title: Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus.
abstract: OBJECTIVE
  To determine the immunologic effects of anti-CD154 (CD40L) therapy in the (NZB x NZW)F(1) mouse model of systemic lupus erythematosus.
  
  
  METHODS
  Twenty-week-old and 26-week-old (NZB x NZW)F(1) mice were treated with continuous anti-CD154 therapy. Mice were followed up clinically, and their spleens were studied at intervals for B and T cell numbers and subsets and frequency of anti-double-stranded DNA (anti-dsDNA)-producing B cells. T cell-dependent immunity was assessed by studying the humoral response to the hapten oxazolone.
  
  
  RESULTS
  IgG anti-dsDNA antibodies decreased during therapy and disease onset was delayed, but immune tolerance did not occur. During treatment, there was marked depletion of CD19+ cells in the spleen; however, autoreactive IgM-producing B cells could still be detected by enzyme-linked immunospot assay. In contrast, few IgG- and IgG anti-dsDNA-secreting B cells were detected. Eight weeks after treatment cessation, the frequency of B cells producing IgG anti-dsDNA antibodies was still decreased in 50% of the mice, and activation and transition of T cells from the naive to the memory compartment were blocked. Anti-CD154 treatment blocked both class switching and somatic mutation and induced a variable period of relative unresponsiveness of IgG anti-dsDNA-producing B cells, as shown by decreased expression of the CD69 marker and failure to generate spontaneous IgG anti-dsDNA-producing hybridomas. Treated mice mounted an attenuated IgM response to the hapten oxazolone and produced no IgG antioxazolone antibodies.
  
  
  CONCLUSIONS
  Anti-CD154 is a B cell-depleting therapy that affects multiple B cell subsets. Activation of both B and T cells is prevented during therapy. After treatment cessation, autoreactive B cells progress through a series of activation steps before they become fully competent antibody-producing cells. The general immunosuppression induced during treatment will need to be taken into account when using B cell-depleting regimens in humans.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Weiqing
authors.initials: W
authors.lastname: Huang
authors.forename: Lena E
authors.initials: LE
authors.lastname: Schiffer
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Alla
authors.initials: A
authors.lastname: Akkerman
authors.forename: Kenji
authors.initials: K
authors.lastname: Hiromatsu
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology* / Q000494:pharmacology*; D022801:Complementarity Determining Regions / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006825:Hybridomas; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007165:Immunosuppression Therapy / Q000379:methods; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data
chemical_list: D001323:Autoantibodies; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D023201:CD40 Ligand; D004247:DNA