Abstract
The combination of immunosuppressants and mesenchymal stem cells (MSCs) is a promising therapeutic strategy for systemic lupus erythematosus, since this approach reduces doses of immunosuppressants while maintaining the same therapeutic outcome. However, it is unavoidable for MSCs to be exposed to immunosuppressants. Here, we examined the combination effect of prednisone (PD) or mycophenolate mofetil (MMF) and MSCs. We showed that PD or MMF in combination with MSCs showed better therapeutic effect than single therapy in lupus-prone MRL.Faslpr mice, as assessed by using the following readouts: prolongation of survival, decrease in anti-dsDNA and total IgG levels in serum, decrease in cytokine gene expression in spleen cells, and decrease in inflammatory cell infiltration into the kidney. In vitro, immunosuppressants and MSCs inhibited T cell proliferation in a synergistic manner. However, immunosuppressants did not affect MSC viability and functions such as TGF-β1 and PGE2 production, migration, and immunosuppressive capacity. In summary, our study demonstrates that a combination of immunosuppressants and MSCs is a good strategy to reduce the side effects of PD and MMF without the loss of therapeutic outcome.
Highlights
Systemic lupus erythematosus (SLE) is a multiorgan disease characterized by abnormalities of T and B cells and production of autoantibodies [1]
We examined the effects of an immunosuppressant-mesenchymal stem cells (MSCs) combination on lupus-prone MRL.Faslpr mice and investigated the effects of PD and mycophenolate mofetil (MMF) on survival, soluble mediator production, migration, and immunosuppressive capacity of human bone marrow (BM)-derived MSCs
We observed that only 10% of untreated mice survived until 24 weeks of age, but >80% of mice treated with PD (1 mg/kg) and >70% of mice treated with MSCs (4 × 105 cells/injection) lived until this age
Summary
Systemic lupus erythematosus (SLE) is a multiorgan disease characterized by abnormalities of T and B cells and production of autoantibodies [1]. SLE has been traditionally treated using immunosuppressants, such as cyclophosphamide, prednisone (PD), and mycophenolate mofetil (MMF) [1]. PD, which is metabolized to prednisolone in vivo, acts through a genomic and a nongenomic pathway. PD binds cytosolic receptors to form a regulatory complex, which translocates to the nucleus, binds to DNA, and represses the transcription of many inflammatory mediators [2]. PD activates the expression of genes associated with osteoporosis, cataracts, hyperglycemia, coronary heart disease, and cognitive impairment, which are thought to be responsible for the most serious adverse effects of PD [3]. PD is a strong anti-inflammatory agent that inhibits proliferation of and inflammatory mediator production by immune cells [2].
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