Open AccessEffects of anti‐CD154 treatment on B cells in murine systemic lupus erythematosus
Author(s) -
Wang Xiaobo,
Huang Weiqing,
Schiffer Lena E.,
Mihara Masahiko,
Akkerman Alla,
Hiromatsu Kenji,
Davidson Anne
Publication year - 2003
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.10929
Subject(s) - cd154 , immunology , b cell , antibody , spleen , oxazolone , cd40 , cd19 , immune system , memory b cell , b 1 cell , humoral immunity , medicine , microbiology and biotechnology , t cell , biology , cytotoxic t cell , antigen presenting cell , biochemistry , in vitro
Objective To determine the immunologic effects of anti‐CD154 (CD40L) therapy in the (NZB × NZW)F 1 mouse model of systemic lupus erythematosus. Methods Twenty‐week‐old and 26‐week‐old (NZB × 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.