Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Patent
1996-04-22
1998-10-20
Stanton, Brian R.
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
424 91, 424 92, 4351723, 536 2351, 536 241, A61K 4900, C12N 518, C12N 1509, C12N 1516
Patent
active
058248374
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to expression of human interleukin-1.beta. by a transgenic animal.
BACKGROUND OF THE INVENTION
Human interleukin-1 (IL-1) consists of two proteins, IL-1.alpha. and IL-1.beta.. Encoded by different genes (on the same chromosome), each is produced as a protein that is processed intracellularly by serine 31 kDa proteases and is secreted as a 15- to 17 kDa single-chain protein. The two secreted proteins have only limited amino acid sequence similarity (identity at only 25% to 40% of their positions, depending on the species). IL-1.beta., is the more abundant form, both at the level of mRNA and as a serum protein.
Produced in relatively large amounts by activated macrophages and monocytes, IL-1 is also synthesized by a variety of other cells, including keratinocytes, skin Langerhans cells, activated B cells, corneal epithelial cells, kidney mesangial cells, and large granular lymphocytes.
IL-1 exerts its effects on T and B cells primarily as a costimulator. It acts synergistically with IL-6 to stimulate the secretion of IL-2 and expression of IL-2 receptors on T cells when they respond to antigens and mitogens. IL-1 also enhances the stimulatory effects of IL-4 and IL-6 on the growth and differentiation of B cells.
The extensive effects of IL-1 on a wide variety of other cells and tissues account for many of the manifestations of acute and chronic infections and inflammation of immune origin. For instance, IL-1 causes fever by stimulating release of a pyrogen from the brain (hypothalamus), induces somnolence, diminishes appetite, augments the catabolic effects of the cytokine cachectin, and stimulates proliferation of granulocytes by inducing production of bone marrow colony-stimulating factors. In many of the diverse cells it affects, IL-1 enhances arachidonic acid breakdown into prostaglandins and, perhaps in some cells, into leukotrienes.
IL-1 is a major modulator of the immune response to trauma, infection, and inflammation. Endothelial cells exposed to IL-1 synthesize prostaglandins and platelet-activating factor and show accelerated release of von Willebrand factor. Interestingly, a significant increase in formation of prostaglandin D.sub.2 in frontal cortex of Alzheimer's Disease patients has been described. Systemic administration of IL-1 results in increased hepatic production of serum amyloid A, a precursor of the amyloid fibrils found in a secondary amyloidosis.
IL-1 is expressed in the central nervous system where it is thought to play a number of roles, including a hypothalamic acute-phase response and a stimulation of astroglial proliferation after brain injury. Because of the diverse biological activities of IL-1, the observation that IL-1 enhances expression of the amyloid precursor protein (APP) mRNA transcripts in human endothelial cells is of particular importance. Goldgaber et al., (Interleukin 1 regulates synthesis of amyloid .beta.-protein precursor mRNA in human endothelial cells, 1989, Proc. Natl. Acad. Sci. Vol 86: 7606-7610) described the increased level of IL-1 in brains of patients with Alzheimer's disease and Down's syndrome. Thus, the conditions that may lead to the increased expression of the APP gene are present in both diseases.
Experimental studies of the role of human interleukin-1.beta. in disease would be facilitated by the existence of an appropriate animal model. Accordingly, it is an object of the present invention to provide an animal model in which human interleukin-1.beta. expression can be regulated and measured. A animal model of the present invention is a transgenic mouse that expresses a functional human interleukin-1.beta. gene in a regulated manner. The transgenic mice of the present invention are useful to identify compounds that affect chronic inflammation and Alzheimer's Disease. In addition, the transgenic mice of the present invention may be used to generate cell cultures.
SUMMARY OF THE INVENTION
A transgenic mouse expressing human interleukin-1.beta. is provided. The transgenic mouse may be used t
REFERENCES:
Bradley, et al., "Modifying the Mouse: Design and Desire", Bio. Technology, vol. 10, pp. 534-539 (1992).
Capecchi, Altering the Genome by Homologous Recombination, Science, vol. 244, pp. 1288-1292 (1989).
Capecchi, et al., "The New Mouse Genetics: Altering the Genome by Gene Targeting", Trends in Genetics, vol. 5, pp. 70-76 (1989).
Frohman, et al., "Cut, Paste & Save: New Approaches to Altering Specific Genes in Mice", Cell, vol. 56, pp. 145-147 (1989).
Jaenisch, "Transgenic Animals", Science, vol. 240, pp. 1468-1474 (1988).
Wagner, "On Transferring Genes into Stem Cells and Mice", The EMBO Journal, vol. 9, pp. 3025-3032 (1990).
Velander, et al., "Production of Biologically Active Human Protein C in the Milk of Transgenic Mice", Animals of the NY Acad. of Sci., vol. 665, pp. 391-403 (1992).
Goldgaber, et al., "Interleukin 1 Regulates Synthesis of Amyloid B-Protein precursor mRNA in Human Endothelial Cells", Proc. Natl. Acad. Sci., vol. 86, pp. 7606-7610 (1989).
Vandenabeele, et al., "Is Amyloidogenesis During Alzheimer's Disease Due to an IL-1/IL-6-Mediated `Acute Phase Response` in the Brain", vol. 12, pp. 217-219 (1991).
Tocci, et al., "Expression in Escherichia Coli of Fully Active Recombinant Human IL 1B: Comparison with Native Human IL 1B", J. Immunol. vol. 138, pp. 1109-1114 (1987).
Tocci et al J. Immunol 138 1109, 1987.
Vandenabeele 12 217, 1991.
Chen Howard Y.
Hofmann Kathryn J.
Shaw Alan R.
Trumbauer Myrna E.
Van Der Ploeg Leonardus H. T.
Coppola Joseph A.
Merck & Co. , Inc.
Stanton Brian R.
Tribble Jack L.
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