OBJECTIVE: Pre-clinical and uncontrolled studies in patients with systemic lupus erythematosus (SLE) showed that mesenchymal stromal cells (MSCs) have a potential therapeutic role in refractory cases. The optimal therapeutic strategy in these patients remain to be elucidated. Our aim was to test the hypothesis that repeated administrations of 1×10⁶/kg body weight of allogenic MSCs, that is a significantly lower dosage with respect to the fixed 1×10⁶ MSC used in animal models, can be effective in improving the clinical course of a murine SLE model. METHODS: Bone marrow derived MSCs were obtained from 12-week-old C57BL/6J mice. Seventy-five 8 weeks old female NZ mice were randomly assigned to receive via caudal vein the following alternative treatments: 1) single infusion of 10⁶ MSCs/kg body weight at 18 weeks of age (NZ(s18)) or at at 22 weeks of age (NZ(s22)); 2) multiple monthly infusions of 10⁶ MSCs/kg body weight starting at 18 weeks of age (NZ(M18)) or at 22 weeks of age (NZ(M22)); 3) saline infusions (NZ(c)) Fifteen 8 weeks old C57BL/6J mice (Envigo, Huntingdon, UK) were used as untreated controls (C). Weekly, body weight was recorded and twenty-four hour urines were collected by metabolic cages for each animal; proteinuria was detected by dipstick analysis. At sacrifice, peripheral blood samples were collected from mice and anti-dsDNA antibodies were detected by enzyme immunoassorbent assay (ELISA) method using commercial kits. At sacrifice, kidneys were analyzed for histopathology and immunohistochemical analysis for B220, CD4, MPO, CD4⁺Foxp3, F40/80 infiltration was performed. RESULTS: Proteinuria occurrence was delayed NZ(S) and NZ(M) mice, no differences were observed in anti-dsDNA autoantibody titer among the groups at the different time-points; at 36 weeks, no significant differences were observed in term of nephritis scores. Inflammatory cells deposition (MPO and F4/80 positive cells) in NZM was significantly higher than in NZ and NZ(S). An overexpression of B lymphocytes (B220) was found in NZ(M) while T regulatory cells (CD4⁺ Foxp3⁺ cells) were reduced in both NZ(S) and NZ(M) with respect to NZ(c). CONCLUSIONS: Overall, our study failed to show a positive effect of a treatment with murine MSCs in this model and, for some aspects, even deleterious results seem to be observed.
Animals ; Antibodies ; B-Lymphocytes ; Body Weight ; Bone Marrow ; Female ; Humans ; Kidney ; Lupus Erythematosus, Systemic* ; Lupus Nephritis ; Mesenchymal Stromal Cells* ; Methods ; Mice ; Models, Animal ; Nephritis ; Proteinuria ; Veins