We propose to study the specificity, function and control of T-helper cells which recognize idiotypes produced by B-cells. Selected myeloma and hybridoma anti-PC antibodies will be used as carriers in a TNP-specific B-cell response. T-helper cells recognizing the idiotypes of these PC binding antibodies are generated by priming with: a) PC binding idiotypes, b) low doses of anti-idiotypic antibodies or c) with PC-hemocyanin. Limiting numbers of T-cells are transferred to athymic syngeneic recipients and fragment cultures are prepared from the recipient spleens. The cultures are immunized with TNP-coupled anti-PC idiotypes and the production of anti-TNP antibodies is measured by ELIAS or RIA. Since the idiotype recognizing T helper cells are generated indirectly by anti-idiotype priming or by antigen exposure, the cellular circuits in the induction of T help will be studied. The role of T suppressor cells and antibodies will be investigated by adoptive transfers. Next, the fine specificity of idiotype recognizing helper T cells will be determined by in vitro inhibition of idiotype recognition using idiotype variants, anti-idiotype antibodies and isolated H and L chains. Single idiotope recognizing T helpers will be generated by monoclonal anti-idiotypic antibodies and their fine specificity will be analyzed using T15 variant hybridomas as TNP-antigens. Although the anti-TNP readout does not exactly mimic events which occur after exposure to antigen, this approach permits us to study idiotype-specific T-B interactions. Preliminary findings indicate that T helper cells recognize shared determinants on the T15 idiotype which are related to the site for PC. Since these target idiotopes are shared among serologically different idiotypes and appear to be stable during evolution they might function as specialized """"""""Regulatory Idiotopes"""""""" in the control of the anti-PC response. Of particular interest is the long-term observation of possible changes in the specificity of T cells in aging, primed mice. Finally, attempts will be made to obtain T helper cell clones and to use their factors to study possible restriction in T-B interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG004180-03
Application #
3115000
Study Section
Experimental Immunology Study Section (EI)
Project Start
1983-07-01
Project End
1986-09-29
Budget Start
1985-07-01
Budget End
1986-09-29
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Kaveri, S V; Wang, H; Rowen, D et al. (1993) Monoclonal anti-idiotypic antibodies against human anti-thyroglobulin autoantibodies recognize idiotopes shared by disease-associated and natural anti-thyroglobulin autoantibodies. Clin Immunol Immunopathol 69:333-40
Chen, J J; Kaveri, S V; Kohler, H (1992) Cryptic T cell epitopes in polymorphic immunoglobulin regions: evidence for positive repertoire selection during fetal development. Eur J Immunol 22:3077-83
Halpern, R; Kaveri, S V; Kohler, H (1991) Human anti-phosphorylcholine antibodies share idiotopes and are self-binding. J Clin Invest 88:476-82
Kaveri, S V; Halpern, R; Kang, C Y et al. (1991) Antibodies of different specificities are self-binding: implication for antibody diversity. Mol Immunol 28:773-8
Saeki, Y; Chen, J J; Shi, L F et al. (1990) Idiotype-specific T helper clones recognize a variable H chain determinant. J Immunol 144:1625-8
Kaveri, S V; Kang, C Y; Kohler, H (1990) Natural mouse and human antibodies bind to a peptide derived from a germline VH chain. Evidence for evolutionary conserved self-binding locus. J Immunol 145:4207-13
Kaveri, S V; Halpern, R; Kang, C Y et al. (1990) Self-binding antibodies (autobodies) form specific complexes in solution. J Immunol 145:2533-8
Saeki, Y; Chen, J J; Shi, L F et al. (1989) Idiotypic intramolecular help. Induction of tumor-specific antibodies by monoclonal anti-idiotypic antibody with the help of Fc-specific T helper clones. J Immunol 142:2629-34
Chang, H C; Muller, S; Kohler, H (1989) Perturbation of the idiotypic network. II. Transfer of suppression to neonatal mice. Cell Immunol 119:373-81
Muller, S; Chang, H C; Kohler, H (1989) Perturbation of the idiotypic network. I. Induction with multiple alloantigen stimulation. Cell Immunol 119:353-72

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