title: Effect of B-cell depletion using anti-CD20 therapy on inhibitory antibody formation to human FVIII in hemophilia A mice.
abstract: We herein tested the effect of B-cell depletion on tolerance induction to factor VIII (FVIII) in a mouse model of hemophilia A. Two subclasses of anti-mouse CD20 monoclonal antibodies with differential depletion effects were used. Thus, IgG1 anti-CD20 selectively depleted follicular B cells and spared marginal zone B cells, whereas IgG2a anti-CD20 efficiently depleted both. In FVIII primed mice, a single dose of either IgG1 or IgG2a anti-CD20 pretreatment prevented the increase in inhibitor formation in the majority of treated mice by subsequent daily, high-dose FVIII intravenous injection as a model for immune tolerance induction. However, the IgG1, but not the IgG2a, anti-CD20 pretreatment led to a significant increase of regulatory T cells in the spleen. Importantly, 3 months after the partial B-cell depletion with IgG1 anti-CD20, the FVIII-specific hyporesponsive state remained. We suggest a tolerogenic role of the remaining marginal zone B cells as a potential mechanism for anti-CD20 therapy.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Zhang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Skupsky
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000008:administration & dosage; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007074:Immunoglobulin G; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII