title: Activated protein C attenuates systemic lupus erythematosus and lupus nephritis in MRL-Fas(lpr) mice.
abstract: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease leading to inflammatory tissue damage in multiple organs (e.g., lupus nephritis). Current treatments including steroids, antimalarials, and immunosuppressive drugs have significant side effects. Activated protein C is a natural protein with anticoagulant and immunomodulatory effects, and its recombinant version has been approved by the U.S. Food and Drug Administration to treat severe sepsis. Given the similarities between overshooting immune activation in sepsis and autoimmunity, we hypothesized that recombinant activated protein C would also suppress SLE and lupus nephritis. To test this concept, autoimmune female MRL-Fas(lpr) mice were injected with either vehicle or recombinant human activated protein C from week 14-18 of age. Activated protein C treatment significantly suppressed lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuated cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen were suppressed by activated protein C. The latter was associated with lower total plasma IgM and IgG levels as well as lower titers of anti-dsDNA IgG and rheumatoid factor. Together, recombinant activated protein C suppresses the abnormal systemic immune activation in SLE of MRL-Fas(lpr) mice, which prevents subsequent kidney, lung, and skin disease. These results implicate that recombinant activated protein C might be useful for the treatment of human SLE.
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Campus Innenstadt, Klinikum der Universität München-LMU, 80336 München, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Lichtnekert
authors.forename: Khader Valli
authors.initials: KV
authors.lastname: Rupanagudi
authors.forename: Onkar P
authors.initials: OP
authors.lastname: Kulkarni
authors.forename: Murthy Narayana
authors.initials: MN
authors.lastname: Darisipudi
authors.forename: Ramanjaneyulu
authors.initials: R
authors.lastname: Allam
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D002469:Cell Separation; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011486:Protein C / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D011486:Protein C; D011994:Recombinant Proteins