Journal
ARTHRITIS AND RHEUMATISM
Volume 48, Issue 2, Pages 495-506Publisher
WILEY-LISS
DOI: 10.1002/art.10929
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Funding
- NIAID NIH HHS [AI-47291] Funding Source: Medline
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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 inummospot 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 inummosuppression induced during treatment will need to be taken into account when using B cell-depleting regimens in humans.
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