Neutralization of IL-17 ameliorates uveitis but damages photoreceptors in a murine model of spondyloarthritisReport as inadecuate




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Arthritis Research and Therapy

, 14:R18

First Online: 23 January 2012Received: 25 October 2011Revised: 12 December 2011Accepted: 23 January 2012

Abstract

IntroductionUveitis, 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.

MethodsAntigen 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.

ResultsTCR-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.

ConclusionsThese 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.

AbbreviationsACanterior chamber

ASankylosing spondylitis

CBciliary body

Cocornea

DDAdimethyl dioctadecyl ammonium bromide

Ffemur

GCLganglion cell layer

GKO-TCR-Tg miceTCR-Tg mice deficient in IFNγ

ICisotype control antibody

INLinner nuclear layer

i.p.intraperitoneal

Iriris

Lilimbus

ONLouter nuclear layer

PGthe proteoglycan aggrecan

PRLphotoreceptor layer

Ttibia

TCR-Tg micetransgenic mice expressing the TCR for the arthritogenic epitope of PG

Vivitreous

WTwild-type.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3697 contains supplementary material, which is available to authorized users.

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Author: Jelena M Kezic - Tibor T Glant - James T Rosenbaum - Holly L Rosenzweig

Source: https://link.springer.com/



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