title: Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice.
abstract: We have previously reported that IL-10(+) regulatory B cells, known to play an important role in controlling autoimmunity and inflammatory disorders, are contained within the transitional 2 immature (T2) B cell pool (T2 Bregs). Therapeutic strategies facilitating their enrichment or enhancing their suppressive activity are highly attractive. In this study, we report that agonistic anti-CD40 specifically targets T2 B cells and enriches Bregs upon short-term in vitro culture. Although transfer of unmanipulated T2 B cells, isolated from mice with established lupus, failed to confer protection to diseased mice, transfer of in vitro anti-CD40-generated T2 B cells (T2-like-Bregs) significantly improved renal disease and survival by an IL-10-dependent mechanism. T2-like-Bregs readily accumulated in the spleen after transfer, suppressed Th1 responses, induced the differentiation of IL-10(+)CD4(+)T cells, and conveyed a regulatory effect to CD4(+)T cells. In addition, in vivo administration of agonistic anti-CD40, currently on trial for the treatment of cancer, halted and reversed established lupus. Taken together, our results suggest a novel cellular approach for the amelioration of experimental lupus.
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Blair
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.|Department of UIM en Immunologia, Hospital de Pediatria, CMN Siglo XXI, IMSS, México.
authors.forename: Karina A
authors.initials: KA
authors.lastname: Chavez-Rueda
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.
authors.forename: Jamie G
authors.initials: JG
authors.lastname: Evans
authors.affiliation: Department of Laboratory Medicine and Immunology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.affiliation: Department of Molecular Immunology Unit, Institute of Child Health. 30 Guilford Street, London, WC1N 1EH.
authors.forename: Ayad
authors.initials: A
authors.lastname: Eddaoudi
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ehrenstein
authors.affiliation: Department of Centre For Rheumatology Research, Department of Medicine, University College London. 46 Cleveland Street London W1T4 JF United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens