Objectives: Systemic lupus erythematosus (SLE) is a classical autoimmune disorder characterised by the production of IgG autoantibodies against double-stranded DNA (dsDNA). Activation of FcR-bearing effector cells by immune complexes (ICs) is a key event in SLE pathogenesis since lupus-prone NZB/NZW F1 hybrids lacking activating Fc receptors (FcR) are protected against inflammatory kidney damage despite glomerular deposition of ICs. Moreover, soluble FcRs inhibit IC-caused Arthus reaction in vivo. Therefore, recombinant human soluble FcRII (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-opsonized 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”, 150µg/week husCD32) or continuously from week 24 (“therapeutic”; 100µg/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-opsonized MRBCs by peritoneal macrophages indicating disruption of IgG:FcR 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 anemia 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.
- NZB/NZW F1 mouse
- Systemic Lupus Erythematosus
- soluble Fc receptors