Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus

Arthritis Rheum. 2003 Feb;48(2):495-506. doi: 10.1002/art.10929.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Autoantibodies / blood
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology*
  • CD40 Ligand / immunology*
  • CD40 Ligand / pharmacology*
  • Complementarity Determining Regions / genetics
  • Complementarity Determining Regions / immunology
  • DNA / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Hybridomas
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin G / blood
  • Immunosuppression Therapy / methods
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / immunology*
  • Mice
  • Mice, Inbred NZB
  • Molecular Sequence Data


  • Autoantibodies
  • Complementarity Determining Regions
  • Immunoglobulin G
  • CD40 Ligand
  • DNA