Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-04-22
2003-10-14
Martinell, James (Department: 1633)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C536S024100, C536S023100
Reexamination Certificate
active
06632604
ABSTRACT:
This application claims priority under 35 U.S.C. §§119 and/or 365 to Patent Application No. 97-04954 filed in France on Apr. 22, 1997; the entire content of which is hereby incorporated by reference.
The present invention relates to novel nucleic acid sequences which can be involved in controlling and regulating the expression of genes encoding MHC type II molecules and to their use, in particular as drugs for treating disorders in which it is desirable to act on the level at which genes encoding MHC type II molecules are expressed.
The molecules of the class II major histo-compatibility complex (termed MHC in that which follows) are heterodimeric transmembrane glycoproteins which are directly involved in activating T helper CD4+ lymphocytes during the course of the immune response.
In man, this class II complex is represented by the molecules which belong to the HLA (human leucocyte antigen) system. The genes which encode the &agr; and &bgr; chains of which the HLA-DR, HLA-DQ and HLA-DP molecules are composed are located within the D region of chromosome 6.
Expression of these genes is very highly regulated. In contrast to the genes which encode the MHC type I molecules, which are expressed ubiquitously, expression of the genes which encode the MHC class II molecules is either constitutive, in only a few cell types such as B lymphocytes, activated T lymphocytes, macrophages, cells of the thymic epithelium, or dendritic cells such as the Langerhans cells, or is induced following stimulation, for example by cytokines, more specifically by interferon &ggr; (INF &ggr;) or interleukin 4 (IL4), in several other cell types such as cells which belong to the macrophage or monocyte line, endothelial cells, fibroblasts, muscle cells or cancer cells such as melanoma cells.
Furthermore, expression of the genes which encode MHC class II molecules in B lymphocytes is transient. Thus, differentiation of the B cells into plasma cells which produce the immunoglobulins is accompanied by the suppression of certain genes including those which encode MHC class II.
Similarly, it has been shown that the level at which MHC type II molecules are expressed is a determining factor in the process of T cell activation.
As a consequence, it is clearly apparent that the molecular mechanisms by which expression of these genes is regulated constitute a key element in the efficacy of the immune response. Any defect in this regulatory process may result in significant immunological disorders or autoimmune diseases. Thus, abnormal expression of the MHC class II genes has in some cases been observed at the surface of cells which should not normally express these genes. Similarly, it is possible to observe over-expression of these genes, leading to an activation of the CD4+ lymphocytes which is aberrant and uncontrolled [Bottazzo et al., 1986, Immunol. Rev., 94, 137-169]. Events of this kind could, at least in part, be responsible for disorders such as insulin-dependent diabetes, multiple sclerosis, rheumatoid arthritis and lupus erythematosus. Conversely, it has been possible to demonstrate an immunodeficiency in some patients which has resulted from a disturbance in the expression of MHC class II genes. Mention may, for example, be made of the BLS (bare lymphocytes syndrome) syndrome which is a recessive autosomal disorder in which expression of the MHC class II genes is very limited if not to say non-existent, a situation which finds expression in the absence of cellular and humoral immune responses and is accompanied by a large number of infections which are often fatal.
Several scientific groups have analysed the mechanisms by which expression of the MHC class II genes is regulated and have identified a number of transactivating molecules which are capable of binding, directly or indirectly, to promoter sequences which are specific for the said genes [for a review, see Mach et al., 1996, Annu. Rev. Immunol. 14, 301-331].
The applicant has previously identified and characterized one of these factors, i.e. the CIITA factor (class II transactivator) [Steimle et al., 1993, Cell 75, 135-146 and EP 648836]. Furthermore, document WO 9606107 shows that there are two domains within the CIITA factor which are more involved in activating transcription of the MHC class II genes, more specifically the domain which is defined by SEQ ID No. 21 of the present invention and which corresponds to the translation of the nucleic acid sequence according to SEQ ID No. 17. Nevertheless, surprisingly and contrary to that which is observed in the case of other factors which are involved in regulating expression of the MHC class II genes (Cogswell et al., 1991, Crit. Rev. Immunol. 11, 87-112), Steimle et al. have demonstrated that expression of the CIITA factor coincides strictly with expression of the MHC class II genes and is required absolutely both for constitutively expressing and for inducing the said MHC genes. Furthermore, Silacci et al. (1994, J. Exp. Med., 180, 1329-1336) have demonstrated that suppression of the MHC class II genes during plasma cell differentiation is associated with suppression of the gene which encodes CIITA factor.
Moreover, Lennon et al. (1997, Immunogenetics, 45, 266-273) have identified the promoter sequence of a CIITA gene, which sequence is responsible for the differential expression of this factor in B cells. However, the existence of this sequence alone does not explain why differential expression of the CIITA factor is observed in different cell types. Furthermore, it does not account for induction by cytokines.
Using samples derived from different tissues of human origin, the applicant has now identified the complex organization of the sequences which ensure regulation of the expression of the CIITA factor, has isolated and characterized other promoter regions and has demonstrated the existence of several forms of CIITA factor, and has also demonstrated the existence of different CIITA genes.
The expression “CIITA gene” is understood as meaning a nucleic acid sequence which consists of a promoter (P) moiety, an untranslated (UT) moiety and a coding (Prot) moiety, with the coding moiety encoding one of the identified forms of CIITA factor.
More precisely, the inventors have identified a number of nucleic acid sequences which represent CIITA genes and which are therefore capable, in particular, of being involved in controlling and regulating the expression of genes encoding MHC class II molecules. The expression “nucleic acid sequence which represents CIITA genes” is understood as meaning that the sequence in question comprises all or part of a nucleic acid sequence corresponding to the mRNAs which derive from the different tissues or cell lines which express CIITA activity either constitutively or following induction. Such sequences can therefore equally well be sequences which are at least partially coding, as for example sequences which are involved in controlling the expression, in particular, of sequences which possess a transcriptional promoter activity.
The expression “nucleic acid sequence” is understood as meaning a natural, isolated, or synthetic, double-stranded or single-stranded DNA and/or RNA fragment which designates a precise linked-up series of modified or unmodified nucleotides and which makes it possible to define a fragment or a region of a nucleic acid.
The expression “polypeptide” is understood as meaning a precise, natural, isolated, or synthesized, modified or unmodified linked-up series of amino acids, independently of its size or its function.
The expression “allelic variant” of a polypeptide is understood as meaning the entirety of the mutated polypeptides and the polymorphisms which can exist in man, and which are obtained, in particular, by truncating, substituting, deleting or adding on amino acid residues, as well as the artificial variants which are employed in vitro.
The expression “nucleic acid sequence which exhibits a transcriptional promoter activity” is understood as meaning a nucleic acid sequence which makes it possibl
Elrifi, Esq. Ivor R.
Martinell James
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
Novimmune SA
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