title: Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritis.
abstract: BACKGROUND
  Uveitis, or intraocular inflammatory disease, is a frequent extra-articular manifestation of several forms of arthritis. Despite the frequent co-occurrence of uveitis and arthritis, little is understood of the eye's predisposition to this disease. We recently described a previously unreported uveitis in a murine model of spondyloarthropathy triggered by autoimmunity to aggrecan, a prominent proteoglycan (PG) macromolecule in cartilage. In contrast to the joint and spine, wherein interferon-gamma (IFNγ) deficiency reduced disease, IFNγ deficiency worsened uveitis. Given the regulatory role of IFNγ on the Th17 response and the current focus of anti-interleukin-17 therapeutics in patients with uveitis and spondyloarthritis, we sought to determine the extent to which interleukin (IL)-17 mediates uveitis in the absence of IFNγ.
  
  
  METHODS
  Antigen specific T cell cytokine production was measured in splenocyte cultures using multiplex-ELISA. Transgenic (Tg) mice expressing the T cell receptor (TCR) recognizing the dominant arthritogenic epitope in the G1 domain of PG (TCR-Tg), also lacking IFNγ, were immunized with PG. Mice were then systemically administered an anti-IL-17 neutralizing antibody. The onset and severity of peripheral arthritis was evaluated by clinical scoring criteria and histology. Uveitis was assessed using intravital videomicroscopy, which visualizes leukocyte trafficking within the vasculature and tissue of the iris, and by histology.
  
  
  RESULTS
  TCR-Tg splenocytes stimulated in vitro with recombinant G1 peptide demonstrated exacerbated production of cytokines, such as macrophage inflammatory protein (MIP)-1α, MIP-1β, IL-1β, and most notably IL-17A as a consequence of IFNγ deficiency. In vivo, IL-17 inhibition prevented the component of PG-induced arthritis that occurs independently of IFNγ. Blockade of IL-17 ameliorated the ongoing leukocyte trafficking responses within the iris vasculature and tissue, which coincided with reduced infiltration of leukocytes within the anterior and posterior eye segments. However, the anti-IL-17 treatment resulted in unanticipated photoreceptor toxicity.
  
  
  CONCLUSIONS
  These data support a protective, regulatory role for IFNγ in suppression of IL-17-mediated intraocular disease and to a lesser extent, joint disease. The unanticipated photoreceptor toxicity raises some caution regarding the use of anti-IL-17 therapeutics until the mechanism of this potential effect is determined.
authors.affiliation: Casey Eye Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd,, Portland, OR 97239, USA.
authors.forename: Jelena M
authors.initials: JM
authors.lastname: Kezic
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: James T
authors.initials: JT
authors.lastname: Rosenbaum
authors.forename: Holly L
authors.initials: HL
authors.lastname: Rosenzweig
mesh_terms: D053674:Aggrecans / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025241:Spondylarthritis / Q000150:complications* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014605:Uveitis / Q000150:complications / Q000276:immunology / Q000517:prevention & control*
chemical_list: D053674:Aggrecans; D057134:Antibodies, Neutralizing; D016207:Cytokines; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma