Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1994-08-29
1997-03-18
Walsh, Stephen G.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4352523, 43525411, 4353201, 435325, 4353651, 536 2351, 536 2431, 536 235, 530350, 530351, 424 851, C12N 1519, A61K 3819, C07K 1452
Patent
active
056121954
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new cytokine which is a specific antagonist of induction by interferon-gamma (IFN-.gamma.) of the expression of class II histocompatibility antigens at the cell surface.
All the cells in the body express glycoproteins known as class I histocompatibility antigens at their surface.
There is also a category of glycoproteins expressed only by immunocompetent cells, the class II histocompatibility antigens. These antigens are encoded by a family of genes located in man on chromosome 6, and which is known as the major histocompatibility complex (MHC), or (HLA) in man.
Class II histocompatibility antigens play an important part during the immune response, especially in the context of interactions between B and T cells or between antigen presenting cells and T cells. Interferon-gamma promotes the functions of immunocompetent cells by inducing the expression of antigens of the major histocompatibility complex (MHC) by numerous cell types (Becker, 1985). The capacity to present the antigen is proportional to the amount of (HLA) class II molecules present on the surface of the accessory cells. Interferon-gamma hence enables these cells to express enough (HLA) class II molecules to present the antigen. The mechanism of interferon-gamma-dependent regulation has not yet been elucidated.
Class II (HLA) antigens are also considered to be differentiation markers: this has been demonstrated for the cells of myeloid lines (Radka et al., 1986) or of fetal liver (Natali et al., 1984), but their function during cell differentiation is not yet established. In addition, the presence of class II antigens might play a part during the phenomenon of tumorigenesis (Festenstein and Garrido, 1986).
The expression of class II antigens is constitutive on B cells. Accolla et al. (1985) and De Pr eval et al. (1985) have shown that this expression is under the control of a factor which acts in trans at gene level.
A model of regulation of the class II antigens has been proposed by Boss and Strominger (1986). In this model, there are at genomic level, in the 5' flanking region of the gene, 4 successive regions controlling the expression of the histocompatibility antigens: a negative regulatory element, 2 positive control regions and another negative control region. More recent work on the regulation of HLA class II antigens at genomic level has led to the demonstration of a promoter, known as E, in the 5' region of the genes of the major histocompatibility complex, and 2 proteins capable of binding to the E.alpha. promoter (Dorn et al., 1988; Dorn et al., 1989; Koch et al., 1989).
The efficacy of induction differs according to the cell system in question. In effect, some cell lines (K562 leukemic line, embryonic fibroblasts, etc.) are inducible only with difficulty, if at all, whereas other lines (adult fibroblasts, colon carcinoma cells, etc.) express HLA class II antigens after induction by low doses of interferon-gamma.
It was shown in the context of the present invention that the difficulty in obtaining induction of HLA class II antigens by interferon-gamma on so-called refractory cells was due to the spontaneous production of a soluble endogenous inhibitor.
Thus, the present invention relates to a cytokine which is a specific antagonist of induction by interferon-gamma of the expression of class II histocompatibility antigens at the cell surface, and which ID NO:2), as well as the variants that retain the biological activity described above, and eukaryotic cells.
Although the preferred compound according to the present invention corresponds to the formula in FIG. 1a, the present invention also relates to the variants of this cytokine, in particular the variants obtained by deletion, in particular, of the N- or C-terminal ends, the variants obtained by substitution of one or more amino acids and the addition variants obtained by adding one or more amino acid(s), for example the amino acid methionine, at the N-terminal end when the cytokine is expressed in a bacterium.
The present invention also relates t
REFERENCES:
patent: 5461033 (1995-10-01), Donnet et al.
Hofer, E. (1987) Gen Bank database record, acc. No. Y00083.
European Journal of Immunology, vol. 17, No. 7, 1987, Weinheim; DE. pp. 1-1025.
Proceedings of the American Association for Cancer Research Annual Meeting, vol. 29, p. 80, Mar. 1988, New Orleans, Louisiana; US Abst. No. 318.
Biological Abstracts, vol. 88, No. 1, 1989, pp. 413-656, abst. No. 6547.
Augery-Bourget Yvette
Azzarone Bruno
Boucheix Claude
Jasmin Claude
Krief Patricia
Fitzgerald David L.
Institut National de la Sante et de la Recherche Medicale (INSER
Walsh Stephen G.
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