Objectives: Systemic lupus erythematosus (SLE) is a classical autoimmune disorder characterised by the production of IgG autoantibodies against double-stranded DNA (dsDNA). Activation of FcγR-bearing effector cells by immune complexes (ICs) is a key event in SLE pathogenesis as lupus-prone NZB/NZW F1 hybrids lacking activating Fcγ receptors (FcγR) are protected against inflammatory kidney damage despite glomerular deposition of ICs. Moreover, soluble FcγRs inhibit IC-caused Arthus reaction in vivo. Therefore, recombinant human soluble FcγRII (CD32) was evaluated as a novel therapeutic strategy in lupus-like disease in NZB/NZW F1 hybrids.
Methods: Binding of husCD32 to murine IgG was studied in vitro by binding to IgG-coated erythrocytes and inhibition of phagocytosis of IgG-opsonised murine erythrocytes. In order to examine therapeutic impact of husCD32 in vivo, female NZB/NZW F1 mice were treated either from week 16 to 20 (“prophylactic”, 150 μg/week husCD32) or continuously from week 24 (“therapeutic”; 100 μg/week husCD32) by subcutaneous injections. Controls received buffered saline.
Results: In vitro investigations of husCD32 revealed binding to murine erythrocytes coated with murine IgG. Moreover, husCD32 substantially diminished phagocytosis of murine IgG-opsonised murine red blood cells by peritoneal macrophages indicating disruption of IgG–FcγR interaction. There was a therapeutic efficacy of husCD32 to attenuate lupus pathology indicated by significantly delayed onset of proteinuria and weight loss, reduced histopathological findings, delayed development of anaemia and improved survival by prophylactical application. Therapeutic treatment did not reverse nephritis but significantly prolonged survival despite apparent kidney damage. B cell count, concentration of IgG anti-dsDNA autoantibodies and deposition of glomerular ICs was not significantly affected by the application of husCD32.
Conclusions: The results demonstrate binding properties of husCD32 to ICs in vitro and as a proof-of-principle therapeutic efficacy in inhibiting chronic murine lupus pathology in vivo.
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Competing interests: None.
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