A study of similar design was conducted in nonimmunocompromised rats of normal VA status to assess the effects of RA, given at a dose resembling a chemotherapeutic regimen, on TD antibody production (DeCicco et al., 2001). Rats were treated with 100-mg RA ± 20-mg PIC on day 1 with continued administration of 100 mg of RA daily for 11 days, after which antibody production changes in lymphocyte populations, and cell proliferation were evaluated. In another study conducted for just 21 h, early changes in lymphocyte populations and gene expression were measured. Similar to previous results in VA-deficient rats, the combination of RA + PIC significantly potentiated anti-tetanus IgG levels in VA-adequate rats. This combination also increased the numbers of B-cells and MHC class II+ cells in spleen and lymph nodes, determined by flow cytometry, and the number of NK cells in spleen and blood (see Section V). RA + PIC significantly increased the levels of IL-10, IL-12, and STAT-1 mRNA, and STAT-1 protein, suggestive of heightened immune stimulation. Because tetanus toxoid is a TD antigen, the proliferative response of T-cells ex vivo was further studied after short-term treatments administered in vivo, as a model for the early stages of T-cell activation in vivo. RA combined with PIC significantly increased T-cell proliferation stimulated by anti-CD3/phorbol myristyl acetate + IFNa ex vivo. These changes in antibody production, cell distribution, cytokine gene expression, and T-cell proliferation suggest that the combination of RA + PIC stimulates humoral and cell-mediated immunity. It was interesting, however, that the strong synergy between RA and PIC on anti-tetanus antibody production was not apparent in the VA-sufficient rat model.
To further investigate the potential for RA and PIC to promote immunity in the VA-adequate state, studies were conducted in adult mice immunized with tetanus toxoid and treated with RA and/or PIC at priming (Ma et al., 2005). Three independent studies of short and long duration were conducted to evaluate early responses to treatment and long-term outcomes on antibody titers and memory formation. Anti-tetanus IgG isotypes were measured to further assess the effect of treatment on Th1/type 1 immunity, associated with higher IgG2a responses, and Th2/type 2 immunity associated with higher IgG1 production. Whereas RA and PIC differentially regulated both primary and secondary anti-TT IgG isotypes, the combination of RA + PIC stimulated the highest level of total anti-TT IgG (Fig. 1A and B). Concomitantly, the ratio of IgG1 to IgG2a was similar to that of the control group, indicating that the combination of RA + PIC promoted a higher but normally balanced response.
Antibody production was strongly associated with type 1/type 2 cytokine gene expression, assessed as IFNg and IL-12 mRNA as indicators of type 1 response, and IL-4 and IL-12 mRNA as indicators for type 2 response.
Adult primary response d
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