The purpose of this research is to find some maneuvers to suppress the IgE antibody response to allergen in an antigen-specific manner. Previous studies have shown that a lipomodulin-like lymphokine, i.e., glycosylation inhibiting factor (GIF), facilitated the generation of antigen-specific suppressor T cells (Ts), which form their own GIF. Upon antigenic stimulation, the antigen-specific Ts form GIF that has affinity for nominal antigen. The antigen-binding GIF appears to be identical to antigen- specific Ts factor (TsF), and composed of antigen-binding chain and nonspecific GIF. Based on the findings, we established an immmunological maneuver to construct Ts hybridomas from antigen-primed murine spleen cells, and demonstrated that antigen-binding GIF from the hybridomas suppressed the antibody response of the donor of the spleen cells to homologous antigen. As the results of application of the same method to peripheral blood mononuclear cells of a patient, allergic to bee venom, we established human T cell hybridomas which produce antigen-binding GIF upon cross-linking of CD3 on the cells. Since murine GIF was isolated to biochemical homogeneity, i) attempts will be made to isolate human nonspecific GIF, and to biochemically characterize antigen-binding GIF of both species. ii) Based on the structure of murine nonspecific GIF, CDNA clone encoding the lymphokine will be isolated, and the experiments will be extended to obtain CDNA encoding human GIF. iii) We shall test the hypothesis that antigen-binding GIF as well as T cell receptors of the cell source of the factor recognize a common epitope representing an external structure in the antigen molecule, and that a certain epitope specificity of the lymphokine is essential for immunosuppressive effects. iv) Finally, mechanisms of immunosuppression by GIF will be investigated in murine system. Since our recent studies indicated that GIF suppresses presentation of antigen by splenic adherent cells to T cells, the effect of antigen-binding GIF on antigen-presenting cells will be analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI011202-23
Application #
2059772
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1978-02-01
Project End
1996-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
23
Fiscal Year
1995
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Ishizaka, K; Ishii, Y; Nakano, T et al. (2000) Biochemical basis of antigen-specific suppressor T cell factors: controversies and possible answers. Adv Immunol 74:Jan-60
Ishizaka, K; Nakano, T; Ishii, Y et al. (1996) Controversial issues and possible answers on the antigen-specific regulation of the IgE antibody response. Adv Exp Med Biol 409:317-25
Nakano, T; Ishii, Y; Ishizaka, K (1996) Biochemical characterization of antigen-specific glycosylation-inhibiting factor from antigen-specific suppressor T cells. I. Identification of a 55-kilodalton glycosylation-inhibiting factor peptide with TCR alpha-chain determinant. J Immunol 156:1728-34
Ishii, Y; Nakano, T; Ishizaka, K (1996) Biochemical characterization of antigen-specific glycosylation-inhibiting factor from antigen-specific suppressor T cells. II. The 55-kDa glycosylation-inhibiting factor peptide is a derivative of TCR alpha-chain and a subunit of antigen-specific glycosyl J Immunol 156:1735-42
Ishii, Y; Nakano, T; Ishizaka, K (1996) Cellular mechanisms for the formation of a soluble form derivative of T-cell receptor alpha chain by suppressor T cells. Proc Natl Acad Sci U S A 93:7207-12
Nakano, T; Liu, Y C; Mikayama, T et al. (1995) Association of the ""major histocompatibility complex subregion"" I-J determinant with bioactive glycosylation-inhibiting factor. Proc Natl Acad Sci U S A 92:9196-200
Ishii, Y; Nakano, T; Honma, N et al. (1995) Preparation of soluble recombinant T cell receptor alpha chain by using a calmodulin fusion expression system. J Immunol Methods 186:27-36
Gomi, H; Tagaya, Y; Nakano, T et al. (1994) Antigen-binding glycosylation inhibiting factor from a human T-cell hybridoma specific for bee venom phospholipase A2. Proc Natl Acad Sci U S A 91:2824-8
Liu, Y C; Nakano, T; Elly, C et al. (1994) Requirement of posttranslational modifications for the generation of biologic activity of glycosylation-inhibiting factor. Proc Natl Acad Sci U S A 91:11227-31
Mori, A; Thomas, P; Tagaya, Y et al. (1993) Epitope specificity of bee venom phospholipase A2-specific suppressor T cells which produce antigen-binding glycosylation inhibiting factor. Int Immunol 5:833-42

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