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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI015446-13
Application #
2667668
Study Section
Special Emphasis Panel (ZRG5-IMB (02))
Project Start
1988-12-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Kang, H K; Mikszta, J A; Deng, H et al. (2000) Processing and reactivity of T cell epitopes containing two cysteine residues from hen egg-white lysozyme (HEL74-90). J Immunol 164:1775-82
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Mikszta, J A; Kim, B S (1996) Conversion of low antibody responders into high responders by up-regulating the T cell response to a selective epitope. J Immunol 157:2883-90
Mikszta, J A; Waltenbaugh, C; Kim, B S (1995) Impaired antigen presentation by splenocytes of ethanol-consuming C57BL/6 mice. Alcohol 12:265-71
Jang, Y S; Mikszta, J A; Kim, B S (1994) T cell epitope recognition involved in the low-responsiveness to a region of hen egg lysozyme (46-61) in C57BL/6 mice. Mol Immunol 31:803-12
Liu, K J; Parikh, V S; Tucker, P W et al. (1994) Surface immunoglobulins mediate efficient transport of antigen to lysosomal compartments resulting in enhanced specific antigen presentation by B cells. Eur J Immunol 24:2755-60
Liu, K J; Parikh, V S; Tucker, P W et al. (1993) Role of the B cell antigen receptor in antigen processing and presentation. Involvement of the transmembrane region in intracellular trafficking of receptor/ligand complexes. J Immunol 151:6143-54
Kim, B S; Jang, Y S (1992) Constraints in antigen processing result in unresponsiveness to a T cell epitope of hen egg lysozyme in C57BL/6 mice. Eur J Immunol 22:775-82

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