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  • Apoptosis via Fas FasL system

    2022-01-20

    Apoptosis via Fas/FasL system has been evidenced to play a role in the pathogenesis of many diseases [26], [27], [28], [29], [30], [31], [32], [33], [34]. Along with these, Fas/FasL system has an important role in progressive renal disease and organ rejection in renal, cardiac and liver transplantation [35], [36], [37]. In a study done by Cappelesso et al., they have revealed that Fas −670GG genotype of the donor was associated with lower level of rejection episodes in renal transplant recipients [3]. Liver transplant recipients with the Fas −670AA genotype showed significantly lower graft survival rate than those with the AG genotype [38]. The present study revealed that sFasL levels were significantly higher in transplant recipients children than that in controls but no significant difference was found between children with AR vs children without. In transplantation, apoptosis is concerned in harmful events such as ischemia, reperfusion injury or graft rejection, but it may also play a key role – by depletion of alloreactive T-cells, apoptosis actively allows transplantation tolerance or decreases the frequency of rejection episodes [39].Seino et al. reported that the recipients of related liver transplants had elevated serum sFas concentrations, but not sFasL levels [40]. Prednisolone, used in this study as an anti-rejection drug, had been reported to induce apoptosis of peripheral T-lymphocytes shortly after intravenous administration [41]. It has also had a stabilizing effect on the plasma membrane, which may inhibit the release of soluble sFas and sFasL molecules from the membranes. In a study of soluble apoptotic markers in liver transplant recipients, serum sFas levels were significantly elevated in acute rejection patients and were brought to normal values by immunosuppressive therapy [42]. AR is under genetic control involving MHC polymorphisms and other different genes [43]. Such single nucleotide polymorphisms may modify the susceptibility of recipient T adenosine receptor agonist to FasL-mediated apoptosis [43]. In this study, we observed an association between FasL gene polymorphisms and an acute cellular rejection episode. Both in renal transplantation and in animal models of obstruction- induced renal tubular cell apoptosis, mRNA expression of FasL and associated caspases was found to be increased [44]. The FasL expression has been reported to be increased in peripheral blood and urine samples as well as in biopsy specimens from patients with AR [19], [20]. Similarly, FasL expression has been detected to be significantly correlated with subacute graft rejection [45]. However, previous studies have failed to find a relationship between Fas gene polymorphisms and AR [43]. Also, Fas gene polymorphisms were not found to be different between transplant recipients and controls [43]. These findings are similar to our results in children that showed similar allele frequencies of Fas gene in controls and transplant children as well as cases with and without AR. Fas expression in renal tubular epithelial cells and accumulation of FasL expressing lymphocytes during reperfusion contributes to the Fas-mediated tissue damage [46]. Therefore, these findings are important in the interpretation of our results that FasL gene polymorphisms are associated with acute cellular rejection episode. Our results were free of genotyping errors/mistakes in data manipulation (“blind” genotyping or validation using different methodologies) and were in accordance with results of others as Ertan et al. [43]. Previously, we demonstrated that expression of CD 25on peripheral blood T cells correlates closely with the presence of acute graft rejection in renal allograft pediatric recipients. Measurement of this surface marker may provide a rapid, noninvasive, and accurate means by which graft rejection can be identified [47]. A high significant positive correlation was found between serum FasL level and ischemia time. Tubular and/or glomerular Fas is elevated in progressive tubular atrophy, ischemia–reperfusion, experimental endotoxemia [24], and remnant renal glomerulosclerosis. In humans, Fas is elevated in proliferative glomerulonephritis. Fas initiates tubular injury during ischemia—reperfusion, as the tubular damage was reduced in B6 LPR mice when compared to B6 mice [24]. Also, an intact FasL/Fas system is required to restrict certain inflammatory responses, and constancy of systemic inflammation, including renal inflammation, follows murine CMV infection, in spite of clearance of the virus, in B6 LPR/LPR mice but not in control B6 mice [48].