Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance

Abstract

BackgroundInduction therapy can improve kidney transplantation (KTx) outcomes, but little is known about the mechanisms underlying its effects.MethodsThe mRNA levels of T cell-related genes associated with tolerance or rejection (CD247, GZMB, PRF1, FOXP3, MAN1A1, TCAIM, and TLR5) and lymphocyte subpopulations were monitored prospectively in the peripheral blood of 60 kidney transplant recipients before and 7, 14, 21, 28, 60, 90 days, 6 months, and 12 months after KTx. Patients were treated with calcineurin inhibitor-based triple immunosuppression and induction with rabbit anti-thymocyte globulin (rATG, n = 24), basiliximab (n = 17), or without induction (no-induction, n = 19). A generalized linear mixed model with gamma distribution for repeated measures, adjusted for rejection, recipient/donor age and delayed graft function, was used for statistical analysis.ResultsrATG treatment caused an intense reduction in all T cell type population and natural killer (NK) cells within 7 days, then a slow increase and repopulation was observed. This was also noticed in the expression levels of CD247, FOXP3, GZMB, and PRF1. The basiliximab group exhibited higher CD247, GZMB, FOXP3 and TCAIM mRNA levels and regulatory T cell (Treg) counts than the no-induction group. The levels of MAN1A1 and TLR5 mRNA expressions were increased, whereas TCAIM decreased in the rATG group as compared with those in the no-induction group.ConclusionThe rATG induction therapy was associated with decreased T and NK cell-related transcript levels and with upregulation of two rejection-associated transcripts (MAN1A1 and TLR5) shortly after KTx. Basiliximab treatment was associated with increased absolute number of Treg cells, and increased level of FOXP3 and TCAIM expression.

A Comparison of Two Types of Rabbit Antithymocyte Globulin Induction Therapy in Immunological High-Risk Kidney Recipients: A Prospective Randomized Control Study

“…Also we observed a sustained low B-cell count at several time points. Krepsova et al found beside a long lasting suppression of T-cells as well suppression of NK-cells after induction treatment with Thymo [29]. All these mechanisms of action together (T-cell depletion, immunomodulatory effects, interference with B cells, NK cells and regulatory T-cells) are providing the potent immunosuppressive effect of ATGs.…”

A composite score associated with spontaneous operational tolerance in kidney transplant recipients

“…The “stable” population appears to be the most clinically relevant as future potential candidates for minimization protocols. Nevertheless, because immunosuppression has been shown to alter gene expression 41, 42, 52, 53 and particularly circulating B cells 54 , immunosuppression may affect cSoT. Unfortunately, samples before immunosuppression withdrawal are not available notably as TOL are mainly non-compliant and as intentional immunosuppression withdrawal trials have failed 18, 20 .…”

Long‑term survival in a recipient of kidney transplant without maintenance immunosuppression: A case report

“…Therefore, strategies for operational tolerance including the pharmacological, biological and cellular therapies were categorized by T cell agents, B cell agents and cellular therapies. Krepsova et al (16) reported that basiliximab induction may result in an increase of regulatory T cells and various biomarkers associated with operational tolerance expression. Additionally, long-term allograft acceptance was achieved by B cell depletion treatment in kidney transplant recipients (17).…”