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Πέμπτη 28 Φεβρουαρίου 2019

Molecular Patterns Discriminate Accommodation and Subclinical Antibody-Mediated Rejection in Kidney Transplantation

Background: Accommodation in AB0-incompatible (AB0i) transplantation and subclinical antibody-mediated rejection in HLA-incompatible (HLAi) transplantation share several morphological similarities. Because the clinical long-term outcomes differ, we hypothesized different molecular processes involved in AB0i transplantation and subclinical antibody-mediated rejection. Methods: Using Illumina Human HT-12 v4 Expression BeadChips, the whole transcriptome was evaluated based on 3-month protocol C4d+ biopsies in otherwise stable AB0i and HLAi kidney grafts as well as in C4d-negative HLA-compatible grafts exhibiting normal histological findings. Top differently regulated genes were further validated using RT-qPCR in another patient cohort and complement regulatory proteins by immunohistochemistry. Results: In the case of genes involved in immune response-related biological processes, AB0i and HLAi cohorts had similar transcriptomic profiles to C4d-negative controls. The majority of deregulated genes in the AB0i and HLAi groups consisted of metallothioneins and epithelial transporter genes. Increased expression of epithelial transporters (SLC4A1; SLC4A9; SLC17A3; SLC12A3; SLC30A2) and class 1 metallothioneins (MT1F, MT1G and MT1X) in HLAi transplantation was validated by RT-qPCR. In comparison to controls, both incompatible cohorts were characterized by the upregulation of intrarenal complement regulatory genes. CD46 and CD59 transcripts were increased in the AB0i cohort while CD46 solely in HLAi group, CD59 protein expression was similar in both incompatible groups. In conclusion, several epithelial transporters and metallothioneins discriminate subclinical antibody-mediated rejection in HLAi transplantation from accommodation in AB0i transplantation, which suggest different involved downstream mechanisms and increased risk of injury in HLAi settings. Metallothioneins with their antioxidative properties may help to attenuate the inflammation response induced by DSA binding. Financial disclosure: This work was supported by the Grant Agency of the Ministry of Health of the Czech Republic (No. 15-26865A). Conflict of interest: The authors declare no conflicts of interest. Corresponding Author: Ondrej Viklicky, MD, PhD, Professor of Medicine, Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic. E-mail: ondrej.viklicky@ikem.cz, Phone: + 420 23605 4110, Fax: +420 23605 3168 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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