Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation

Pierre-Olivier Delpech (1) , Raphael Thuillier (1, 2) , Thibault Saintyves , Jerome Danion , Sylvain Le Pape (1) , Edwin van Amersfoort , Beatrijs D. Oortwijn (3) , Gilles Blancho (4) , Thierry Hauet (1, 2)

1 IRTOMIT - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques
2 CHU de Poitiers - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
3 Laboratory for Thrombosis and Haemostasis
4 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie

Background: Ischemia reperfusion injury (IRI) induced immune response is a critical issue in transplantation. Complement and contact system activation are among its key mechanisms. Study design: We investigated the benefits of pre-reperfusion treatment with recombinant human C1INH (rhC1INH), inhibitor of both complement and contact activation, in a pig model of kidney autotransplantation, subjecting the organ to 60 min warm ischemia prior to 24 h static preservation to maximize damage. Results: Serum creatinine measurement showed that treated animals recovered glomerular function quicker than the Vehicle group. However, no difference was observed in tubular function recovery, and elevated level of urinary NGal (Neutrophil gelatinase-associated lipocalin) and plasma AST (Aspartate Aminotransferase) were detected, indicating that treatment did not influence IRI-mediated tubular cell necrosis. Regarding chronic graft outcome, rhC1INH significantly prevented fibrosis development and improved function. Immunohistochemistry and western blot showed decreased invasion by macrophages and T lymphocytes, and reduction of epithelial to mesenchymal transition. We determined the effect of treatment on complement activation with immunofluorescence analyses at 30 min post reperfusion, showing an inhibition of C4d deposition and MBL staining in treated animals. Conclusions: In this model, the inhibition of complement activation by rhC1INH at reperfusion, while not completely counteracting IRI, limited immune system activation, significantly improving graft outcome on the short and long term.

Mots clés: Drug evaluation; Ischemia; Kidney transplantation; Preclinical; Reperfusion injury

Mots clés: Complement system proteins

Domaines: Sciences du Vivant [q-bio]; Médecine humaine et pathologie

Pierre-Olivier Delpech, Raphael Thuillier, Thibault Saintyves, Jerome Danion, Sylvain Le Pape, et al.. Inhibition of complement improves graft outcome in a pig model of kidney autotransplantation. Journal of Translational Medicine, 2016, 14 (1), pp.1-13. ⟨10.1186/s12967-016-1013-7⟩. ⟨hal-01928671⟩