Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2001-03-05
2004-08-17
Landsman, Robert (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S252300, C435S320100, C435S325000, C435S471000, C536S023500, C530S300000, C530S350000
Reexamination Certificate
active
06777204
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel seven-pass transmembrane receptor protein found in immature dendritic cells and a DNA encoding the same. More particularly, the present invention is concerned with a human seven-pass transmembrane receptor protein having the amino acid sequence of SEQ ID NO:2 and a DNA encoding the same. By the use of the seven-pass transmembrane receptor protein and the DNA encoding the same which are provided according to the present invention, it has become possible to screen a substance which can be used for treating or preventing diseases mediated by the functions of dendritic cells, and to provide a method and a reagent for the diagnosis of such diseases. Also, the present invention is concerned with a replicable recombinant DNA which comprises a replicable expression vector and, operably inserted therein, the above-mentioned DNA; a cell of a microorganism or cell culture (transformant), which is transformed with the above-mentioned replicable recombinant DNA; a seven-pass transmembrane receptor protein which is produced on the cell surface of the above-mentioned transformant; a method for screening a ligand which binds to the above-mentioned seven-pass transmembrane receptor protein, and a method for screening a substance which inhibits the ligand from binding to the seven-pass transmembrane receptor protein; and an antibody which binds to the above-mentioned seven-pass transmembrane receptor protein. The present invention is also concerned with a method for the diagnosis of an inflammatory disease, which comprises determining the amount of the seven-pass transmembrane receptor protein expressed in human leukocytes.
2. Prior Art
When the living body of an organism suffers a disorder, such as an infection or inflammation, the cells at the site of the disorder release various protein factors, thereby transmitting the information of the disorder to the cells participating in the biological defense mechanism. In the case of infections, leukocytes, especially granulocytes (for example, neutrophils) and macrophages, have the function to trigger the biological defense mechanism. Like the granulocytes, dendritic cells (i.e., star-shaped cells having outwardly extending dendrites wherein the star-shaped cells are found in lymph nodes and germinal centers) are derived from myeloid hematopoietic stem cells, and play an important role in immunity and inflammation, especially in antigen presentation.
A macrophage is one type of the antigen presenting cells and it presents an antigen to activated T and B cells (Sornasse et al., J. Exp. Med., 175, 15-21, 1992). However, the activation of helper T cells depends on the antigen presentation by the dendritic cells. It is considered that the dendritic cells capture antigens in peripheral blood, and move to lymph, and mature in lymph nodes. It has been reported that both macrophages and dendritic cells at any stage of maturation can present an antigen to the activated T cells; however, only matured dendritic cells can sensitize naive T cells (Mehta-Damani et al., J. Immunology, 153, 996-1003, 1994). Dendritic cells are derived from hematopoietic stem cells, but precursor dendritic cells and immature dendritic cells are found in blood and lymph, and fully matured dendritic cells are found in spleen and lymph nodes. In general, the immature dendritic cells have the high ability to take in an antigen, and the higher the degree of the maturation of the dendritic cells, the higher their ability to perform antigen presentation becomes. The dendritic cells presenting an antigen express large amounts of MHC (Major Histocompatibility Complex) class I proteins and class II proteins.
As described above, the dendritic cells participate in immunity and inflammation in the living body and serve to protect the living body by a beneficial immune response. However, in some cases, the dendritic cells also cause an undesirable immune response (such as an autoimmune response) and an undesirable inflammatory reaction. Therefore, it is considered that if a method for regulating the functions of the dendritic cells can be found out, it will become possible to treat infections and tumors by causing a beneficial immune response and to treat autoimmune diseases and the like by suppressing an adverse immune response.
The functions of the dendritic cells, such as proliferation, differentiation, activation and chemotaxis, are regulated by various receptor proteins expressed by the dendritic cells. A receptor is a protein which is present on the surface of a cell and which binds, with high affinity, to a specific substance (a signaling molecule) which is found on the surface of another cell or in body fluid. When the signaling molecule binds to the receptor, the binding (which is an extracellular event) is converted by the receptor into an intracellular signal to thereby cause a cellular response (Alberts, Bruce et al. eds., “Molecular Biology of the Cell”, 2nd ed., Garland Publishing, Inc., pp. 681-726, 1989). The substance which binds to a receptor is generally called a “ligand”. It is conceived that a substance which affects the functions of a receptor expressed by the dendritic cells can be used for negative or positive regulation of the dendritic cell functions thereby treating diseases caused by excess functioning or insufficient functioning of the dendritic cells. Examples of substances which affect the functions of a receptor expressed by the dendritic cells include a substance which binds to the receptor to thereby stimulate the cells, a substance which binds to the receptor to thereby inhibit the receptor from being stimulated by other ligands, and a substance which binds to the receptor to thereby inhibit a stimulation by other ligands from being transduced into the cell.
Examples of various receptors known in the art include cytokine receptors, EGF (Epidermal Growth Factor) receptors and seven-pass transmembrane receptors (“The Leukocyte Antigen Facts Book”, Academic Press Inc., 38-49, 1993), and the functions of these receptors are diverse. A seven-pass transmembrane receptor, which is one of the above-mentioned receptors, is also called a “G-protein coupled receptor (GPCR)” or a “rhodopsin-type receptor”. Studies on the seven-pass transmembrane receptors have begun only recently, and it is believed that a large number of still unknown seven-pass transmembrane receptors exist.
An explanation is made below taking leukocytes as an example. Examples of receptors which have been identified as the seven-pass transmembrane receptors present in leukocytes include receptors which bind to anaphylatoxins, receptors which bind to chemokines and receptors which bind to PAF (Platelet-Activating Factor). An anaphylatoxin receptor participates in the functions of neutrophils and macrophages, such as the production of active oxygen, chemotaxis and activation of cell adhesion (Bouley, F. et al., Biochemistry, 30, 2993-2999, 1991). Further, the below-described observation has been reported in connection with IL-8 (Interleukin 8) receptor, which is one of chemokine receptors. When an inflammation inducer is intra-abdominally administered to a mouse deficient in a homologue of IL-8 (Interleukin 8) receptor, various phenomena are observed, such as a decrease in neutrophil infiltration, an onset of neutrophilia (phenomenon wherein activation and proliferation of neutrophils occur, but infiltration by neutrophils does not take place), and an increase in granulocytes and plasma cells in bone marrow and lymph nodes (Hisashi IIZASA and Kouji MATSUSHIMA, “Rinsho Men-eki (Clinical Immunology)”, 28, 731-737, 1996). Among the substances which act on the receptors, the substances which are considered to have the possibility of being useful as pharmaceuticals include substances (such as IL-8 and MCP-1 (Monocyte Chemotactic Protein 1)) which bind to the receptors to thereby stimulate cells, and the substances (such as IL-8 mutants) which bind to the receptors to thereby inhibit the receptors from being stimulate
Ishimaru Hiroshi
Kanno Kimiyoshi
Ono Mitsuharu
Takahashi Chiaki
Takahashi Tsuneo
Asahi Kasei Kabushiki Kaisha
Landsman Robert
Young & Thompson
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