Altered Th17 Pathway in Tolerant Kidney Transplant Patients: A “Chicken-or-the-Egg” Dilemma?

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An ultimate goal in transplantation is induction of immune tolerance to transplants, a state of unresponsiveness to the allograft in a competent immune system without immunosuppression. Albeit rare, operational tolerance, generally defined as stable graft function without clinical features of chronic rejection in the absence of any immunosuppressive drugs for at least 1 year, has been observed in kidney transplant recipients after intentional weaning of immunosuppression or in nonadherent patients who have stopped their medication.1 Whereas some of these patients have been off immunosuppression for more than 5 years without signs of rejection, a number of patients developed rejection at some point after withdrawal, which in most cases resulted in loss of the graft. Unraveling immunologic mechanisms that play a role in the development of operational tolerance and defining biomarkers and predictors of tolerance is paramount for the development of strategies to achieve operational tolerance in a safe manner.
Various studies have investigated the transcriptional profile and/or immunophenotypic characteristics of operational tolerant kidney transplant recipients in comparison to healthy individuals, kidney transplant patients with chronic rejection and/or patients with stable function on immunosuppression. Unique peripheral blood mononuclear cell gene signatures associated with operational tolerance in kidney transplant patients have been described.2-4 Differences in the B-cell compartment were observed in tolerant kidney transplant recipients compared with the other groups.3,4 Frequencies of activated CD4+ T cells as well as gene expression levels of markers associated with T-cell activation and proinflammatory Th1/Th2 responses were lower in tolerant patients than in chronically rejecting patients.2,3 Additionally, frequencies of CD25highCD4+ T cells and FOXP3 expression levels in tolerant patients were comparable to that in healthy individuals, whereas patients with chronic rejection had significantly lower levels.3,5 Whether these alterations in B- and T-cell compartment play a role in the induction of tolerance in operational tolerant patients, or whether they contribute to the maintenance of tolerance in the absence of immunosuppression, remains to be elucidated.
In this issue of Transplantation, Nova-Lamperti et al6 show that tolerant kidney transplant recipients have an altered peripheral Th17 compartment compared with healthy controls and patients with chronic rejection. Gene expression analysis revealed lower levels of retinoic acid receptor-related orphan receptor C, a master regulator of Th17 cells, and phenotypic analysis showed a lower proportion of Th17 cells in tolerant kidney transplant recipients versus healthy controls and chronically rejecting patients. In addition, the authors describe an impaired Th17 polarization in tolerant recipients which may be attributed to reduced extracellular signal-regulated kinase (ERK) phosphorylation after T-cell stimulation. The ERK pathway, one of the major signaling cassettes of the mitogen-activated protein kinase (MAPK) signaling pathway, is important for various cellular processes, including cell proliferation and differentiation. Interestingly, Nova-Lamperti et al7 recently demonstrated reduced ERK phosphorylation in B cells of tolerant patients after B-cell stimulation as well. These findings suggest that an impaired ERK/MAPK pathway may be important for tolerance induction.
This study sheds new light on immunologic pathways that may play a role in the development and/or maintenance of operational tolerance. The findings give rise to several crucial questions and create a “chicken-or-the-egg” dilemma. Did the altered peripheral Th17 compartment contribute to the induction of tolerance in these patients or is it merely the result of other immunoregulatory mechanisms that were key in the tolerance induction? Did it develop after transplantation, possibly due to the effects of immunosuppression or graft-host interaction, or was it “naturally” occurring and were these patients therefore more prone to tolerance induction? It would be interesting to investigate peripheral blood samples of the tolerant patient group at earlier time points to assess the Th17 compartment before tolerance induction or even before transplantation.
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