The mechanisms involved in the regulation of antibody and T-cell responses to antigen remain a central question in immunology today. It is hypothesized that alterations in atigen processing by either internal or external modification of an antigen may result in the enhancement of immunity in low-responder mice as well as lead to the development of autoimmunity. In order to investigate this possibility, the immune response to hen egg lysozyme (HEL) in non/low-responder C57BL/6 mice and HEL-transgenic C57BL/6 mice will be analyzed. This system provides many advantages, e.g., the simple and well characterization structure as well as the thoroughly studied immune response to the antigen. It has been demonstrated that immunization of non/low-responder mice with phosphorylcholine (PC)-conjugated HEL (PC-HEL) can convert these low- responder mice into high-responders for antibody as well as T-cell proliferative responses to HEL. Further analysis strongly suggests that PC-conjugation may alter the antigen processing pattern resulting in the generation of epitope-bearing peptides which favor the stimulation of T- cells specific for certain epitopes. A similar enhancement of T-cell stimulation is also seen with the mutant HEL molecules containing single amino acid substitutions at certain positions. Furthermore, preliminary studies have indicated that immunization of HEL-Tg mice with PC-HEL was able to break the self tolerance to HEL and induce a significant level of antibodies to HEL. This application will: (1) investigate the type and extent of HEL modification required for the development of immunity in HEL-Tg mice; (2) analyze immunity to HEL induced by immunization with modified HEL; (3) identify potential mechanisms involved in the development of immunity; and (4) generate HEL-Tg mice expressing HEL selectivity in the central nervous system. These proposed studies will provide information regarding the relationship between antigen modification and alteration of the immune response and help lead to a better understanding of the mechanisms involved in immune unresponsiveness and the development of immunity.
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