Activation of the lectin pathway of complement in pig-to-human xenotransplantation models

Bongoni, Anjan; Kiermeir, David; Jenni, Hansjörg; Wünsch, Annegret; Bähr, Andrea; Ayares, David; Seebach, Jörg D; Wolf, Eckhard; Klymiuk, Nikolai; Constantinescu, Mihai Adrian; Vögelin, Esther; Rieben, Robert (2013). Activation of the lectin pathway of complement in pig-to-human xenotransplantation models. Transplantation, 96(9), pp. 791-799. Lippincott Williams & Wilkins 10.1097/TP.0b013e3182a3a52b

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BACKGROUND

Natural IgM containing anti-Gal antibodies initiates classic pathway complement activation in xenotransplantation. However, in ischemia-reperfusion injury, IgM also induces lectin pathway activation. The present study was therefore focused on lectin pathway as well as interaction of IgM and mannose-binding lectin (MBL) in pig-to-human xenotransplantation models.

METHODS

Activation of the different complement pathways was assessed by cell enzyme-linked immunosorbent assay using human serum on wild-type (WT) and α-galactosyl transferase knockout (GalTKO)/hCD46-transgenic porcine aortic endothelial cells (PAEC). Colocalization of MBL/MASP2 with IgM, C3b/c, C4b/c, and C6 was investigated by immunofluorescence in vitro on PAEC and ex vivo in pig leg xenoperfusion with human blood. Influence of IgM on MBL binding to PAEC was tested using IgM depleted/repleted and anti-Gal immunoabsorbed serum.

RESULTS

Activation of all the three complement pathways was observed in vitro as indicated by IgM, C1q, MBL, and factor Bb deposition on WT PAEC. MBL deposition colocalized with MASP2 (Manders' coefficient [3D] r=0.93), C3b/c (r=0.84), C4b/c (r=0.86), and C6 (r=0.80). IgM colocalized with MBL (r=0.87) and MASP2 (r=0.83). Human IgM led to dose-dependently increased deposition of MBL, C3b/c, and C6 on WT PAEC. Colocalization of MBL with IgM (Pearson's coefficient [2D] rp=0.88), C3b/c (rp=0.82), C4b/c (rp=0.63), and C6 (rp=0.81) was also seen in ex vivo xenoperfusion. Significantly reduced MBL deposition and complement activation was observed on GalTKO/hCD46-PAEC.

CONCLUSION

Colocalization of MBL/MASP2 with IgM and complement suggests that the lectin pathway is activated by human anti-Gal IgM and may play a pathophysiologic role in pig-to-human xenotransplantation.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Herz und Gefässe 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery > Hand Surgery 04 Faculty of Medicine > Department of Orthopaedic, Plastic and Hand Surgery (DOPH) > Clinic of Plastic and Hand Surgery > Plastic, Reconstructive and Aesthetic Surgery
UniBE Contributor:	Bongoni, Anjan, Kiermeir, David, Constantinescu, Mihai Adrian, Vögelin, Esther, Rieben, Robert
Subjects:	600 Technology > 610 Medicine & health
ISSN:	0041-1337
Publisher:	Lippincott Williams & Wilkins
Language:	English
Submitter:	Jörg Arnoldi
Date Deposited:	07 Feb 2014 08:25
Last Modified:	05 Dec 2022 14:28
Publisher DOI:	10.1097/TP.0b013e3182a3a52b
PubMed ID:	23958924
URI:	https://boris.unibe.ch/id/eprint/41208