ABSTRACT
Objective To investigate the role and mechanism of SDF-1/CXCR4 in the development of chronic rejection (CR) in rat models.Methods CR rat models were established using Fisher 344 to Lewis rats.In the blank control group (n=10),Lewis rats getting isotransplantation were treated with Cyclosporine A.CR rat models were established in positive group (n=10) and the rats were treated with Cyclosporine A.CR rat models were also established in CXCR4 antagonism group (n=10) and the rats were treated with both Cyclosporine A and AMD3100 (1 mg/kg).The serum creatinine levels were monitored every week.Kidney grafts were harvested 12 weeks after transplantation for histological analysis.We evaluated graft injuries using chronic allograft damage index (CADI) scores.Q-PCR and Western blotting were used to measure CXCR4,TGF-β1/Smad3 signaling pathway and α-smooth muscle actin (α-SMA) expression in renal allograft tissues.Results The serum creatinine levels in blank control group and CXCR4 antagonism group were significantly lower than those in positive control group (P<0.05).The blank control group and CXCR4 antagonism group presented milder pathological manifestations of CR.The CADI score in CXCR4 antagonism group was 3.54,which was lower than that of positive control group (P<0.05).The expression of biological markers in TGF-β1/Smad3 signaling pathway and SDF-1/CXCR4 signaling pathway was significantly lower in blank control group and CXCR4 antagonism group than in positive control group (P<0.05).Conclusion SDF-1/CXCR4 signaling pathway may play a crucial role in the development of CR.The usage of SDF-1/CXCR4 antagonist can protect renal allograft by inhibiting the TGF-β1/Smad3 pathway.Therefore,antagonism of CXCR4 may provide a novel way to prevent the development of CR.
ABSTRACT
Objective To explore the influence of up-regulated Foxp3 on Treg function and kidney transplantation chronic rejection reaction in rat model.Method The kidney transplantation chronic rejection reaction rat model was established.The F344 kidney was transplanted to Lewis rats,and retroviruses highly expressing Foxp3 were constructed.The Banff 97 hierarchical diagnostic criteria were used to diagnose chronic renal allograft nephropathy (CAN).The rat models were divided into three groups by random number table.In experimental group,the pSCV-BsdRFP-FoxP3 retroviruses were injected into the rats via the tail vein after operation.In negative control group,the pSCV-BsdRFP retroviruses were injected into the rats via the tail vein after operation.In blank group,the normal saline was injected into the rats via the tail vein after operation.Enzyme-linked immunosorbent assay (ELISA) was used to detect the changes of interleukin-10 (IL-10) and tumor necrosis factor-β (TGF-β) immediate,1,2,3,and 4 weeks after operation.The rats were killed at 4th week after operation,and kidney tissues were taken out for pathological examination.Result The pathological changes of CAN were observed at 4th week.The typical chronic rejection change was seen at 12th week.The levels of IL-10 and TGF-β were increased,and reached the peak at 3rd week.The levels of IL-10 and TGF-β in experimental group were higher than in negative control group and blank group at 1st,2nd,3rd,and 4th week.At 4th week,obviously different degrees of intimal thickening,and mild hyperplasia of interstitial fibers,glomerular sclerosis and infiltration with lymphocytes and plasma cells were observed in the three groups.In the experimental group,the lesions were mildest,and apparent neointimal hyperplasia was found.Conclusion pSCV-BsdRFP FoxP3 retroviruses can reduce the kidney transplantation chronic rejection reaction in rat model,and have the potential treatment effect.
ABSTRACT
Chronic rejection in the form of cardiac allograft vasculopathy is one of the major factors that affects long-term graft and patient survival after heart transplantation. Whereas multiple factors contribute to the development of cardiac allograft vasculopathy, immunologic mechanisms play the predominant role in the chronic rejection process, because both alloimmune and autoimmune responses are causal factors. In addition, many nonimmune donor and recipient factors also affect the development of cardiac allograft vasculopathy, including hyperlipidemia, cytomegalovirus infection, baseline coronary artery disease, and the mechanism of brain death in the donor. Modern immunosuppression maintenance therapies have the potential to limit the development of cardiac allograft vasculopathy in the long term. Further research initiatives are needed to identify patient-specific immunosuppressive drug regimens and to elucidate factors that contribute to the chronic rejection of cardiac transplant allografts.
