title: Monoclonal anti-interleukin-6 receptor antibody attenuates donor-specific antibody responses in a mouse model of allosensitization.
abstract: Interleukin 6 is an immune regulatory cytokine that impacts the development and maturation of T-cell, B-cell, and antibody producing plasma cells. A monoclonal antibody to the IL-6R (Tocilizumab®) was recently approved by the FDA for treatment of rheumatoid arthritis. Although anti-IL-6R anitbodies can reduce autoantibody levels in human disease, the use of anti-IL-6R for alloantibody suppression has not been examined. Here, we report on our experience with a mousenized rat-anti-mouse IL-6R (mMR16-1) for attenuating donor-specific antibody (DSA) responses. C57BL/6 mice were sensitized with skin allografts from a HLA.A2 transgenic mouse, and treated with intraperitoneal injections of mMR16-1 or control antibody. DSA responses were monitored weekly for 5weeks by measurement of serum anti-HLA.A2 antibodies in a flow cytometric antibody binding assay. Results show that mMR16-1 significantly reduced DSA IgM, IgG2a and IgG1 responses, respectively, while normalizing serum amyloid A (SAA), an acute phase reactant induced by IL-6 (p<0.01 vs. control). mMR16-1 injections increased mononuclear cell apoptosis in the spleens, as detected by annexin V staining and TUNEL. In conclusion, anti-IL6R attenuates de novo DSA responses and suppresses inflammatory markers (SAA). The data indicate that antibody therapy targeting the IL-6/IL-6R pathway may serve as a strategy to suppress DSA generation.
authors.affiliation: Comprehensive Transplant Center at Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. gordon.wu@cshs.org
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: N
authors.initials: N
authors.lastname: Chai
authors.forename: Irene
authors.initials: I
authors.lastname: Kim
authors.forename: A S
authors.initials: AS
authors.lastname: Klein
authors.forename: S C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000917:Antibody Formation; D000918:Antibody Specificity; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C577686:interleukin-6, mouse