ABSTRACT
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although advances have been made in the treatment of MS, such as the use of IFN-β, glucocorticoids and stem cells, the therapeutic effects of these treatments are not sufficient. In the present study, we evaluated whether the combination of methylprednisolone (MP) and human bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the therapeutic effectiveness in experimental autoimmune encephalomyelitis (EAE), a model for MS. EAE was induced by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55). The immunized mice received an intraperitoneal injection of MP (20 mg/kg), an intravenous injection of BM-MSCs (1 × 10⁶ cells) or both on day 14 after immunization. Combination treatment significantly ameliorated the clinical symptoms, along with attenuating inflammatory infiltration and demyelination, compared to either treatment alone. Secretion of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17) was significantly reduced, and anti-inflammatory cytokines (IL-4, IL-10) was significantly increased by the combination treatment as compared to either treatment alone. Flow cytometry analysis of MOG-reactivated T cells in spleen showed that combination treatment reduced the number of CD4⁺CD45⁺ and CD8⁺ T cells, and increased the number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Furthermore, combination treatment enhanced apoptosis in MOG-reactivated CD4⁺ T cells, a key cellular subset in MS pathogenesis. Combination treatment with MP and BM-MSCs provides a novel treatment protocol for enhancing therapeutic effects in MS.
Subject(s)
Animals , Humans , Mice , Apoptosis , Central Nervous System , Clinical Protocols , Cytokines , Demyelinating Diseases , Encephalomyelitis, Autoimmune, Experimental , Flow Cytometry , Glucocorticoids , Immunization , Injections, Intraperitoneal , Injections, Intravenous , Mesenchymal Stem Cells , Methylprednisolone , Multiple Sclerosis , Myelin-Oligodendrocyte Glycoprotein , Spleen , Stem Cells , T-Lymphocytes , T-Lymphocytes, Regulatory , Therapeutic UsesABSTRACT
OBJECTIVE: Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-beta) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-beta on gliomas. METHODS: We engineered human MSCs to secret mouse IFN-beta (MSC-IFN-beta) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-beta treatment. RESULTS: In vitro, the combination of MSC-IFN-beta and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-beta and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. CONCLUSION: These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-beta and TMZ could be considered as a new option for the treatment of malignant gliomas.