Novel Diagnostics in Transplantation

Mj, Ansari; Tb, Strom; Ansari, M. Javeed

doi:10.1016/b978-1-4377-0987-2.00042-x

Cited by 2 publications

(1 citation statement)

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“…These processes involve both MHC class I and II molecules of which peptide loading into MHC class II but not class I molecules is controlled by Cat-S (Rise et al, 1996). In support of this concept, Cat-S inhibition suppressed lymphocyte proliferation in a mixed lymphocyte assay, an accepted in vitro model of alloantigen recognition (Ansari and Strom, 2010). Our in vivo data further demonstrate that preemptive Cat-S inhibition was sufficient to suppress some aspects of acute renal allograft rejection, namely, tubulitis and arteritis, while, e.g., interstitial inflammation was hardly affected.…”

Section: Discussionmentioning

confidence: 84%

Cathepsin S and Protease-Activated Receptor-2 Drive Alloimmunity and Immune Regulation in Kidney Allograft Rejection

Lei

Ehle

Kumar

et al. 2020

Front. Cell Dev. Biol.

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Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate proteaseactivated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed CatS expression in intrarenal mononuclear phagocytes. In vitro, CatS inhibition suppressed CD4 + T cell lymphocyte activation in a mixed lymphocyte assay. In vivo, we employed a mouse model of kidney transplantation that showed preemptive CatS inhibition significantly protected allografts from tubulitis and intimal arteritis. To determine the contribution of PAR-2 activation, first, Balb/c donor kidneys were transplanted into Balb/c recipient mice without signs of rejection at day 10. In contrast, kidneys from C57BL/6J donor mice revealed severe intimal arteritis, tubulitis, interstitial inflammation, and glomerulitis. Kidneys from Par2-deficient C57BL/6J mice revealed partial protection from tubulitis and lower intrarenal expression levels for Fasl, Tnfa, Ccl5, and Ccr5. Together, we conclude that CatS and PAR-2 contribute to immune dysregulation and kidney allograft rejection, possibly involving CatS mediated activation of PAR-2 on recipient parenchymal cells in the allograft.

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Section: Discussionmentioning

confidence: 84%