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Treatment of lupus-prone NZB/NZW F1 mice with recombinant soluble Fcγ receptor II (CD32)
  1. Sonja Werwitzke (werwitzke.sonja{at}mh-hannover.de)
  1. Department of Clinical Immunology, Hannover Medical School, Germany
    1. David Trick
    1. Department of Clinical Immunology, Hannover Medical School, Germany
      1. Peter Sondermann
      1. Max-Planck-Institute Martinsried, Germany
        1. Kenji Kamino (kamino.kenji{at}mh-hannover.de)
        1. Institute of Cell and Molecular Pathology, Hannover Medical School, Germany
          1. Brigitte Schlegelberger
          1. Institute of Cell and Molecular Pathology, Hannover Medical School, Germany
            1. Katja Kniesch
            1. Department of Clinical Immunology, Hannover Medical School, Germany
              1. Andreas Tiede (tiede.andreas{at}mh-hannover.de)
              1. Medical School Hannover, Germany
                1. Uwe Jacob
                1. SuppreMol, Germany
                  1. Reinhold E. Schmidt
                  1. Department of Clinical Immunology, Hannover Medical School, Germany
                    1. Torsten Witte (witte.torsten{at}mh-hannover.de)
                    1. Department of Clinical Immunology, Hannover Medical School, Germany

                      Abstract

                      Objectives: Systemic lupus erythematosus (SLE) is a classical autoimmune disorder characterised by the production of IgG autoantibodies against double-stranded DNA (dsDNA). Activation of FcR-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 (FcR) are protected against inflammatory kidney damage despite glomerular deposition of ICs. Moreover, soluble FcRs inhibit IC-caused Arthus reaction in vivo. Therefore, recombinant human soluble FcRII (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:FcR 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.

                      • CD32
                      • NZB/NZW F1 mouse
                      • Systemic Lupus Erythematosus
                      • soluble Fc receptors

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