[The treatment by expanded ex vivo autologous regulatory T-cells CD4+CD25+FoxP3+CD127low restores the balance of immune system in patients with remitting-relapsing multiple sclerosis]. / Lechenie vyrashchennymi ex vivo autologichnymi regulyatornymi T-kletkami CD4+CD25+FOXP3+CD127low vosstanavlivaet balans immunnoi sistemy patsientov s remittiruyushchim rasseyannym sklerozom.

AIM: To assess clinical efficacy and safety of the autologous (own) regulatory T-cells (Tregs)CD4+CD25+Foxp3+CD127low isolated from the blood of patients with remitting-relapsing multiple sclerosis. Patients with autoimmune diseases have the decreased number of peripheral Tregs (pTreg) and impaired suppressive ability. In order to restore levels of pTreg, it is possible to isolate precursor cells, enter expanded ex vivo autologous Treg cells and introduce an expanded amount of autologous cells as Treg vaccine. MATERIAL AND METHODS: A method of ex vivo Tregs expansion by 30-40 times within 5-7 days has been developed. Expanded ex vivo Tregs are more than 90% CD4+CD25+Foxp3+CD127low and have high suppressor activity. Fourteen patients with remitting-relapsing multiple sclerosis were included in pilot studies.Ex vivoTregs were introduced subcutaneously in dosefrom 2.8 to 4.5 108 cell per injection. The duration of follow-up was 1 year. RESULTS AND CONCLUSION: The numbers of pTregs in the blood of these patients elevated by 1.5-2 times. No adverse-effects, a decrease of relapses and stabilization of disability index were observed. It has been suggested that ex vivo expanded Tregs can compensate the impaired function of pTregs and can be used for adoptive immunotherapyof multiple sclerosis.

[No support for the hypothesis of chronic cerebrospinal venous insufficiency in multiple sclerosis]. / Nedokazannost' gipotezy khronicheskoi tserebrospinal'noi venoznoi nedostatochnosti pri rasseiannom skleroze.

Objective. To evaluate the jugular veins (IJV) using duplex sonography in patients with multiple sclerosis (MS). Material and methods. The study included 21 MS patients with different disease course, degree of disability and disease duration. A control group consisted of 8 healthy volunteers. Results. IJV changes that meet the CCSVI criteria have not been found. These findings are consistent with the results of recently published large studies. Possible reasons of non-confirmation of this hypothesis are discussed. Conclusion. Currently vascular intervention in MS is not recommended.

[Compensatory mechanisms in multiple sclerosis(review)].

Neuroprotective mechanisms of delay of neurodegeneration and recovery of function in multiple sclerosis are reviewed. Different adaptive reactions(neuroprotective autoimmunity, neuroplasticity, sodium channels expression and function changes, remyelination) are described. The possibility of neurogenesis, axonal regeneration and synaptic changes is discussed. Understanding the compensatory mechanisms in multiple sclerosis is fundamental basis for the development of new therapeutic approaches.

[Physical rehabilitation in multiple sclerosis: general principles and high-tech approaches].

In a chronic and disabling disease like multiple sclerosis, rehabilitation programs are of major importance for the preservation of physical, physiological, social and professional functioning and improvement of quality of life. Currently, it is generally assumed that physical activity is an important component of non-pharmacological rehabilitation in multiple sclerosis. Properly organized exercise is a safe and efficient way to induce improvements in a number of physiological functions. A multidisciplinary rehabilitative approach should be recommended. The main recommendations for the use of exercise for patients with multiple sclerosis have been listed. An important aspect of the modern physical rehabilitation in multiple sclerosis is the usage of high-tech methods. The published results of robot-assisted training to improve the hand function and walking impairment have been represented. An important trend in the rehabilitation of patients with multiple sclerosis is the reduction of postural disorders through training balance coordination. The role of transcranial magnetic stimulation in spasticity reducing is being investigated. The use of telemedicine capabilities is quite promising. Due to the fact that the decline in physical activity can lead to the deterioration of many aspects of physiological functions and, ultimately, to mobility decrease, further research of the role of physical rehabilitation as an important therapeutic approach in preventing the progression of disability in multiple sclerosis is required.

[Prion diseases].

Prion diseases are a family of progressive neurodegenerative disorders caused by prions. There are four human prion diseases: Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal insomnia and Kuru. They can arise in three different ways: acquired, familial or sporadic. We review clinical presentations, pathophysiology, morphological picture, diagnostic procedures and available treatment options of prion diseases.

[Results of a comparative clinical trial of the Russian Β - interferon-1b bioanalogue (infibeta)].

Results of annual comparative clinical research of the Russian biosimilar of beta-IFN - 1в at 122 patients with multiple sclerosis are presented. There were positive dynamics on EDSS scores in both groups (in the main group and group of control) in a year of treatment. There were positive dynamics in frequency of relapses in the main group (with 1.5 to 0.4 in a year) and in group of control (with 1.4 to 0.37 in a year). Positive dynamics according to MRI was also fixed in both groups. In both groups, good tolerability of the treatment was noted. This research didn't reveal essential distinctions on efficiency and safety parameters in both groups.

[Diffusion-tensor magnetic resonance tomography and tractography in multiple sclerosis: a review].

Multiple sclerosis is the most common chronic progressive inflammatory demyelinating disease of the central nervous system characterized by different clinical phenotypes, degrees of central nervous system damage and disease progression. Conventional magnetic resonance imaging has become a useful tool for diagnosis, differential diagnosis and monitoring disease progression. Recent innovations in magnetic resonance imaging give an opportunity to specify certain aspects of multiple sclerosis pathogenesis. This article is a review of diffusion-tensor magnetic resonance tomography and tractography usage in the brain and spinal cord of patients with different clinical phenotypes of multiple sclerosis. Main features of pathologically damaged white and grey matter observed using diffusion-tensor magnetic resonance tomography and tractography, correlations between different diffusion indices and disability are described. The problems of pathogenesis are discussed.

[Clinical significance of T-regulatory cells in multiple sclerosis].

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that develops due to the activation of selfreactive T-cells specific for myelin components. Regulatory T-cells CD4+CD25+Foxp3+ (T-reg) play an important role in the autoimmunity control and inhibition of T-cells-mediated myelin destruction. The aim of the study was to determine a number of T-reg in the blood of patients in different stages of disease, to evaluate their functional activity and to obtain T-reg induced ex vivo. The phenotypic analysis revealed the 2-3 fold reduction of T-reg in the exacerbation phase of MS and the increase of their content in the remission while the level of T-reg in the donor's blood remained significantly higher. The inverse correlation between the degree of severity and duration of MS and the number of T-reg was found. The suppression function of T-reg of MS patients was substantially decreased in the exacerbation and remission stages. The induction of ex vivo T-reg allows to increase the number of these cells by 30-90 times during 6-8 days. The induced T-reg have phenotypic and functional characteristics of native T-reg. The adaptive cell treatment using induced T-reg may become an instrument for correction of immune dysfunction in MS.

[The role of regulatory T cells in the development of autoimmune process in multiple sclerosis].

In the maintenance of immunological tolerance important role belongs to the recently discovered population of regulatory T-cells CD4+CD25+FoxP3 +. These cells have potential in suppressing pathologic immune responses observed at various autoimmune diseases including multiple sclerosis. We have shown a reduction in the number and functional activity of T-reg in peripheral blood of patients with multiple sclerosis in the acute stage, the increase in their number during remission, duration of the relationship of the autoimmune process and the degree of disability of patients with the contents of T-reg. The possibility of using the grown ex vivo T-reg for the correction of immunopathological process in multiple sclerosis.

[Axonopathy in the pathogenesis of multiple sclerosis, peripheral diffuse and local motor neuropathies and motor neuron disease].

Two hundreds and seventy-six patients including 43 patients with multiple sclerosis, 24 - with acute inflammatory demyelinating polyneuropathy (AIDP), 144 - with chronic inflammatory demyelinating polyneuropathy (CIDP), 27 - with motor multifocal neuropathy (MMN), 38 - with lateral amyotrophic sclerosis (LAS) have been examined. Symptoms of axonal degeneration, manifested in denervation phenomena in both clinical and instrumental studies (electromyography, transcranial magnetic stimulation, MRT), were revealed in all groups of patients. The formation of excitation conduction blocks is an universal pathophysiological mechanism of the axonopathy development in AIDP, CIDP, MMN and LAS. Symptoms of axonopathy and peripheral demyelinization in patients with multiple sclerosis and LAS suggest the possibility of transformation of immunopathological process from the central nervous system to the peripheral one.

[Differential diagnosis of multifocal motor neuropathy and related diseases].

Multifocal motor neuropathy (MMN) is a rare disease of the peripheral nervous system pathogenetically related to local demyelinization and formation of excitation conduction blocks. MMN affect only those nerves and their segments that comprise excitation conduction blocks. Such blocks have a persistent character and show a mosaic pattern over motor fibres which accounts for the specific clinical picture of MMN.

[Cortical reorganization in multiple sclerosis with movement disorders detected by functional MRI (own observations and literature data)].

Cortical reorganization in multiple sclerosis (MS) has been recently suggested as an additional potential contributor to the recovery or maintenance of function in the irreversible tissue damage. Functional cortical changes have been demonstrated in all MS phenotypes using motor fMRI paradigms. Data from available studies suggest that movement-associated cortical reorganization in patients with MS seems to vary across individuals at different stages of disease. Cortical reorganization may play a role in limiting the impact of structural tissue damage in MS patients and, conversely, its progressive exhaustion with disease progression may be one of the factors contributing to the accumulation of irreversible disability. The enhancement of any beneficial effects of this cortical adaptive plasticity should be considered as a potential target of therapy for MS.

[The role of apolipoprotein E in patients with amyotrophic lateral sclerosis (a clinical and genetic study)].

The apolipoprotein E (apoE) gene plays an important role in forming predisposition and modulating the course of Alzheimer's disease, primary parkinsonism and some other human neurodegenerative disorders. In this study, for the first time in the Russian population, we performed the analysis of genetic association of apoE gene variants in 62 patients with a sporadic form of amyotrophic lateral sclerosis (ALS) aged from 20 to 75 years (49.5+/-14.2); age at disease onset was from 18 to 74 years (47.1+/-15.2). No statistically significant differences in the distribution of apoE genotypes between patients and controls were found. It was shown that the frequency of the apoE-e2 allele was significantly higher in the young group characterized by more benign course of ALS (spinal variant, slow rate of progression of ALS and longer survival) as well as in patients with a more "benign" spinal form of the disease. On the contrary, the chance of carrying the apoE-e4 allele is higher in the older age group in which a prognostically more severe bulbar form is also more prevalent. Therefore, the apoE-e2 allele may be regarded as a neuroprotective factor in the development of neurodegenerative process in patients with ALS.

Pathophysiological aspects of the formation of neurological deficit in multiple sclerosis.

The results of complex studies were used to formulate a concept of the development of neurological impairments in multiple sclerosis (MS). Acutely developing impairments to spike propagation, reaching the level of conduction blockade, due to the active pathological process with demyelinating and axonal damage to the CNS lead to the formation of neurological impairments in exacerbations of MS, while complete or partial reversion (regression) of these symptoms in the stage of remission results from compensatory changes in the nature of conduction, which were not, however, accompanied by recovery of electrophysiological measures. The development of stable neurological deficit in secondary-progressive MS is determined by impairments to spike conduction processes associated with significant levels of demyelination and atrophic changes in the CNS, with myelin loss and axon death. Finally, the severity of cognitive changes is determined by differences in the severities of both the focal demyelinating process and diffuse damage to brain substance in MS, including the neurodegenerative component. The main factor in transient increases in symptoms is the universal lability of electrophysiological parameters, including those developing on the background of ion and neurotransmitter imbalance.

The role of axonopathy in the mechanisms of development of demyelination processes in the central and peripheral nervous system.

The role of axonopathy in the development of demyelinating processes in the CNS and peripheral nervous system was addressed in studies of 43 patients with multiple sclerosis (MS) and 144 patients with chronic inflammatory demyelinating polyneuropathy (CIDPN). Patients with MS were found to have foci of reduced MRI intensity in the T1 regime ("black holes," present in 28%) and regional atrophy of the cerebral cortex (in 46%), which showed a significant association with the degree of invalidity on the EDSS (Kendall tau = 0.38 and 0.43; p = 0.038 and 0.021, respectively). The mean fatigue score on the FSS was 4.9 (3.6; 5.4). A significant increase in the central conduction time on the background of fatigue (p = 0.016), along with an absence of signs of impaired reliability of neuromuscular transmission and an absence of past-activation phenomena, suggested that central mechanisms were predominant in the formation of fatigue phenomena in MS. In addition, 34.9% of patients with MS showed signs of peripheral nervous system involvement, while the clinical-electrophysiological pattern in 12.5% of patients with CIDPN showed signs of CNS involvement. These data widen existing concepts of the mechanisms of formation of axonopathy in the CNS, based on evidence for the development of axon-demyelinating processes in CIDPN, which is the most accessible model of demyelination for study using contemporary neurophysiological methods.

Gene therapy of amyotrophic lateral sclerosis.

Two-year experiments were performed to evaluate the neurotrophic effect of hypoxia-inducible factors (vascular endothelial growth factor and angiogenin) expressed in recombinant human adenoviruses in amyotrophic lateral sclerosis. Randomized placebo-controlled trial demonstrated safety and good tolerability of the recombinant antiviral drugs. The life span of patients under conditions of hypoxia increased after treatment with the test drug, which was probably related to improved resistance of motoneurons. The presence of virus-neutralizing antibodies decreases the effectiveness of adenoviral vectors, which necessitates differential approach to the selection of patients and continuous monitoring of gene therapy.

[A role of the adhesive properties of leucocytes and blood serum in the pathogenesis of multiple sclerosis].

Adhesive properties of leucocytes were studied using an original technique based on the leukocyte adherence inhibition reaction and measuring the values of spontaneous adhesion index (SAI) and adhesion-strengthening effect (ASE) under the influence of autoserum. One hundred patients with multiple sclerosis (MS) and 53 controls were included in the study. Immunophenotyping of lymphocytes (LP) with monoclonal antibodies--markers CD3, CD4, CD8, CD16, CD20, CD25, HLA-DR and CD95--and determination of IgG, IgA, IgM and content of immune complexes were carried out in parallel. The increase of adhesion parameters (ASE and SAI) was found in MS. It was most significant in patients with primary progressive course and in disease exacerbation. The greatest changes of phenotypic LP content were associated with debut and exacerbation-remission periods. Significant positive correlations between higher SAI values and phenotypes CD20, CD95, HLA-DR and amount of natural killer cells were revealed in patients with MS in contrast to the negative correlations of SAI with CD3 and CD4 in the control group. A role of membrane and soluble forms of adhesion molecules in the initiation and progression of immunopathological process in MS is discussed.