treatments commonly used in the treatment of MS are the cytotoxic drugs like mitoxantrone or cyclophosphamide and more recently, mycophenolate mofetil. Mitoxantrone has strong and proven efficacy on the inflammatory process of the disease, but with cardiac and haematological toxicity. Due to these side effects, mitoxantrone is used with caution when other treatments have failed.
New drugs have recently emerged in the treatment of MS: most of them being monoclonal antibodies (mAb). The first mAb used in MS was natalizumab (Tysabri), on the market since 2007 and one of the most effective therapies for MS, reducing the risk of relapse by 60%. The main action of natalizumab is on the inhibition of the migration of the immune cells into the CNS. A major consequence is decreased immunosurveillance of the CNS, with an increased risk of an opportunistic infection (progressive multifocal leunkoencephalopathy) due to the John Cunningham virus.
Several other mAbs may be used in MS, and most of them are in current clinical trials. Alemtuzumab is directed against CD52 and depletes almost all of the T-, B- and NK cells. It also has a strong efficacy both on clinical and MRI parameters. Daclizumab is directed against the receptor of IL2 and mainly targets the activated T-cells and some NK cells. Finally, rituximab is directed against CD20 and allows a complete depletion of the B-cells only. It is a well-tolerated drug with a good efficacy, at least on MRI parameters. Additional clinical trials are necessary to assess its clinical efficacy in MS patients.
Emerging therapies
Oral treatments will soon be available to treat MS. For example, cladribine is an immunosuppressant drug with a specific antilymphocyte effect. The drug interferes with DNA synthesis, inducing apoptosis of the target cells, particularly in the T- and B-cell pool. The drug is well tolerated by patients and easy to use, with four weeks of treatment during the first year of therapy and two weeks of treatment during the second year. Its efficacy has been shown against placebo in recently published trials, both on clinical (significant reduction of relapse) and radiological (significant reduction of lesional activity and burden) endpoints.
However, the drug induces a sustained and sometimes profound depletion of the circulating lymphocytes. Moreover, a risk of cancer cannot be excluded after a long-term therapy with this type of cytotoxic agent.
A new class of treatment, the sphingosine-1-phosphate (S1P) receptor modulators, has recently emerged. Fingolimod (FTY) is the first of these drugs that is proven to be effective in the treatment of MS.
The drug has shown its efficacy by reducing the risk of patients with MS experiencing clinical relapse and disability progression, and also on radiological parameters (gadolinium-positive lesions and progression of T2 lesion burden) against placebo and interferon-beta treated patients.
FTY is a sphingosine-like molecule that combines with its specific receptor on the cell membrane, inducing its long-lasting internalisation. To date, five subtypes of S1P receptors have been identified, termed S1P1 to S1P5, with distinctive patterns of expression: S1P1, S1P2 and S1P3 are widely expressed in the immune, cardiovascular and central nervous systems, whereas S1P4 and S1P5 are predominantly expressed in lymphoid cells and oligodendrocytes, respectively. S1P1, the dominant receptor subtype expressed on lymphocytes, is a major regulator of lymphocyte trafficking. In particular, egress of mature T-cells from the thymus, and of T- and B-cells from lymph nodes depends on signalling through S1P1.
As FTY downregulates S1P1, the naïve and central memory T-cells are trapped within the lymph nodes. Effector memory T-cells are spared, however, and are still able to circulate because these pre-activated T-cells do not need an S1P1 signal to egress from the lymph nodes. This suggest that the adaptative immune system is at least partially effective in treated patients.
Moreover, as FTY is a lipophilic molecule, the drug is able to cross the BBB and thus may have a direct influence on neuropathologic processes within the CNS. In vitro studies have shown that FTY may promote survival, differentiation, proliferation, process extension and migration of human oligodendrocyte progenitor cells. The functional inactivation of S1P1 on astrocytes by FTY may also reduce astrogliosis secondary to inflammatory injury, and then may also influence cytokine production and limit demyelination and axonal damage. Thus, modulation of S1P receptors on glial cells by FTY could also reduce the inflammatory damage in MS.
