Abstract
BackgroundAcute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. For these reasons, a standard non-invasive molecular tool to detect is desirable to offer a simpler monitoring of kidney transplant recipients (KTRs). The purpose of our study was to examine, in peripheral blood before and after transplantation, the expression patterns of regulatory T cell (Treg)-related genes: the forkhead box P3 (FOXP3) and the two CTLA-4 isoforms (full-length and soluble) to predict acute rejection onset, de novo donor-specific antibodies (DSA) development and renal dysfunction 1 year after transplantation.MethodsWe profiled by using a relative quantification analysis (qRT-PCR) circulating mRNA levels of these biomarkers in peripheral blood of 89 KTRs within the first post-transplant year (at baseline and 15, 60 and 365 days, and when possible at the acute rejection) and compared also the results with 24 healthy controls.ResultsThe three mRNA levels drastically reduced 15 days after transplantation and gradually recovered at 1 year in comparison with baseline, with very low levels at the time of aTCMR for FOXP3 (RQ = 0.445, IQR = 0.086–1.264, p = 0.040), maybe for the pro-apoptotic role of FOXP3 during inflammation. A multivariate Cox regression analysis evidenced a significant relation between aTCMR onset and thymoglobuline induction (HR = 6.749 p = 0.041), everolimus use (HR = 7.017, p = 0.007) and an increased risk from the solCTLA-4 expression at 15 days, mainly considering recipients treated with Mycophelolic acid (HR = 13.94 p = 0.038, 95%CI:1.157–167.87). Besides, solCTLA-4 also predisposed to graft dysfunction (eGFR< 60 mL/min/1.73m2) at 1 year (AOR = 3.683, 95%CI = 1.145–11.845, p = 0.029). On the other hand, pre-transplant solCTLA-4 levels showed a protective association with de novo DSAs development (HR = 0.189, 95%CI = 0.078–0.459, p < 0.001).ConclusionsmRNA levels of Treg-associated genes, mainly for solCTLA-4, in peripheral blood could put forward as candidate non-invasive biomarkers of cellular and humoral alloreactivity in clinical transplantation and might help shape immunosuppression, tailor monitoring and achieve better long-term outcomes of kidney transplantation in the wake of “precision medicine”.
Highlights
Acute T-cell mediated rejection is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes
By examining the trend of the expression of the three candidate biomarkers up to 1 year in correlation with the de novo donor-specific antibodies (DSA) development (Fig. 6), we found out a different time-dependent trend for solCTLA-4 molecule between two groups of patients, which decreased after 15 days from transplantation but Acute T-cell mediated rejection (aTCMR) (n = 11)
We found that solCTLA-4 was negatively associated with DSA development at baseline (OR = 0.284, 95%confidence interval (CI) = 0.085–0.896 p = 0.042), 15 days (OR = 0.325, 95%CI = 0.116–0.911 p = 0.033), and at 60 days (OR = 0.167, 95%CI = 0.044–0.636 p = 0.009)
Summary
Acute T-cell mediated rejection (aTCMR) is still an issue in kidney transplantation, for it is associated with chronic rejection, graft loss, and overall worse outcomes. Risk prediction and early diagnosis of aTCMR through non-invasive methods can be crucial for allograft survival and immunosuppression management [1,2,3,4] For these reasons, developing a standard clinical and molecular assessment procedure offers a simpler monitoring of KTRs. The study of biomarkers of aTCMR and immune dysregulation in renal transplantation has progressively focused on regulatory T cells (Tregs). The study of biomarkers of aTCMR and immune dysregulation in renal transplantation has progressively focused on regulatory T cells (Tregs) This CD4+CD25+FOXP3+ lymphocytic subpopulation, which spreads from the thymus as effector and memory suppressive cells, is essential in suppressing alloimmune response and maintaining tolerance in transplantation FOXP3 expression is the major determinant of Tregs phenotype and function. The inhibitory function of CTLA-4 is carried out through several different mechanisms, comprehending the cell-extrinsic action of its soluble form responsible for competition with CD28, namely the CTLA-4 counterpart, which transduces instead a proliferation signal for T cells [6,7,8,9]
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