title: Prolonged effects of short-term anti-CD20 B cell depletion therapy in murine systemic lupus erythematosus.
abstract: OBJECTIVE
  Although B cells are implicated in the pathogenesis of systemic lupus erythematosus, the role of B cell depletion (BCD) as a treatment is controversial, given the variable benefit in human disease. This study was undertaken to test the effects of BCD therapy in a murine lupus model to better understand the mechanisms, heterogeneity, and effects on disease outcomes.
  
  
  METHODS
  (NZB x NZW)F(1) female mice with varying degrees of disease severity were treated with an anti-mouse CD20 (anti-mCD20) antibody (IgG2a), BR3-Fc fusion protein (for BAFF blockade), or control anti-human CD20 monoclonal antibody (approximately 10 mg/kg each). Tissue samples were harvested and analyzed by flow cytometry. The development and extent of nephritis were assessed by monitoring proteinuria (using a urine dipstick) and by immunohistochemical analysis of the kidneys. Serum immunoglobulin levels were measured by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  After a single injection of anti-mCD20, BCD was more efficient in the peripheral blood, lymph nodes, and spleen compared with the bone marrow and peritoneum of normal mice as well as younger mice with lupus. Since depletion of the marginal zone and peritoneal B cells was incomplete and variable, particularly in older mice with established nephritis, a strategy of sequential weekly dosing was subsequently used, which improved the extent of depletion. BAFF blockade further enhanced depletion in the spleen and lymph nodes. Early BCD therapy delayed disease onset, whereas BCD therapy in mice with advanced disease reduced the progression of nephritis. These effects were long-lasting, even after B cell reconstitution occurred, and were associated with a reduction in T cell activation but no significant change in autoantibody production.
  
  
  CONCLUSIONS
  The lasting benefit of a short course of BCD therapy in lupus-prone mice with an intact immune system and established disease highlights the validity of this treatment approach.
authors.affiliation: University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Kai W
authors.initials: KW
authors.lastname: Bekar
authors.forename: Teresa
authors.initials: T
authors.lastname: Owen
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn
authors.forename: Travis
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wang
authors.forename: Roger
authors.initials: R
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barnard
authors.forename: Sean
authors.initials: S
authors.lastname: Brady
authors.forename: Sarah
authors.initials: S
authors.lastname: Nevarez
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Goldman
authors.forename: Marilyn
authors.initials: M
authors.lastname: Kehry
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D016009:Chi-Square Distribution; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D051379:Mice; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D018951:Antigens, CD20; D001323:Autoantibodies