The objective is to study the development of the idiotype network during the ontogeny of mice. The focus in our work is on the role of T helper cells which recognize the dominant T15 idiotype in the response of BALB/c mice to phosphorylcholine (PC). The hypothesis to be tested states that early in ontogency, germ line encoded B cell idiotypes influences the repertoire of regulatory T cells. The proposed role of regulatory, idiotype recognizing T cells is to maintain a basic B cell repertoire necessary to preserve a functional network. We have established assays to measure T help of idiotype recognizing T cells for B cells responding to an idiotype hapten carrier antigen. We have observed that T15 specific helper cells recognize a shared idiotope which is expressed by the heavy chain. We also defined an inducer T cell which primes the idiotype recognizing helper cell. The specificity of the inducer T cells is anti-idiotypic. This T-T cell circuit can be triggered by PC antigen and may therefore be involved in the response to bacterial PC containing antigens. We propose to prepare T cell line, clones and hybridomas, which are idiotype specific. We will test these cell lines for their fine specificity, MHC restriction and role as regulatory idiotypes in the response to PC in vivo and in vitro. Monoclonal anti-idiotypes of defined biological activities will be administered to neonatal mice and the alteration of the network in the response to PC in the B and T cell compartments will be analyzed. One of the anti-idiotopes expresses the internal image of PC, i.e., is an Ab2Beta. The precursor frequency of T15 recognizing T helper cells will be followed as a neonatally manipulated mature mice; further, the idiotype fine specificity will be analyzed. A search for T suppressor cells will also be done using adoptive transfer protocols developed earlier in our lab. Finally, transgenic mice will be prepared to study the effect of idiotype and anti-idiotype expressing genes on the ontogeny of the immune network. This approach allows us to manipulate the immune system at a time in ontogeny before any rearrangements and committments to idiotype expression is made in B and T cells. We expect tha these idiotype manipulations will have profound effects on the development of the network. We will analyze these alterations by focusing on the T15/PC response in both the T helper cell and the B cell compartments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG004180-09
Application #
3115002
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-07-01
Project End
1992-04-30
Budget Start
1991-06-01
Budget End
1992-04-30
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Sidney Kimmel Cancer Center
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92121
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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