title: Inhibition of the classical and lectin pathway of the complement system by recombinant LAIR-2.
abstract: Activation of complement may cause severe tissue damage in antibody-mediated allograft rejection and other antibody-mediated clinical conditions; therefore, novel potent complement inhibitors are needed. Previously, we described binding of the inhibitory receptor LAIR-1 and its soluble family member LAIR-2 to collagen. Here, we investigated binding of LAIR-1 and LAIR-2 to the complement proteins C1q and MBL, which both have collagen-like domains, and evaluated the effect of this binding on complement function. We demonstrate specific binding of recombinant LAIR proteins to both C1q and MBL. Surface plasmon resonance experiments showed that LAIR-2-Fc protein bound C1q and MBL with the highest affinity compared to LAIR-2-HIS. We, therefore, hypothesized that LAIR-2-Fc is a potent complement inhibitor. Indeed, LAIR-2-Fc inhibited C4 fixation to IgG or mannan, reduced activation of C4 by aggregated IgG in plasma and inhibited iC3b deposition on cells. Finally, LAIR-2-Fc inhibited complement-mediated lysis of cells sensitized with anti-HLA antibodies in an ex vivo model for antibody-mediated transplant rejection. Thus, LAIR-2-Fc is an effective novel complement inhibitor for the treatment and prevention of antibody-mediated allograft rejection and antibody-mediated clinical conditions.
authors.affiliation: Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marloes J M
authors.initials: MJ
authors.lastname: Olde Nordkamp
authors.forename: Peter
authors.initials: P
authors.lastname: Boross
authors.forename: Cafer
authors.initials: C
authors.lastname: Yildiz
authors.forename: J H Marco
authors.initials: JH
authors.lastname: Jansen
authors.forename: Jeanette H W
authors.initials: JH
authors.lastname: Leusen
authors.forename: Diana
authors.initials: D
authors.lastname: Wouters
authors.forename: Rolf T
authors.initials: RT
authors.lastname: Urbanus
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.forename: Linde
authors.initials: L
authors.lastname: Meyaard
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D015922:Complement C1q / Q000378:metabolism; D037582:Complement Pathway, Mannose-Binding Lectin / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007105:Immune Complex Diseases / Q000276:immunology / Q000628:therapy*; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007167:Immunotherapy; D007518:Isoantibodies / Q000378:metabolism; D020014:K562 Cells; D011485:Protein Binding / Q000187:drug effects; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
chemical_list: D006680:HLA Antigens; D007127:Immunoglobulin Constant Regions; D007518:Isoantibodies; C431503:LAIR-2 receptor; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C108073:leukocyte-associated immunoglobulin-like receptor 1; D015922:Complement C1q