Transgenic mice expressing human toll-like receptor 8
Provided herein are human Toll-like receptor 8 (TLR8)-expressing transgenic s and methods of use thereof.
1. A transgenic mouse whose genome comprises a nucleotide sequence encoding human Toll-like receptor 8 (TLR8 ), wherein said human TLR8 is expressed in the transgenic mouse, 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.
2. The transgenic mouse of claim 1 , wherein said transgenic mouse is a chimeric transgenic mouse in which both human TLR8 and mouse TLR8 is expressed.
3. The transgenic mouse of claim 1 , wherein said nucleotide sequence encoding human TLR8 is present at a copy number of from 1 to 5.
4. The transgenic mouse of claim 1 , wherein said nucleotide sequence encoding human TLR8 is present at a copy number of 1 or 2.
5. The transgenic mouse of claim 1 , wherein said transgenic mouse is predisposed to development of inflammation in one or more organs as compared to a control, non-transgenic mouse.
6. The transgenic mouse of claim 1 , wherein said transgenic mouse is predisposed to development of arthritis as compared to a control, non-transgenic mouse.
7. A method of screening candidate agents, the method comprising:
administering a candidate agent to the transgenic mouse of claim 1 ; and determining the effect of said candidate agent on a TLR8-mediated response of said mouse.
8. The method of claim 7 , wherein the effect comprises inhibition of said TLR8-mediated response.
9. The method of claim 7 , wherein the effect comprises stimulation of said TLR8-mediated response.
10. The method of claim 7 , wherein the effect is evidenced by a change in TLR8-mediated cytokine production, cell proliferation, and/or cell surface marker expression.
11. The method of claim 10 , wherein said TLR8-mediated cytokine production comprises production of one or more of the group consisting of TNF, IL-12, IL-6, MIP-1α, IFNγ, IP-10, IL-1α, and IL-1β.