We are continuing to probe the molecular basis of immune recognition through the application of modern techniques of experimental cellular immunology to the genetically defined murine model. The extremely well-characterized protein antigen, hen egg-white lysozyme (HEL), other avian and mammalian lysozymes, peptide fragments of HEL, specifically derivatized HEL, and synthetic peptides related to HEL are all utilized in this study. At each level of recognition there appears to be severe immune focusing to a highly restricted region of HEL that, however, is different for each cell type: B cells, helper T cells, and suppressor T cells. In addition, the response is dominated by a single public idiotype, IdXL. At the B-cell level, we are more extensively exploring the early transient recognition by B cells of an epitope including the three N-terminal amino acids of HEL that normally appear obligatory for subsequent recognition of other epitopes by B cells. In particular, we are attempting to disrupt this ordered read-out by a number of alternative modes of immunization and pretreatments. We have shown that the ultimate epitopes recognized by B cells seem confined to a single face of HEL, and we have more carefully defined this restriction through an extensive study of the degree to which monoclonal antibodies directed against HEL show competitive binding. We have established a library of HEL-specific T-cell clones and through the use of synthetic peptides are extending our studies of the fine specificity of these clones. In particular, we are investigating changes in specificity as a function of immunizing antigen and of haplotype. We are investigating in detail the nature of IdXL-recognizing T cells raised in response to HEL. The fine specificity of T suppressor cells active in tolerance is being explored. The nature of IdXL in molecular terms has been studied through recombination studies with monoclonal antibodies, and it has been established that IdXL is dependent on light chains, whereas fine specificity is determined by heavy chains. DNA studies suggest that multiple variable region genes code for both heavy and light chains of IdXL-positive monoclonal antibodies. (LB)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37CA024442-26
Application #
2087253
Study Section
Special Emphasis Panel (NSS)
Project Start
1978-05-01
Project End
1995-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
26
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gabaglia, C R; Pedersen, B; Hitt, M et al. (1999) A single intramuscular injection with an adenovirus-expressing IL-12 protects BALB/c mice against Leishmania major infection, while treatment with an IL-4-expressing vector increases disease susceptibility in B10.D2 mice. J Immunol 162:753-60
Moudgil, K D; Wang, J; Yeung, V P et al. (1998) Heterogeneity of the T cell response to immunodominant determinants within hen eggwhite lysozyme of individual syngeneic hybrid F1 mice: implications for autoimmunity and infection. J Immunol 161:6046-53
Moudgil, K D; Sekiguchi, D; Kim, S Y et al. (1997) Immunodominance is independent of structural constraints: each region within hen eggwhite lysozyme is potentially available upon processing of native antigen. J Immunol 159:2574-9
Nanda, N K; Arzoo, K K; Geysen, H M et al. (1995) Recognition of multiple peptide cores by a single T cell receptor. J Exp Med 182:531-9
Grewal, I S; Moudgil, K D; Sercarz, E E (1995) Hindrance of binding to class II major histocompatibility complex molecules by a single amino acid residue contiguous to a determinant leads to crypticity of the determinant as well as lack of response to the protein antigen. Proc Natl Acad Sci U S A 92:1779-83
Nanda, N K; Sercarz, E E (1995) The positively selected T cell repertoire: is it exclusively restricted to the selecting MHC? Int Immunol 7:353-8
Kumar, V; Bhardwaj, V; Soares, L et al. (1995) Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4/5 or interferon gamma by T cells. Proc Natl Acad Sci U S A 92:9510-4
Soares, L R; Sercarz, E E; Miller, A (1994) Vaccination of the Leishmania major susceptible BALB/c mouse. I. The precise selection of peptide determinant influences CD4+ T cell subset expression. Int Immunol 6:785-94
Manca, F; Dessi, V; Shastri, N et al. (1994) Isolation of lysozyme-specific T cell clones that discriminate between native and denatured antigen. Cell Immunol 154:420-9
Gammon, G; Edger, D; McBride, W H et al. (1994) Complications in the functional analysis of transfected MHC genes. Cell Immunol 154:219-30

Showing the most recent 10 out of 31 publications