Activation of the ICOS/ICOS-Ligand Pathway in Antibody-Mediated Kidney Graft Rejection

V. Cantaluppi¹, G. Merlotti¹, M. Quaglia¹, G. Rosso¹, N. Clemente¹, G. Cappellano¹, A. Chiocchetti¹, G. Castellano², U. Dianzani¹, G. Camussi³

¹Nephrology and Kidney Transplantation Unit, University of Piemonte Orientale (UPO), Novara, Italy, ²Nephrology, Dialysis and Kidney Transplantation Unit, University of Foggia, Foggia, Italy, ³Department of Medical Sciences, University of Torino, Torino, Italy

Meeting: 2020 American Transplant Congress

Abstract number: 244

Keywords: Antibodies, Co-stimulation, Endothelial activation, Kidney transplantation

Session Information

Session Name: Kidney Chronic Antibody Mediated Rejection

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

Presentation Time: 3:27pm-3:39pm

Location: Virtual

*Purpose: The costimulatory pathway ICOS/ICOS-Ligand may represent a new therapeutic target in antibody-mediated rejection (ABMR), the major cause of long term kidney graft failure. The aim of this study is to evaluate the role of ICOS/ICOS-Ligand activation in a monocentric cohort of biopsy-proven ABMR in the period 2013-2018.

*Methods: We first performed an epidemiological analysis evaluating ABMR incidence and patient/graft survival at 1, 3 and 5 years, identifying predictors for ABMR with univariate and multivariate Cox regression. We then analyzed plasma levels of ICOS and ICOS-Ligand (ELISA) and their histological expression by immunohistochemistry, comparing ABMR patients with a sex- and age-matched cohort with stable renal function (protocol biopsies). Plasma Extracellular Vesicles (EV) were analyzed by NanoSight technology and FACS/RT-PCR for their protein and RNA content, respectively.

*Results: 367 patients were enrolled (median observation 44 months, IQR 23-64 months): rejection incidence was 13.6% at 1 year and significantly higher in patients with second transplantation (20% vs 9% first , p = 0.034). Graft survival of rejection patients was significantly lower than the control group (p=0.03). Cox multivariate analysis showed that duration of DGF strongly correlated with disease-free survival, which is reduced by 6% for every day of DGF (HR 1,06; p = 0,004). Plasma ICOS levels were significantly higher in ABMR vs. control groups (p<0.05). No difference was observed for ICOS-L plasma levels. By contrast, ICOS-L expression was up-regulated in ABMR patients both at glomerular (p<0,0001) and tubular (p=0,02) level. Staining for ICOS-L was observed in tubular epithelial cells and in endothelial cells in the glomeruli and in peritubular capillaries. Of interest, we also observed intraglomerular staining with ICOS in infiltrating cells characterized by immunohistochemistry as NK cells. Moreover, by Nanosight analysis we observed a significant increase of circulating EV in the ABMR group. EV express on their surface different costimulatory molecules including ICOS, ICOS-L, CD40, CD40L.

*Conclusions: In our monocentric analysis we observed graft and patient survivals in short and medium term similar to those observed in most European centers (respectively 94,3-99,3% at 1 year; 87,3-92,7% at 5 years). Biopsy-proven rejection and DGF were independent determinant of graft loss. ICOS/ICOS-L pathway seems to be a potential therapeutic target in ABMR: the evaluation of soluble ICOS levels, ICOS-carrying circulating EV and ICOS-L expression in biopsies are promising biomarkers of ABMR activity.

To cite this abstract in AMA style:

Cantaluppi V, Merlotti G, Quaglia M, Rosso G, Clemente N, Cappellano G, Chiocchetti A, Castellano G, Dianzani U, Camussi G. Activation of the ICOS/ICOS-Ligand Pathway in Antibody-Mediated Kidney Graft Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/activation-of-the-icos-icos-ligand-pathway-in-antibody-mediated-kidney-graft-rejection/. Accessed July 12, 2025.

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