Comparison On The Curative Effect Of Mesenchymal Stem Cell Transplantation And Low-Dose Interleukin-2 Treatment On Systemic Lupus Erythematosus

Background:Mesenchymal stem cells(MSCs)transplantation has become a promising treatment for refractory systemic lupus erythematosus(SLE).One of the major therapeutic mechanisms is inducing regulatory T cells(Treg cells)generation and proliferation.Interleukin2(IL-2),which has long been known for its role in sustaining Treg cell survival and function,has recently been proved to be able to alleviate lupus symptoms.Thus,it is interesting to determine the similarities and differences between the two therapies in controlling SLE progression.Moreover,it is of great importance to see whether combination of MSCs and IL2 could be more helpful.Methods:In this study,lupus-prone mice,the MRL/MpJ-Faslpr(MRL/lpr)strain,were used to compare both the short-and long-term curative effects of MSCs,low-dose IL-2 and MSCs+IL2 treatment.After administration,autoantibodies,immunocomplex deposition,kidney function,and T cell responses were monitored.The concentrations of serum IL-2 were measured after MSCs infusion.Peripheral blood mononuclear cells(PBMCs)from lupus patients and lupus mice splenocytes were used in the mechanism studies.At last,the role of IL-2 in MSC-induced increase of Treg cells was confirmed by introducing neutralizing antibodies.Results:MSCs,low-dose IL-2 and MSCs+IL-2 showed similar short-term therapeutic effects in treating lupus.All of them alleviate the lupus-like symptoms of mice and decrease the mouse serum antibody titers.Short-term MSCs and low-dose IL-2 treatments all instantly reduced albuminuria,serum creatine and blood urea nitrogen(BUN),while kidney histological examination showed that mice in MSCs-related treatment groups had remarkably prolonged reduction of lymphocytic infiltration and glomerular lesions.MSCs transplantation can persistently increase the proportion of Treg cells.Production of IL-2 by PBMCs was significantly upregulated after co-cultured with MSCs.Moreover,the percentages of Treg cells increased accordingly.However,when IL-2 was deprived by neutralizing antibodies,upregulation of Treg cells by MSCs vanished.When co-culturing PBMCs isolated from SLE patients with MSCs,we found that MSCs up-regulated IL-2 production and promoted Treg cells generation.Consistent with the in vitro data,Serum IL-2 in patients also increased after infusion of MSCs.Moreover,increase of IL-2 was positive correlated with reduction of disease activity.Conclusion:Our data demonstrated that compared to multiple administration of low-dose IL2 treatment,single-dosing of MSCs treatment showed prolonged curative effect.Most importantly,we found that MSCs can promote and sustain the production of IL-2 by SLE patients for a long time.Moreover,IL-2 is involved in MSC-induced upregulation of Treg cells and positively correlated with the therapeutic effects of MSCs.In summary,by providing a novel mechanism to elucidate the therapeutic effects of MSCs,our findings make MSCs a replaceable choice for IL-2 treatment in other related diseases.