Tlr8 transgenic animals

Abstract

Provided herein are human Toll-like receptor 8 (TLR8)-expressing transgenic animals and methods of use thereof.

1 - 6 . (canceled) 
     
     
         7 . A hematopoietic cell obtained from a transgenic mouse whose genome comprises a nucleotide sequence encoding human Toll-like receptor 8 (TLR8), wherein said human TLR8 is expressed in the cell, and wherein at least one inflammatory cytokine selected from the group consisting of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12 p40 (IL-12B), chemokine cc motif ligand 2 (CCL-2) and interferon-gamma-inducible protein 10 (IP10) is present in sera from the transgenic mouse at an elevated level as compared to a control, non-transgenic mouse. 
     
     
         8 - 12 . (canceled) 
     
     
         13 . A method of screening candidate agents, the method comprising: contacting the cell of  claim 7  with a candidate agent; and determining the effect of said candidate agent on a TLR8-mediated response of said cell. 
     
     
         14 . The method of  claim 13 , wherein the effect comprises inhibition of said TLR8-mediated response. 
     
     
         15 . The method of  claim 13 , wherein the effect comprises stimulation of said TLR8-mediated response. 
     
     
         16 . The method of  claim 13 , wherein the effect is evidenced by a change in TLR8-mediated cytokine production, cell proliferation, and/or cell surface marker expression. 
     
     
         17 . The method of  claim 16 , wherein the effect is evidenced by a change in TLR8-mediated production of one or more cytokines of the group consisting of tumor necrosis factor-alpha (TNF-alpha), interferon-alpha (IFN-alpha), interferon-beta (IFN-beta), interferon-gamma (IFN-gamma), interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-12 (IL-12), interferon-gamma-inducible protein 10 (IP10), and macrophage inflammatory protein-1alpha (MIP-1alpha). 
     
     
         18 . The method of  claim 16 , wherein the effect is evidenced by a change in TLR8-mediated production of one or more cytokines of the group consisting of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-12 (IL-12). 
     
     
         19 . The method of  claim 16 , wherein the effect is evidenced by a change in TLR8-mediated cell proliferation. 
     
     
         20 . The method of  claim 16 , wherein the effect is evidenced by a change in TLR8-mediated expression of one or more cell surface markers selected from the group consisting of CD40, CD80, CD86, glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL), OX40 ligand (OX40L), and programmed death ligand-1 (PDL-1). 
     
     
         21 . The method of  claim 13 , wherein the candidate agent is an antibody. 
     
     
         22 . The method of  claim 13 , wherein the candidate agent is a small molecule. 
     
     
         23 . The method of  claim 13 , wherein the candidate agent is a polynucleotide. 
     
     
         24 . The cell of  claim 7 , wherein said transgenic mouse is a chimeric transgenic mouse in which both human TLR8 and mouse TLR8 are expressed. 
     
     
         25 . The cell of  claim 7 , wherein said nucleotide sequence encoding human TLR8 is present at a copy number of from 1 to 5. 
     
     
         26 . The cell of  claim 7 , wherein said nucleotide sequence encoding human TLR8 is present at a copy number of from 1 or 2. 
     
     
         27 . The cell of  claim 7 , wherein the hematopoietic cell is a population of cells comprising bone marrow. 
     
     
         28 . The cell of  claim 7 , wherein the hematopoietic cell is a population of cells comprising splenocytes. 
     
     
         29 . The cell of  claim 7 , wherein the hematopoietic cell is a population of cells comprising one or more of monocytes, myeloid dendritic cells and neutrophils.