| Non-immune renal diseases have witnessed an increasing morbidity in clinical practice with histopathologic feature of renal tubulointerstitial fibrosis and chronic renal failure in the later stage. But up till now, there is still short of specific therapies. Further demonstration of mechanism of non-immune renal disease could provide new way for the efficient treatment to such disease. Previous studies have showed that costimuiatory signals play an important role in the progression and development of immune renal disease and interventional therapy in experiment through blocking costimuiatory signals also received exciting results. Especially in recent years, the observation of infiltration of immunocompetent cells like macrophage and T lymphocyte in the kidney of non-immune renal disease, together with the expression of costimuiatory molecules on renal residual cell, indicated that pathologic mechanism of non-immune renal disease correlated closely with costimuiatory signal and immunocompetent cells, while lack of reports. Covering this, in this study, folic acid induced nephropathy (FAN) in mice was adopted to analyse systematically the dynamic changes of costimuiatory molecules expression and lymphocyte infiltration during the process of FAN, and agonistic anti-4-1BB mAb was used for the intervention therapy, so as to explore the possible immunopathologic mechanism of FAN and the potential mechanism of 4-1BB antibody's intervention. So, it could provide new therapy for non-immune renal disease with theoretical and experimental evidence.Part one: explosion of immunopathologic mechanism of FAN in miceAs the model of renal failure and renal tubulointerstitial fibrosis, FAN was caused because of acute tubulointerstitial sclerosis which was caused by FA crystal in renal tubules after folic acid injection i.p.. It is reported that during the progression of FAN, abnormal expressions of costimulatory molecules were observed, while immunopathologic mechanism of FAN required further explosion. In this part, FAN mice model was used and samples were collected. Blood was collected for the detection of renal function, kidney for histoimmunochemistry staining, and spleen for lymphocyte isolation and T cell subsets detection.Results showed that FAN mice experienced quite different stages. At the earlier stage, levels of Bun and Cr were significant higher in FA group than that of control one, and mortality reached 49%. At the later stage, levels of Bun and Cr were decreased and mortality rose to 60%. During the process of FAN, number of infiltrated cells was increased sharply at the later stage, especially macrophage and T lymphocyte in renal interstitial and fibrosis region. Interestingly, 4-1BB was highly expressed for twice in FAN development. On the third day, 4-1BB was highly expressed on renal tubular epithelial cell, then down-regulated while highly again on the fourteenth day. FCM assay showed that number of CD3+ and CD4+T lymphocytes was significant higher in FA group than that in control one at the earlier stage, while lower at the later stage. And number of CD8+T lymphocyte remained unchanged significantly during the process of FAN.Above results indicated that mice of FAN experienced two stages with two different types of immune response. That is the acute renal failure at the earlier stage with strong immune response mediated by CD3+ and CD4+T lymphocytes and the chronic renal failure at the later stage with weak immune response. And 4-IBB was up-regulated and CD4+T lymphocyte mainly mediated the immune response of FAN.Part two: intervention of agonistic anti-4-1BB mAb to FAN andexplosion of its mechanism.In this study, mice of FAN were intervened by agonistic anti-4-1BB mAb to further the explosion of 4-1BB costimulatory signal in FAN process, so as to provide new therapeutic way to non-immune renal disease.Mice were injected i.p. with anti-4-lBB mAb together with FA for intervention test Samples like blood, kidney and spleen were collected for renal function, immunohistochemistry, ly...
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