| Objectives:Organ transplantation is an effective way to treat organ failure and end-stage disease.However,the immunological rejection after organ transplantation greatly restricts the development of organ transplantation.Patients undergoing organ transplantation need immunosuppressive drugs for a long time because of the immunological rejection.However,various immunosuppressive drugs are not only ineffective but have obvious toxic and side effects,meanwhile,it also induces tumors and all kinds of difficult complication symtoms,which greatly affect the postoperative patient's quality of life.Therefore,the development of a ideal immunosuppressive drugs is an urgent need to resolve post-transplant rejection.In this study,the Temsirolimus which is the derivative of rapamycin is applied to the field of organ transplantation for the first time to explore the immunosuppressive effect of temsirolimus and its possible mechanism.Methods:A cardiac allograft model from donor mouse BalB/C to recipient mouse C57BL/6 is established using a mouse cervical cannula method.The duration of cardiac graft survival is compared by intragastric administration of temsirolimus and a blank liquid to investigate whether temsirolimus could prolong graft survival.Next,lymphocyte transformation experiments and lymphocyte mixing experiments are performed to find out whether temsirolimus inhibited the activation and proliferation of splenic T cells.Flow cytometry tests are performed to examine the proportion of regulatory T cells?CD4+T cells?CD8+T cells and CD19+B cells to investigate the effect of temsirolimus on changes about T and B cell subsets.The related cytokines such as IL-4,IL10,IFN-y,and TGF-? are detected by ELISA and qPCR assay to furtherly investigate the effect of temsirolimus on the graft survival time and the immunosuppressive mechanism.Results:In the temsirolimus-administered group,the number of days about heart transplantation survival is significantly longer than that of the control group,and the weight of the mice which is in the appropriate concentration range of the temsirolimus-administered group is not change.In the group treated with temsirolimus,the number of T lymphocytes in the spleen decreased significantly;and the proportions of CD4+ T cells?CD8+ T cells and CD 19+ B cells decrease at a certain extent;relatively specific antibodies IgG1?IgG2?IgM in the serum decrease significantly;the proportion of Treg cells in the spleen and lymph nodes increases significantly.In the group treated with temsirolimus,the related cytokines IL-4?TGF-??Foxp3?IL-10 all show a significant increase,and the cytokine IFN-y shows a significant decrease.In the experiment about withdrawal of temsirolimus,it is found that the days of survival of grafts in the discontinuation group are significantly less than those in the continuous administration group.Conclusions:Temsirolimus prolongs the survival time of heart allograft,relieves the degree of inflammatory cell infiltration in heart graft and has good immunosuppressive function.Temsirolimus in a suitable concentration range does not affect its health status in mouse experiments.Temsirolimus inhibits cellular immunity in recipient mice and also suppresses humoral immunity by inhibiting the production of antibodies such as IgG1?IgG2 and IgM;it also promotes the production of Treg cells and the related cytokines such as TGF-??Foxp3 and IL-10 to induce the Long-term survival of recipient mice.This study is the first time to investigate the immunosuppressive effect of the temsirolimus in mouse heart transplantation and provides the possibility to develop a new type of ideal immunosuppressive agent that is both anti-tumor and anti-rejection and has profound significance in clinical application. |
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