Pathogenesis of amyotrophic lateral sclerosis (ALS) involves several mechanisms resulting in a shift from a neuroprotective to a neurotoxic immune reaction. A promising tool for ALS treatment is represented by mesenchymal stem cells (MSCs), which possess both regenerative potential and immunomodulatory properties. In this study, we aimed to compare the immunomodulatory properties of MSCs isolated from the bone marrow of patients suffering from ALS and healthy donors. Moreover, the influence of proinflammatory cytokines on the immunoregulatory functions of MSCs was also evaluated. We found that MSCs from ALS patients and healthy donors comparably affected mitogen-stimulated peripheral blood mononuclear cells and reduced the percentage of T helper (Th)1, Th17 and CD8+CD25+ lymphocytes. These MSCs also equally increased the percentage of Th2 and CD4+FOXP3+ T lymphocytes. On the other hand, MSCs from ALS patients decreased more strongly the production of tumour necrosis factor-α than MSCs from healthy donors, but this difference was abrogated in the case of MSCs stimulated with cytokines. Significant differences between cytokine-treated MSCs from ALS patients and healthy donors were detected in the effects on the percentage of CD8+CD25+ and CD4+FOXP3+ T lymphocytes. In general, treatment of MSCs with cytokines results in a potentiation of their effects, but in the case of MSCs from ALS patients, it causes stagnation or even restriction of some of their immunomodulatory properties. We conclude that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines. Graphical Abstract Treatment of mesenchymal stem cells (MSCs) with cytokines results in a potentiation of their effects, but in the case of MSCs from amyotrophic lateral sclerosis (ALS) patients, it causes stagnation (an equal reduction of the percentage of CD8+CD25+ T lymphocytes) or even restriction (no increase of proportion of CD4+FOXP3+ T lymphocytes) of some of their immunomodulatory properties. It means that MSCs from ALS patients exert comparable immunomodulatory effects to MSCs from healthy donors, but respond differently to stimulation with proinflammatory cytokines.
- Klíčová slova
- Amyotrophic lateral sclerosis, CD4+FOXP3+ T lymphocytes, Helper T lymphocytes, Immunomodulation, Mesenchymal stem cells, Proinflammatory cytokines,
- MeSH
- amyotrofická laterální skleróza imunologie MeSH
- buňky kostní dřeně imunologie MeSH
- cytokiny metabolismus MeSH
- imunologické faktory farmakologie MeSH
- imunomodulace MeSH
- leukocyty mononukleární účinky léků imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mezenchymální kmenové buňky imunologie MeSH
- mitogeny farmakologie MeSH
- T-lymfocyty pomocné-indukující účinky léků imunologie MeSH
- TNF-alfa biosyntéza MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cytokiny MeSH
- imunologické faktory MeSH
- mitogeny MeSH
- TNF-alfa MeSH
Immunosuppressive drugs are used to suppress graft rejection after transplantation and for the treatment of various diseases. The main limitations of their use in clinical settings are severe side effects, therefore alternative approaches are desirable. In this respect, mesenchymal stem cells (MSCs) possess a regenerative and immunomodulatory capacity that has generated considerable interest for their use in cell-based therapy. Currently, MSCs are tested in many clinical trials, including the treatment of diseases which require simultaneous immunosuppressive treatment. Since the molecular targets of immunosuppressive drugs are also present in MSCs, we investigated whether immunosuppressive drugs interact with the activity of MSCs. Human MSCs isolated from the bone marrow (BM) or adipose tissue (AT) were cultured in the presence of clinical doses of five widely used immunosuppressive drugs (cyclosporine A, mycophenolate mofetil, rapamycin, prednisone and dexamethasone), and the influence of these drugs on several factors related to the immunosuppressive properties of MSCs, including the expression of immunomodulatory enzymes, various growth factors, cytokines, chemokines, adhesion molecules and proapoptotic ligands, was assessed. Glucocorticoids, especially dexamethasone, showed the most prominent effects on both types of MSCs and suppressed the expression of the majority of the factors that were tested. A significant increase of hepatocyte growth factor production in AT-MSCs and of indoleamine 2,3-dioxygenase expression in both types of MSCs were the only exceptions. In conclusion, clinically relevant doses of inhibitors of calcineurin, mTOR and IMPDH and glucocorticoids interfere with MSC functions, but do not restrain their immunosuppressive properties. These findings should be taken into account before preparing immunosuppressive strategies combining the use of immunosuppressive drugs and MSCs.
- Klíčová slova
- Chemokine, Cytokine, Growth factor, Immunomodulation, Immunosuppressive drug, Mesenchymal stem cell,
- MeSH
- imunosupresiva farmakologie MeSH
- interferon gama agonisté biosyntéza MeSH
- kultivované buňky MeSH
- leukocyty mononukleární účinky léků metabolismus MeSH
- lidé MeSH
- mezenchymální kmenové buňky účinky léků metabolismus MeSH
- proliferace buněk účinky léků fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- imunosupresiva MeSH
- interferon gama MeSH
The aim of this study was to investigate the effects of systemically administered bone-marrow-derived mesenchymal stromal cells (MSCs) on the early acute phase of inflammation in the alkali-burned eye. Mice with damaged eyes were either untreated or treated 24 h after the injury with an intravenous administration of fluorescent-dye-labeled MSCs that were unstimulated or pretreated with interleukin-1α (IL-1α), transforming growth factor-β (TGF-β), or interferon-γ (IFN-γ). Analysis of cell suspensions prepared from the eyes of treated mice on day 3 after the alkali burn revealed that MSCs specifically migrated to the damaged eye and that the number of labeled MSCs was more than 30-times higher in damaged eyes compared with control eyes. The study of the composition of the leukocyte populations within the damaged eyes showed that all types of tested MSCs slightly decreased the number of infiltrating lymphoid and myeloid cells, but only MSCs pretreated with IFN-γ significantly decreased the percentage of eye-infiltrating cells with a more profound effect on myeloid cells. Determining cytokine and NO production in the damaged eyes confirmed that the most effective immunomodulation was achieved with MSCs pretreated with IFN-γ, which significantly decreased the levels of the proinflammatory molecules IL-1α, IL-6, and NO. Taken together, the results show that systemically administered MSCs specifically migrate to the damaged eye and that IFN-γ-pretreated MSCs are superior in inhibiting the acute phase of inflammation, decreasing leukocyte infiltration, and attenuating the early inflammatory environment.
- MeSH
- alkálie toxicita MeSH
- alografty MeSH
- antivirové látky farmakologie MeSH
- chemické popálení patologie terapie MeSH
- interferon gama farmakologie MeSH
- interleukin-1alfa metabolismus MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nika kmenových buněk * MeSH
- popálení oka chemicky indukované metabolismus patologie terapie MeSH
- transformující růstový faktor beta metabolismus MeSH
- transplantace mezenchymálních kmenových buněk * MeSH
- zánět chemicky indukované metabolismus terapie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alkálie MeSH
- antivirové látky MeSH
- interferon gama MeSH
- interleukin-1alfa MeSH
- transformující růstový faktor beta MeSH
