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Abstract Number: 725

The Role of Interleukin-23 in Spondyloarthropathy

Jonathan Sherlock1, Barbara Joyce-Shaikh1, Scott Turner1, Cheng-Chi Chao2, Manjiri Sathe1, Jeff Grein1, Dan Gorman1, Eddie P. Bowman2, Terrill McClanahan1, Jennifer Yearley1, Gerard Eberl3, Christopher D. Buckley4, Robert Kastelein1, Robert Pierce1, Drake LaFace1 and Daniel Cua5, 1Merck, Palo Alto, CA, 2Drug Discovery, Merck, Palo Alto, CA, 3Institut Pasteur, Paris, France, 4Center for Translational Inflammation Research, School of Immunity and Infection, MRC Center for Immune Regulation, Birmingham, United Kingdom, 5Discovery Research, Merck Research Laboratory, Palo Alto, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: Ankylosing spondylitis (AS), Enthesitis, interleukins (IL) and spondylarthropathy

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Session Information

Session Title: Plenary Session I: Discovery 2012

Session Type: Plenary Sessions

Background/Purpose:

Spondyloarthropathy is characterized by inflammation and bony pathology at the entheseal insertion of tendons to bone.  Recent investigations have converged upon interleukin(IL)-23, demonstrating firstly that genetic variants in its receptor are associated with disease and secondly that HLA-B27, which is present in 90% of patients with ankylosing spondylitis, has a tendency to misfold and form cell surface homodimers resulting, respectively, in production of IL-23 and stimulation of IL-23R+ cells.  However why such dysregulation of IL-23 should result in inflammation primarily at the enthesis has remained deeply enigmatic. 

We have hypothesized that tissue resident cells fundamentally determine disease localization (Cua and Sherlock, Nature Medicine 17(9):1055-6) and herein extend our previous observations (Sherlock et al. in press) to demonstrate the presence of IL-23R+ cells in the uvea and to further characterize these cells and their effects.    

Methods: We used GFP reporter mice to investigate the tissue distribution of IL-23R+ cells in the main tissues inflamed in spondyloarthropathy: the enthesis, aortic valve and uvea.     Flow cytometric analysis and multiphoton microscopy was employed to characterize the location of such cells and the reactivity of this tissue to IL-23 was determined in vitro and in vivo.

Results: Entheses, the aortic root and the uvea all contain a novel tissue resident IL-23R+ T lymphocyte, negative for both CD4 and CD8, which allows the tissue to respond to IL-23.  Multiphoton microscopy confirms an extremely precise entheseal localization of the IL-23R+ cell type.    These cells are RAG dependent, but express the PLZF transcription factor which confers an ‘innate like’ responsiveness on T cells, allowing them to immediately respond to cytokines.    Entheses can respond within hours to IL-23 in vitro in the absence of further cellular recruitment.    Moreover, IL-23 expression in mice is sufficient by itself to induce hallmark features of spondyloarthropathy, with severe inflammation developing very specifically at the enthesis and aortic root.   Entheseal bone erosion, new bone formation and periostitis are likewise present.   

Conclusion:   The highly restricted anatomical distribution of IL-23R+ cells explains both the exquisitely precise tissue localization of disease in spondyloarthropathy, as well as the known genetic associations with IL-23, and gives a very clear mechanism whereby HLA-B27 and its tendency to cause IL-23 elaboration may predispose to pathology.   These IL-23R+ tissue resident cells thus form the point of integration between the specific immunological dysregulations known to be associated with disease, and the very precise anatomical sites affected.     The importance of these tissue resident cells is emphasized by the ability of IL-23 to drive enthesitis despite depletion of the conventional IL-23 responsive Th17 cells.      Neutralization of IL-23 therefore represents an excellent therapeutic strategy in spondyloarthropathy since it will inhibit a potent molecule associated with known genetic factors, and do so directly at the site of pathology.    


Disclosure:

J. Sherlock,

Merck,

3;

B. Joyce-Shaikh,

Merck,

3;

S. Turner,

Merck Pharmaceuticals,

3;

C. C. Chao,

Merck Pharmaceuticals,

3;

M. Sathe,

Merck,

3;

J. Grein,

Merck Pharmaceuticals,

3;

D. Gorman,

Merck Pharmaceuticals,

3;

E. P. Bowman,

Merck Pharmaceuticals,

3;

T. McClanahan,

Merck Pharmaceuticals,

3;

J. Yearley,

Merck Pharmaceuticals,

3;

G. Eberl,
None;

C. D. Buckley,
None;

R. Kastelein,

Merck Pharmaceuticals,

3;

R. Pierce,

Merck Pharmaceuticals,

3;

D. LaFace,

Merck Pharmaceuticals,

3;

D. Cua,

Merck Research Laboratory,

3.

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