Recombinant Soluble Human FcγR1A (CD64A) Reduces Inflammation in Murine Collagen-Induced Arthritis

Abstract

Binding of immune complexes to cellular FcγRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcγR, rh-FcγRIA (CD64A), was shown to block inflammation in passive transfer models of immune complex-mediated disease. To assess whether rh-FcγRIA could block inflammation in a T cell- and B cell-dependent model of immune complex-mediated disease, the efficacy of rh-FcγRIA in collagen-induced arthritis was evaluated. Mice with established arthritis were treated with a single s.c. injection of rh-FcγRIA (0.2–2.0 mg/dose) given every other day for 11 days. Relative to mice injected with vehicle alone, mice treated with rh-FcγRIA exhibited lower serum concentrations of IL-6, anti-type II collagen Abs, and total IgG2a. These changes were correlated with lower levels of paw swelling and joint damage in the rh-FcγRIA-treated mice and occurred in the presence of a significant murine Ab response to rh-FcγRIA. Comparison of the serum rh-FcγRIA concentration vs time profiles for rh-FcγRIA administered at two dose levels by i.v. and s.c. injection revealed that the bioavailabilty of s.c. administered rh-FcγRIA was 27–37%. Taken together, these data show that rh-FcγRIA is an effective inhibitor of inflammation in a model of established arthritis in mice.

Increased survival and reduced renal injury in MRL/lpr mice treated with a human Fcγ receptor II (CD32) peptide

“…In vitro it has been demonstrated that soluble human FcγRs may not only competitively inhibit Fc : FcR and Fc : rheumatoid factor, but also Fc : Fc interaction. Soluble human FcγRs modulate IC solubility by the inhibition of IC precipitation, 37,38 and soluble human FcγRs have previously been successfully used to ameliorate collagen‐induced arthritis, an animal model for rheumatoid arthritis 39,40 . The ability of human soluble FcγRIIA to mitigate a reverse passive Arthus reaction and IC‐induced alveolitis has established proof‐of‐principle that soluble FcγRs can inhibit Fc : FcR interaction in vivo .…”

Targeting the Fc receptor in autoimmune disease

“…In murine models, infusion of recombinant soluble FcγRIIa and FcγRIIIa can inhibit immune complex triggered inflammation [40]. Synthesized soluble FcγRIa and FcγRIIb have also been shown to absorb pathogenic immune complexes and to reduce disease severity in murine arthritis models [41–43]. Of note, other than serving as decoy receptors for immune complexes, there may be additional pro- or anti-inflammatory effects caused by circulating FcγRs, such as interacting with non-Ig-ligands and inducing the production of IL-12 [44, 45].…”

Crystal Structure of Fcγ Receptor I and Its Implication in High Affinity γ-Immunoglobulin Binding

“…Protein Expression, Purification, and Crystallization-The ectodomain of Fc␥RI (residues 1-282) with its native signal sequence was expressed in Chinese hamster ovary DXB-11 cells and purified via IgG affinity chromatography followed by cation exchange and gel filtration chromatography as described previously (18,19). Before crystallization, Fc␥RI was dialyzed against 10 mM Hepes (pH 7.4) and 0.1 M NaCl and concentrated to a final A 280 nm of 29.…”

“…For example, the infusion of high doses of serum IgG (intravenous immunoglobulins) has been used to treat immune thrombocytopenia and Kawasaki disease in human and arthritis as well as nephrotoxic nephritis in mouse models (13)(14)(15)(16)(17). Because of its unique high affinity antibody binding, Fc␥RI has been developed as a potential therapeutic reagent to treat immune complex-mediated disease (18,19). To further understand the high affinity antibody recognition by Fc␥RI and to facilitate the development of Fc␥RI-mediated immunotherapy, we determined the structure of the full-length extracellular domain of human Fc␥RI, investigated the molecular basis of its high affinity IgG binding using site-directed mutagenesis, and assessed the effects of IgG sialylation on Fc␥RI binding.…”