International Symposium "Stem Cell Transplantation in Multiple Sclerosis", Key-Note Lectures Book, 2009, p. 8-11
Pirogov National Medical Surgical Center, Moscow, Russia
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) caused by autoimmune reactivity of T cells towards CNS myelin components. There is increased evidence that the disease is associated with aberrant immune responses. MS progression inevitably leads to the loss of motor function, sensitive disturbances and cognitive impairment because of the immune-mediated demyelination and axon degeneration.
Autoimmune processes, namely pathological reactions of patient's immune system against myelin sheath of the own central nervous system cells, play the leading role in pathogenesis of the disease. The main mechanism leading to the damage of nervous tissue is the activity of autoimmune T-lymphocytes against myelin protein. Therefore, at present in addition to symptomatic therapy and drugs for reduction of relapses (corticosteroids and cytostatics), the most widely used are drugs of pathogenetic action (disease-modifying treatment). Among them are beta-interferons and glatiramer acetate (Copaxone).
At present a number of mechanisms of pathogenetic actions of beta-interferons (Betaferon, Rebif, Avonex) are known:
- inhibition and modulation of cytokine-interferon activity (main anti-inflammatory cytokine contributing to onsets of multiple sclerosis exacerbations);
- inhibition of co-stimulatory molecules necessary for Т-lymphocytes activation and apoptosis progression of autoreactive T-lymphocytes;
- stimulation of suppressive Т-lymphocytes activity;
- decrease of expression of main hystocompatibility complex molecules on the antigen-presenting cells;
- blockade of matrix metalloproteinase and adhesion molecules (prevention from penetration of activated cells to the brain tissue through blood-brain barrier.
Mechanisms of action of glatiramer acetate (Copaxon) are related with the following:
- formation of close connection with main complex of class II histocompatibility on the membranes of antigen-presenting cells with formation of "false target" for T-lymphocytes;
- proliferation of specific T-cells which depress other autoagressive cell lines activity and are able to penetrate through blood-brain barrier;
- apoptosis of activated T-lymphocytes;
- suppression of anti-inflammatory IL-2 effect;
- stimulation of neurotrophic factor production (neuroprotective factor).
In a large series of investigations it is shown that regular use of Betaferon, Rebif, Avonex and Copaxon is safe and allows to diminish frequency and severity of relapses due to decrease of autoimmune process activity and to some extent to reduce the rate of disability progression. At the same time clinical advantages are confirmed by positive MRT changes such as decrease of the volume of local brain leisure, reduce of the amount and new demyelination foci.
During the last years mitoxantrone is increasingly used in therapy of progressive MS. Mitoxantrone has a particular effect on immune cells: its mechanism of action is related with the penetration between DNA molecule, blockade of replication processes and transcription, inhibition of topoisomerase II, that finally leads to repression of T- and B-lymphocytes proliferation. Mitoxantrone also has some immunomodulating properties: impairs antigen presentation by T-lymphocytes, decreases cytokines secretion, inhibits antibody production and macrophag-mediated myelin degradation, induces lymphocytes apoptosis, blocks inflammatory cells migration to the central nervous system.
According to the data of clinical trials mitoxantrone in a dose of 5 or 12 mg\m2 of body surface delays disease progression in secondary-progressive course and in aggressive course of remitting MS.
At present clinical trials of natalizumab (Tysabri) are being performed. Natalizumab is a selective antagonist of one of the adhesion molecules ( -4 and -1 integrins) on the surface of lymphocytes responsible for lymphocytes fixation on endothelium. The drug is a recombinant humanized monoclonal antibody.
According to AFFIRM study natalizumab decreases average annual frequency of relapses in comparison with placebo and decreases the risk of steady increase of disability by 42%.
Another monoclonal antibody drugs are under investigation - alemtuzumab (Campath), rituximab (Rituxan) and daclizumab (Zenapax). These are drugs from humanized antibodies with the aimed action to suppress T and B-lymphocytes activity, natural killers (NK-cells) and IL-2 inactivation.
Among new trends of MS therapy it is worth to note cladribine (in pills), which is purine nucleoside aimed against certain lymphocytes populations.
At present fingolimod, modulator of sphingosine-1-phosphate receptor which mechanism of action is related with connection with specific receptors on lymphocytes surface leading to their retention in peripheral lymph nodes and blockade of penetration to central nervous system, is being studied. According to the data obtained positive clinical picture and decrease of relapses were noted in 50% of the patients receiving Fingolimod during 6 months.
The effectiveness of such statins as simvastatin (Zocor) and atorvastatin is being discussed. However, in spite of the ability of statins to decrease the risk of cardiovascular diseases and their anti-inflammatory effect, efficacy and safety of statins in prolonged use in MS patients is not proved.
Recently, high-dose immunosuppressive therapy with autologous stem cell transplantation (HDIT+ASCT) was proposed as a new and promising therapy for MS patients. The rationale of this method is that ablation of aberrant immune system followed by reconstitution of the new immune system from haematopoietic stem cells may alter the characteristics of the T-cell responses and other immunological properties which may improve the clinical course of MS. By now centers in Europe, North and South America, Russia, China, Israel and Australia have the experience of use of HDIT+ASCT for MS treatment. Thus, more than 700 successful transplantations have been performed all over the world. Since 1995, several clinical studies have addressed the issue of feasibility and efficacy of HDIT+ASCT in MS and a certain clinical benefit has been shown.