The purpose of this research is to elucidate the mechanisms involved in the regulation of the IgE response, and to find some maneuvors to suppress the IgE antibody formation to allergens. During the current grant period, we found that a lipocortin-like lymphokine, i.e., glycosylation inhibiting factor (GIF), suppressed the primary IgE and IgG antibody responses in the mouse, and diminished the on-going IgE antibody formation. Analysis of cellular mechanisms for the immunosuppression indicated that GIF facilitated the generation of antigen-specific suppressor T cells which formed their own GIF. In the present proposal, attempts will be made to generate antigen-specific suppressor T cells in vitro from antigen-primed T cells, and to elucidate the cellular and molecular mechanisms involved. Experiments will be carried out to determine whether GIF may change the function of antigen-primed T cells, and may affect the antigen-presenting cells. It was also shown that antigen-specific suppressor T cells form GIF which has affinity for the antigen, and that the antigen- specific GIF suppresses the in vivo antibody response in a carrier- specific manner. Mouse T cell hybridomas were constructed from an ovalbumin-primed mouse T cell clone. One of the T cell hybridomas form antigen-specific GIF upon incubation with antigen-pulsed syngenic macrophages. In this proposal, antigen- specific GIF will be obtained from the T cell hybridomas, and physicochemical properties of the molecules will be characterized. Comparisons will be made between the antigen- specific GIF and antigen-specific T suppressor factor (TsF) described by other investigators. Analysis will be made to determine whether the MHC compatibility between the cell source of antigen-specific GIF and target cells is essential for the carrier-specific suppression. Based on the findings obtained in mouse lymphocyte systems, attempts will be made to generate antigen-specific suppressor T cells in vitro from the peripheral blood T cells of allergic patients, and to construct human antigen- specific T cell hybridomas which will produce allergen-specific GIF that may suppress the antibody response to the allergen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI011202-17
Application #
3124919
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1978-02-01
Project End
1989-11-30
Budget Start
1989-02-01
Budget End
1989-11-30
Support Year
17
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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