Targeting JAK/STAT Signaling to Prevent Rejection After Kidney Transplantation

Abstract

The profound involvement of cytokines in allograft rejection makes the molecules that control their actions, members of the Jak-Stat pathway, ideal targets for pharmacological intervention. Numerous studies have demonstrated that Jak3 is widely involved in the activation cascade and function of most immune cells. Tofacitinib, an oral Janus kinase inhibitor that targets Jak1/Jak3 dependent Stat activation, has been assessed as a substitute for calcineurin inhibitor therapy after low-to-moderate risk kidney transplantation in 3 randomized trials. Results using fixed-dose regimens showed a low incidence of rejection and better renal function with less interstitial fibrosis/tubular atrophy versus calcineurin inhibitor therapy. However, the safety profile of tofacitinib was poor, including increased incidences of cytomegalovirus disease, herpes zoster, BK virus, and nephropathy, which led to the discontinuation of its development for transplantation. High tofacitinib concentrations were independently associated with serious infection. Dosing according to exposure levels, coupled with pharmacodynamic monitoring based on phosphorylation of Stat5, could improve safety compared to the early fixed-dose regimens. Future studies could assess individualized dosing based on pharmacokinetic and pharmacodynamic monitoring. Additionally, because the increase of viral infections under tofacitinib may have been influenced by overlapping toxicity with concomitant mycophenolic acid, exploration of alternative adjunctive therapies (eg, a mammalian target of rapamycin inhibitor or belatacept) may demonstrate a better efficacy/safety profile. We believe that Jak inhibitors are a good and useful addition to the immunosuppressive armentarium for kidney transplant patients, and that new studies with personalized drug dosing, improved immune monitoring, and better patient selection should be performed.

Gene signatures common to allograft rejection are associated with lymphocytic bronchitis

“…Further, the lack of change in the antibody‐mediated rejection (ABMR) metagene supports the notion that this common pathology is specific to T cell—mediated rejection. One notable gene upregulated across all groups was JAK3, inhibition of which has been shown to prevent allograft rejection in multiple randomized controlled clinical trials, albeit with increased incidence of infection . The most unifying signal we observed is cellular response to interferon, which is upstream of many of the observed upregulated transcripts from both cohorts, including IDO1, HLA Class I, JAK3, and the CXCL9‐11 chemokine family, also known as monokines induced by gamma interferon (MIG) .…”

Tofacitinib Halts Progression of Graft Dysfunction in a Rat Model of Mixed Cellular and Humoral Rejection

“…Several recent reviews postulated again TOFA as an immunosuppressive tool, as long as the infectious problems were solved. [40][41][42] Thus, our results could serve as preliminary experimental data in the reevaluation of TOFA treatment in kidney transplantation. More precisely, we explored the possibility to use TOFA in a particular kind of patients, namely, those patients with antibodymediated and mixed rejection who are likely to develop chronic allograft injury.…”

Transcriptional Profiling of CD8+ CMV-Specific T Cell Functional Subsets Obtained Using a Modified Method for Isolating High-Quality RNA From Fixed and Permeabilized Cells

“…The importance of IL-7 and STAT5 signaling for CMV immunity in immunosuppressed patients has been suggested previously ( 90 ). Moreover, the recent use of JAK/STAT inhibitors for prevention of acute rejection in kidney transplant recipients has been associated with a significantly increased risk of CMV reactivation ( 91 ). Bak et al examined the CMV-specific immunomodulatory effects of the mTORC1 inhibitor sirolimus (rapamycin), finding that not only did therapeutic concentrations (i.e., 10 nM) of sirolimus—which only partially inhibition of mTORC1 activity—improved CMV-specific CD8+ T cell functionality and STAT5 phosphorylation ( 49 ).…”