Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study.

Despite updating knowledge and a growing number of medications for multiple sclerosis (MS), no definite treatment is available yet for patients suffering from progressive forms of the disease. Autologous bone marrow derived mesenchymal stem cell (BM-MSC) transplantation is a promising method proposed as a therapy for MS. Although the safety of these cells has been confirmed in hematological, cardiac and inflammatory diseases, its efficacy in MS treatment is still under study. Patients with progressive MS (expanded disability status scale score: 4.0 -6.50) unresponsive to conventional treatments were recruited for this study. Twenty-five patients [f/m: 19/6, mean age: 34.7±7] received a single intrathecal injection of ex-vivo expanded MSCs (mean dose: 29.5×10(6) cells). We observed their therapeutic response for 12 months. Associated short-term adverse events of injection consisted of transient low-grade fever, nausea /vomiting, weakness in the lower limbs and headache. No major delayed adverse effect was reported. 3 patients left the study for personal reasons. The mean (SD) expanded disability status scale (EDSS) score of 22 patients changed from 6.1 (0.6) to 6.3 (0.4). Clinical course of the disease (measured by EDSS) improved in 4, deteriorated in 6 and had no change in 12 patients. In MRI evaluation, 15 patients showed no change, whereas 6 patients showed new T2 or gadolinium enhanced lesions (1 lost to follow-up). It seems that MSC therapy can improve/stabilize the course of the disease in progressive MS in the first year after injection with no serious adverse effects. Repeating the study with a larger sample size, booster injections and longer follow-up using a controlled study design is advised.

Role of B cells in pathogenesis of multiple sclerosis.

Despite the current limited understanding of the etiology of multiple sclerosis (MS), genetic susceptibility and environmental influences are known driving factors. MS is considered a T-cell-mediated disease given the prevalence of T cells in plaques. Plaque formation is characteristic of this disease attributable to immune mechanisms, triggered by an autoimmune attack aimed at antigens in the myelin sheath or oligodendrocyte proteins. The attack consists of the following: The role of the B cells is twofold: first, as autoreactive B cells they produce autoantibodies, secrete cytokines, clonally replicate memory B cells, and long-living plasma cells which serve to advance the diseased state by their constant production of autoantibodies. Second, as antigen-presenting cells they activate the autoreactive T cells. For this reason, the stipulation that T cell is the cornerstone of MS must be reevaluated. Various studies on pathogenesis of MS have indicated that B cells, as the humoral component of the adaptive immune system, are active participants in pathogenesis and lesion maintenance throughout the disease process. The active role of B cells and autoantibodies makes them an encouraging therapeutic target. Advances in the understanding of B-cell development and activity would allow for an enhanced strategy in the design of autoimmune treatment. For this reason, further investigation is necessary to determine whether depletion of B cells or antibodies may restore immune function.

Microchimerism and stem cell transplantation in multiple sclerosis.

Scientific advances have demonstrated that autoreactive cells are a component of the healthy immune repertoire. If we define autoimmunity as an active induction of autoreaction, the solution should be an active induction of self-tolerance, and may indicate the direction to explore the future therapies. Microchimerism (MC) refers to the presence of a limited number of nonhost cells in the body of an individual. These cells can enter via blood transfusion and organ transplantation or naturally through pregnancy. Chimeric cells engraft in the host body, develop, proliferate, and are accepted by the immune system as self. These include stem cells that enter the maternal body during fetal stages. These stem cells are also postulated to be helpful reservoirs in protecting the host body. MC has been considered a risk factor in autoimmune disease induction. However, today we know it is a natural phenomenon. MC can be considered a natural model of successful transplantation, the earliest engrafting cells being fetal mesenchymal stem cells (MSCs). MSCs have two notable features. They have an immunosuppressive quality when encountering the adoptive immune system and they display repair-inducing potential within damaged tissues. For the fetus, MC appears to be an effective factor in maternal tolerance induction toward the fetal graft and for the mother; these novel fetal cells might be useful in disease conditions occurring after pregnancy. Hematopoietic stem cell transplantation has become an accepted treatment option for both malignant and nonmalignant diseases and this unique procedure is now being investigated as a potential therapy for multiple sclerosis (MS). Due to the dichotomous properties of MSC, suppressing aggressive immune dysfunction while promoting damaged tissue repair, they may be appropriate therapy for MS.

Aging of mesenchymal stem cell in vitro.

BACKGROUND: A hot new topic in medical treatment is the use of mesenchymal stem cells (MSC) in therapy. The low frequency of this subpopulation of stem cells in bone marrow (BM) necessitates their in vitro expansion prior to clinical use. We evaluated the effect of long term culture on the senescence of these cells. RESULTS: The mean long term culture was 118 days and the mean passage number was 9. The average number of PD decreased from 7.7 to 1.2 in the 10th passage. The mean telomere length decreased from 9.19 Kbp to 8.7 kbp in the 9th passage. Differentiation potential dropped from the 6th passage on. The culture's morphological abnormalities were typical of the Hayflick model of cellular aging. CONCLUSION: We believe that MSC enter senescence almost undetectably from the moment of in vitro culturing. Simultaneously these cells are losing their stem cell characteristics. Therefore, it is much better to consider them for cell and gene therapy early on.