Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
*Purpose: Extracellular vesicles (EVs) are released from immune cells upon activation and play direct roles in allograft tolerance and rejection, in part through delivery of encapsulated or membrane-bound cytokines. Through proteomic profiling of EV proteins isolated from plasma of cardiac allograft recipients we recently identified the cytokine TNF-related weak inducer of apoptosis (TWEAK) to be elevated during acute cellular rejection. TWEAK elicits pro-inflammatory effects on endothelial cells through its receptor FN14, primarily mediated via NF-Kappa B signaling. The purpose of this study was to explore a possible role for vesicular TWEAK in ACR pathobiology.
*Methods: The presence of TWEAK on plasma EVs was assessed with immunogold labeling and transmission electron microscopy (TEM), fluorescent nanoparticle tracking analysis and ELISA. TWEAK+EVs were quantified in plasma of cardiac allograft recipients with ACR and non-ACR controls using immunostaining and flow cytometry. The expression and localization of the TWEAK receptor FN14 was analyzed with immunohistochemistry on endomyocardial biopsies from patients with ACR and non-ACR controls and on human coronary artery endothelial cells (HCAECs) using western blot. HCAECs were nucleofected with a NFKB reporter plasmid and stimulated with TWEAK+EVs and/or recombinant TWEAK.
*Results: We show that TWEAK is present on the surface of ~200-800 nm vesicles and that approximately 25% of circulating TWEAK is associated with EVs. Using flow cytometry, we confirm that the plasma concentration of TWEAK+EVs is significantly elevated (p<0.05) in patients with ACR (n=17) compared to non-ACR controls (n=32). We observe a drastic and widespread upregulation of FN14 expression in cardiac tissue from patients with ACR compared to non-ACR controls. In vitro, TWEAK+ EVs potentiate TWEAK-induced NF-Kappa B signaling in HCAECs (p<0.001).
*Conclusions: We provide evidence for direct involvement of the TWEAK/FN14 axis in ACR, mediated by extracellular vesicles and potentially contributing to exacerbation of graft endothelial inflammation.
To cite this abstract in AMA style:Gidlof O, Sadrian J, Grossi M, Alcevska S, Lundgren J, Rådegran G, Smith G. Vesicle-Associated Tweak is Increased During Acute Cellular Rejection and Contributes to Endothelial Inflammation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/vesicle-associated-tweak-is-increased-during-acute-cellular-rejection-and-contributes-to-endothelial-inflammation/. Accessed June 14, 2021.
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