According to the web site of Clinical Trials.gov (a service of the United States National Institutes of Health), more than 418 clinical trials are currently

under way to assess the clinical effects of mesenchymal stem cells isolated from various sources, with purchase Wortmannin the greater part of the trials studying the immunomodulatory effect of autologous or allogeneic MSCs in autoimmune diseases such as ulcerative colitis, multiple sclerosis, primary Sjogren’s syndrom, systemic scleroderma, Crohn’s disease etc. Similarly, numerous trials are devoted to the effect of MSCs on modulating the reactions after allogeneic transplantation, such as chronic graft-versus-host disease (GVHD), poor graft function, etc. In general, the data from these studies have shown that MSCs exert immunomodulatory effects by both cell-to-cell contacts and by secreting biologically active substances, growth factors, cytokines and chemokines. MSCs have been shown to inhibit T-cell activation and proliferation

triggered by mitogenic or antigenic stimulation with allogeneic cells (mixed lymphocyte cultures) or nominal antigens[35,36]. MSCs can also influence T-cell responses indirectly through suppression of CD34+ progenitor cell and monocyte-derived dendritic cell differentiation, as well as through inhibition of their antigen-presenting functions[37-40]. A number of studies have demonstrated that MSCs have the capacity to inhibit B-cell proliferation, differentiation and immunoglobulin production in vitro[41,42] as well as to down-regulate the proliferation, cytokine production and cytotoxicity of NK cells[43,44]. Their ability to promote the generation and to maintain the activity of different subtypes of regulatory T cells (Тr1, CD4+FoxP3+, CD8+FoxP3+) is well documented, especially CD4+FoxP3+, also known as Tregs[45-48]. In addition, MSCs are considered as not being inherently immunogenic as they express low-intermediate levels of HLA class I antigens and either do not express or express negligibly low levels of HLA class II antigens and co-stimulatory molecules, such as CD80, CD86 and CD40[49,50].

Therefore, they should be able to escape not only from the recognition by alloreactive T cells[49,51], Cilengitide but also the cell-specific lysis by cytotoxic T lymphocytes (CTLs)[52] and freshly isolated alloreactive NK cells[53]. Some of these in vitro properties have already been successfully clinically exploited for the treatment of disorders such as acute graft-versus-host disease[54,55], multiple sclerosis[56] and systemic lupus erythematosus[57]. Although the precise mechanisms underlying MSCs immunomodulation are still not completely understood, a number of soluble factors involved in the process have already been identified. The present review discusses some MSC secreted cytokines which are involved in regulation of the immune response. For the purposes of this review, the term “immunoregulation” is used in a very strict sense as an influence on immunocompetent cells.