Compositions and methods for modulating cells via cd14 and toll-like receptor 4 signaling pathway
OwnerBruce Beutler, Zhengfan Jianginventors
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Abstract
Compositions and methods are provided for screening and identifying compounds which modulate signaling of toll-like receptor 4 (TLR4) pathway via CD 14 and a ligand. Methods are provided for treatment of various disease states such as inflammation or autoimmune disease in mammalian subjects by modulating toll-like receptor 4 (TLR4) pathway signaling via CD 14 and a ligand. Transgenic non-human animals and methods for developing transgenic non-human animals are provided wherein the transgenic non-human animals comprise a loss-of-function mutation in the CD 14 gene.
Claims81
A method for treating rhabdovirus infection in a mammalian subject suspected of having an infection comprising administering to the subject a modulator of Toll-like receptor 4-signaling activity via CD14 in an amount effective to reduce or eliminate the rhabdovirus infection or to prevent its occurrence or recurrence.
A method for treating an autoimmune disease in a mammalian subject comprising administering to the mammalian subject a modulator of Toll-like receptor 4-signaling activity via CD14 in an amount effective to reduce or eliminate the autoimmune disease or to prevent its occurrence or recurrence.
A method for treating inflammation in a mammalian subject comprising administering to the mammalian subject a modulator of Toll-like receptor 4-signaling activity via CD14 in an amount effective to reduce or eliminate inflammation or to prevent its occurrence or recurrence.
A method for identifying a modulator of signaling in cells via a toll-like receptor 4 pathway comprising:
- contacting a test compound with a cell-based assay system comprising a cell expressing toll-like receptor 4 capable of signaling responsiveness to a ligand;
- providing CD14 and the ligand to the assay system in an amount selected to be effective to activate toll-like receptor 4 signaling;
- and
- detecting an effect of the test compound on toll-like receptor 4 signaling in the assay system, effectiveness of the test compound in the assay being indicative of the modulation.
A method for screening for a compound to treat an infectious disease comprising:
- contacting a test compound with a cell-based assay system comprising a cell expressing toll-like receptor 4 capable of signaling responsiveness to a ligand;
- providing CD14 and the ligand to the assay system in an amount selected to be effective to activate toll-like receptor 4 signaling;
- and
- detecting an effect of the test compound on toll-like receptor 4 signaling in the assay system, effectiveness of the test compound in the assay being indicative of the modulation of the infectious disease.
A method for screening for a compound to treat an autoimmune disease comprising:
- contacting a test compound with a cell-based assay system comprising a cell expressing toll-like receptor 4 capable of signaling responsiveness to a ligand;
- providing CD14 and the ligand to the assay system in an amount selected to be effective to activate toll-like receptor 4 signaling;
- and
- detecting an effect of the test compound on toll-like receptor 4 signaling in the assay system, effectiveness of the test compound in the assay being indicative of the modulation of the autoimmune disease.
A method for screening for a compound to treat inflammation comprising:
- contacting a test compound with a cell-based assay system comprising a cell expressing toll-like receptor 4 capable of signaling responsiveness to a ligand;
- providing CD14 and the ligand to the assay system in an amount selected to be effective to activate toll-like receptor 4 signaling;
- and
- detecting an effect of the test compound on toll-like receptor 4 signaling in the assay system, effectiveness of the test compound in the assay being indicative of the modulation of the autoimmune disease.
A transgenic non-human animal comprising a heterologous nucleic acid wherein the nucleic acid comprises a loss-of-function allele of a CD14 gene, and the animal exhibits a phenotype, relative to a wild-type phenotype, comprising a characteristic of inhibition of macrophage activation, susceptibility to viral or bacterial infection, a decrease in TNF-α production, or a combination of any two or more thereof.
Dependencies are inferred from the claim text.