A CD59 promotor polymorphism in donor lungs correlates with a higher risk for chronic rejection after lung transplantation

K. Budding, E.A. van de Graaf, T. Kardol-Hoefnagel, J.C.A. Broen, J.M. Kwakkel-van Erp, E.-J.D. Oudijk, D.A. van Kessel, C.E. Hack, H.G. Otten

Chair(s): dr. Hennie G. Otten, medisch immunoloog, UMC Utrecht & dr. Laura B. Bungener, medisch immunoloog, UMC Groningen

Thursday 10 march 2016

10:10 - 10:20h at Zaal 1 & 2

Categories: Parallelsessie (basaal)

Parallel session: Parallelsessie VII - Basaal immunologie

Complement activation primarily leads to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promotor regions, single nucleotide polymorphisms (SNPs) are present that could influence transcription.

We analyzed these SNPs and investigated their influence on protein expression levels on PBMCs and donor derived primary endothelial cells. Furthermore, we analyzed the effect of this SNP configuration on sensitivity to complement mediated cell lysis and subsequent cytokine secretion.

A single SNP configuration in the promotor region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p=0.016) and monocytes (p=0.013). Lung endothelial cells with this SNP configuration secreted more pro-fibrotic cytokines IL-6 (p=0.047) and FGF-β (p=0.036) upon exposure to sublytical complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p<0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p=0.094) and a significantly higher incidence of the bronchiolitis obliterans syndrome (p=0.046) in the recipient.

These findings support a role for complement in the pathogenesis of this post-transplant complication and are the first to show a deleterious association of a donor CD59 promotor polymorphism in lung transplantation.