The hepatitis A vaccines are highly immunogenic and without serious adverse effects. Therefore, the interaction between the antigen and the immune system must be very efficient. This study proposes to examine the cytokine response as an immune mechanism driving the antibody response to hepatitis A immunization and model the pharmacodynamics of this response. Our primary hypothesis is that the interleukin-4 (IL-4) production stimulated by hepatitis A immunization will predict the height of the antibody levels to hepatitis A immunization. To substantiate this hypothesis, we will immunize 25 hepatitis A seronegative subjects who will be followed for two weeks with serial blood draws to determine IL-4 production using three different strategies. Peripheral blood mononuclear cells (PBMC) will be cultured and spontaneous IL-4 production will be measured by ELISA in the supernatant of the cell cultures. IL-4 gene expression will be measured by extracting mRNA from PBMC. The mRNA will be probed with an IL-4 specific DNA probe and the amount of hybridized mRNA will be measured by capillary electrophoresis. Finally, we will measure IL-4 levels in the serum obtained from subjects. Each subject will undergo venipuncture on day 28 following immunization to determine hepatitis A antibody levels. We will then correlate the IL-4 production as determined by each of the methods with the height of the antibody response. Data analysis includes correlation of IL-4 Cmax and IL-4 AUC with the antibody response. We will then choose the appropriate pharmacodynamic model for the relationship between IL-4 production and hepatitis A antibody response. Secondarily, we will determine which of the methods for measuring IL-4 production is most appropriate for use in studies such as this. Ultimately, the specific implications of this work include the opportunity to manipulate the cytokine response or to modify the antigen to improve the immune response to hepatitis A immunization. Since the response to hepatitis A vaccine is excellent, determining the pharmacodynamic model for the IL-4 production and antibody response may be useful in predicting the antigenicity of novel vaccines against other diseases. With knowledge of the optimal cytokine response to a vaccine, clinicians may have the opportunity to manipulate the cytokine response toward one that results in an appropriately vigorous antibody response.
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