New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy

Schinstock, Carrie A.; Stegall, Mark D.; Cosio, Fernando G.

doi:10.1097/mnh.0000000000000070

Cited by 24 publications

(21 citation statements)

References 50 publications

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“…27 The TLR4 senses stimuli which contribute differently to acute kidney injury (AKI) or to CAI, and also to the development of tolerance in either NIC or bone marrowderived cells (BMDC). 23,28…”

Section: General Consequences Of Tlr4 Stimulationmentioning

confidence: 99%

The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells

Zmonarski¹,

Banasik²,

Madziarska³

et al. 2019

Adv Clin Exp Med

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Krajewska M. The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells. AbstractThe innate immune system is activated before an adaptive immune response. An expression of a particular toll-like receptor (TLR) in a transplanted kidney depends on the localization of specific cells (e.g., endothelium, elements of the nephron structure), recent pathology and the time passed since transplantation. The TLR4 receptor is expressed on renal tubular epithelial (RTE) and endothelial cells, podocytes, blood and interstitial monocytes/macrophages, and dendritic cells. While circulating in blood, some monocytes are attracted and penetrate the transplanted organ, where they supplement the donor's resident macrophages. The intensity of migration depends on the local activation of inflammation in the graft and on the expression of specific receptors on kidney endothelial cells and monocytes/macrophages. The percentage of cells with shifted TLR4 expression usually increases in circulating monocytes. The TLR4 and the biochemical stimulation cascade derived from it in any type of cell, including monocytes, undergo multi-level regulation with feedback loops with other components of the primary system, and are also dependent on the action of immunosuppression. Toll-like receptor 4 senses stimuli that make monocytes contribute differently both to acute/chronic kidney injuries and to the development of tolerance. After kidney transplantation, TLR4 expression and related cytokine production capacity may vary depending on past diseases and oncoming problems. Since conventional immunosuppression does not prevent chronic allograft injury (CAI), peripheral blood monocytes and TLR4 constitute candidates for diagnostic and therapeutic targets. Considering the mutual communication among various elements of the primary immune system, future therapeutic intervention should be directed toward factors directly or indirectly regulating the expression or post-receptor signaling of the TLR4 receptor.

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Section: General Consequences Of Tlr4 Stimulationmentioning

confidence: 99%

The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells

Zmonarski¹,

Banasik²,

Madziarska³

et al. 2019

Adv Clin Exp Med

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“…Studies have revealed that CAN is a leading factor, causing 50-80% of allograft loss in renal function in the late period following kidney transplantation (3,35). As CAN is caused by various immune and non-immune factors, and is easily affected by a series of donor-related factors including donor age, brain death and consequences of ischemia-reperfusion injury, the pathogenesis and mechanisms remain unclear (36)(37)(38)(39)(40). Previous studies suggested that HMGB1, which is a pro-inflammatory cytokine released from dying cells, would accumulate as renal function deteriorates and have an important role in CKD (17).…”

Section: Discussionmentioning

confidence: 99%

HMGB1, TGF‑β and NF‑κB are associated with chronic allograft nephropathy

2017

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“…On the other hand, the effect of tofacitinib on NK, T, and B cells may reduce the incidence of chronic antibody mediated rejection. 37 Also, 1 experimental study in mice demonstrated that JAK3/Stat6 stimulates bone marrow-derived fibroblast activation in renal fibrosis. Treatment with tofacitinib significantly reduced myofibroblast transformation, matrix protein expression, interstitial fibrosis development, and apoptosis.…”

Section: Future Investigation In Kidney Transplantationmentioning

confidence: 99%

Targeting JAK/STAT Signaling to Prevent Rejection After Kidney Transplantation

et al. 2016

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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.

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New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy

Cited by 24 publications

References 50 publications

The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells

The role of toll-like receptors in multifactorial mechanisms of early and late renal allotransplant injury, with a focus on the TLR4 receptor and mononuclear cells

HMGB1, TGF‑β and NF‑κB are associated with chronic allograft nephropathy

Targeting JAK/STAT Signaling to Prevent Rejection After Kidney Transplantation

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