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Immune Deviation Away from Th1 in Interferon- Knockout Mice Does Not Enhance TSH Receptor Antibody Production after Naked DNA Vaccination

Autoimmune Disease Unit, Cedars-Sinai Research Institute and University of California School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Sandra M. McLachlan, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048. E-mail: . mclachlans{at}cshs.org

TSH receptor (TSHR) DNA vaccination induces high TSHR antibody levels in BALB/c mice housed in a conventional facility. However, under pathogen-free conditions, we observed a Th1 cellular response to TSHR antigen characterized by interferon- (IFN) production. In the present study we investigated the effect on TSHR DNA vaccination of diverting the cytokine milieu away from Th1 using 1) IFN knockout BALB/c mice, and 2) wild-type mice covaccinated with DNA for the TSHR and for IFN/receptor-Fc protein that prevents IFN from binding to its receptor. Neither approach enhanced TSHR antibody levels, although splenocyte IFN production in response to TSHR antigen was absent (IFN knockouts) or reduced (IFN receptor-Fc). Moreover, production of IL-2, another Th1 cytokine, but not Th2 cytokines, indicated that neither strategy overcame the Th1 bias of im DNA vaccination. Importantly, splenocyte production of IFN and IL-2 provides a sensitive detection system for TSHR-specific T cells. Unexpectedly, higher TSHR antibody levels developed in rare mice. High titer animals had TSHR-specific responses of both Th2 and Th1 types, whereas low titer animals had Th1-restricted TSHR responses. The heterogeneity of responses induced by TSHR DNA vaccination in mice may provide insight into the titers and IgG subclasses of spontaneous autoantibodies in humans.

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