Inhibition of tumor necrosis factor activity minimizes target organ damage in experimental autoimmune uveoretinitis despite quantitatively normal activated T cell traffic to the retina

Abstract

Recent studies demonstrated that administration of a p55-tumor necrosis factor (TNF) receptor IgG-fusion protein (TNFR-IgG) prevented the clinical onset of experimental autoimmune encephalomyelitis but did not alter the number or tissue distribution of autoantigen-specific CD4+ effector T cells which trafficked into the central nervous system. To determine whether specific target tissues of autoimmune damage remain intact after TNFR-IgG treatment despite the presence of inflammatory cells within the tissues, we examined rats with experimental autoimmune uveoretinitis (EAU), as in this model, the main target of autoreactive CD4+ T cells, the retinal rod outer segments (ROS), can be examined readily by light microscopy. As judged by direct ophthalmoscopy, the onset of inflammation in the anterior chamber of the eye in EAU following administration of TNFR-IgG was delayed by 6 days compared to untreated controls, but the magnitude of the response was only slightly less than controls. Histological examination of the retinae and direct assessment of retinal inflammation revealed a disproportionate sparing of ROS in the TNFR-IgG-treated animals despite a level of retinal inflammation not substantially less than controls in which ROS damage was marked. Analysis of retinal leukocytes by immunofluorescence microscopy and flow cytometry indicated that approximately equal numbers of CD4+ alpha beta TCR+ lymphocytes were present in treated and control retinae, more than 30% of CD4+ cells in both experimental groups expressed the CD25 or MRC OX40 activation markers and most cells, which would include the CD4+ T lymphocytes, were activated as evidenced by MHC class II expression. Fewer activated macrophages and granulocytes were present in the treated retinae, possibly reflecting the lower level of tissue damage and subsequent accumulation of these inflammatory cells. The results demonstrate directly that a tissue specifically targeted for autoimmune destruction can be protected despite the influx of fully activated CD4+ T cells.

Doyne lecture 2016: intraocular health and the many faces of inflammation

“…In support, we observe that tissue damage in experimental retinal inflammation is significantly attenuated when macrophages are removed 21,22 or macrophage/monocyte activation is blocked. 16,[23][24][25] Experimentally, we observe that the tissue is protected when TNF-alpha activity is neutralised (and indeed show the requisite requirement of TNF for macrophage activation in ocular inflammation [26][27][28] ), or by reprogramming macrophage activation threshold with CD200R treatment. These consistent observations have led to a pipeline for therapeutic opportunities to redress activation thresholds of immune cells.…”

Effects of ciliary muscle plasmid electrotransfer of TNF-α soluble receptor variants in experimental uveitis

“…9,10 In EAU, neutralizing TNF-a activity with a systemic p55 TNF receptor fusion protein (TNFR-Ig) delayed the onset of inflammation and suppressed Th1 effector mechanisms protecting against retinal damage in the treated rats. 11,12 In patients, systemic TNF-a inhibition with p55 TNFR-Ig had a satisfactory therapeutic index along with a deviation of the Th2 type of immune response. 13,14 Despite these promising initial therapeutic results, it was evident that to achieve therapeutic efficacy repeated systemic administrations of anti-TNF agents were needed.…”

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

“…Biologic agents are attractive as they exert relatively specific effects, and thus with more targeted suppression may induce, much more rapidly and effectively, remission and longer term suppression. 67 An example of success, which followed experimental work neutralising TNF activity via a TNF receptor 1 fusion protein, 68,69 is the finding in early phase trials that 71% of patients with refractory uveitis achieved complete cessation of intraocular inflammation, and reduction in concomitant immunosuppression was possible in 65% of cases. 70,71 There have since been multicentred trials in anti-TNF therapy using the chimeric anti-TNF-a mAb infliximab for treatment of Behcet's disease (BD).…”