The Inhibiting Effects Of Zotarolimus On Allograft Organ Transplantation And Mechanism Research

Objective:clinical organ transplantation postoperative immunological rejection is seriously restricting transplantation recipients' life quality.Clinically,most patients treated with organ transplantation need maintenance therapy.Long-term maintenance of taking medicine will have a strong toxic and side effect,and long-term medication has brought huge inconvenience to patients' life.Thus,organ transplantation is in urgent demand of neo-type immunosuppressant R&D and application.In this experiment,we have firstly applied Sirolimus derivative,Zotarolimus,in researches of organ transplantation and discussed the immunosuppressive action and its immunosuppressive action mechanism of ZotarolimusMethod:Establish BALB/c to C57BL/6 mice cardiac allo-transplantation model,observe the lifetime of mice with heart transplantation in control group and Zotarolimus drug group,and explore whether Zotarolimus can extend transplantation recipients' lifetime based on the heartbeat time.Firstly,discuss whether Zotarolimus can inhibit lymphocyte proliferation through lymphocyte in vitro transformation test,and through in vivo test further verify suppression of lymphocyte proliferation methods of Zotarolimus;detect the content of IL-2,IL-4,TGF-?,IFN-y and other cell factors through ELISA,PCR and other tests to research the influence of Zotarolimus on recipients' overall immune state.Result:Compared with control group,the life time of mice with heart transplantation in Zotarolimus drug group is obviously longer;Zotarolimus has tolerance induction under the circumstance of long-term meditation;CD4+T cell ratio in Zotarolimus drug group has reduced obviously;T lymphocyte proliferation in Zotarolimus drug group has inhibited significantly.Regulatory T cell ratio in Zotarolimus drug group has increased obviously;detection shows that Foxp3,TGF-?and IL-10 tend to rise in Zotarolimus drug group;donor specific antibody in Zotarolimus drug group has reduced significantly.Conclusion:Zotarolimus has shown excellent immunosuppressive action,can extend the lifetime of mice with ardiac allograft transplantation and reduce the immunological rejection of the general sample of transplantation recipient.Application of effective dose of Zotarolimus in animal experiments will not influence the experimental animals' health status.In addition,when long-term maintenance meditation not required,Zotarolimus can induce the tolerance condition of mice with ardiac allograft transplantation.Studies on mechanism of immunosuppression show that immunological rejections that Zotarolimus have inhibited simultaneously include cellular immunity and humoral immunity.Cellular immunity is achieved by stopping the differentiation from ThO to Th1;humoral immunity can be weakened by inhibiting the production of IgG2 antibody.Zotarolimus can induce the tolerance of mice with ardiac allograft transplantation by inducing the generation of regulatory T cells.Tolerance correlation factors Foxp3,TGF-P and IL-1 of mice tend to rise in Zotarolimus drug group.This experiment has firstly studied Zotarolimus inhibiting effect on of allograft organ transplantation immunological rejection,and proved the potential of Zotarolimus as a neo-type immunosuppressant.With great clinical significance,research results have provided solid theoretical basis for the R&D of clinical organ transplantation neo-type immunosuppressant.