Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies

Author:

Mella Alberto1,Lavacca Antonio1,Dodoi Diana Teodora1,Presta Roberto1,Fop Fabrizio1,Campagna Marco1,Manzione Ana Maria1,Dolla Caterina1,Gallo Ester1,Abbasciano Isabella1,Gai Chiara2,Camussi Giovanni2,Barreca Antonella3,Caorsi Cristiana4,Giovinazzo Gloria1,Biancone Luigi1ORCID

Affiliation:

1. Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy.

2. Department of Medical Sciences, University of Turin, Turin, Italy.

3. Division of Pathology, “Città Della Salute e Della Scienza” Hospital, Department of Medical Sciences, University of Turin, Turin, Italy.

4. Immunogenetic and Transplant Biology Center, “Città Della Salute e Della Scienza” Hospital and Department of Medical Sciences, University of Turin, Turin, Italy.

Abstract

Background. Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Methods. Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Results. Differently from TG/DSA+, TG/DSA showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA tends to maintain or increase periglomerular/interstitial infiltration. Conclusions. In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.

Publisher

Ovid Technologies (Wolters Kluwer Health)

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