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Tarnjit K. Khera, David A. Copland, Joanne Boldison, David E. Szymkowski, Andrew D. Dick, Lindsay B. Nicholson; The Dominant-Negative Soluble TNF Inhibitor XPro1595 Can Suppress Experimental Autoimmune Uveitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3013.
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Therapy targeting TNFα is effective in patients with autoimmune uveitis, although this treatment can have significant co-morbidity including reactivation of latent infection and reduced immunosurveillance of tumours. XPro1595 is a TNF-signalling inhibitor that works by exchanging modified TNFα subunits with native subunits, leading to inactive, soluble TNFα heterotrimers (sTNFα), that can no longer bind and signal via TNF receptors (TNFR) -1 and -2; transmembrane TNFα (tmTNFα) signalling remains functional. Previous work has shown that XPro1595 is an effective treatment in models of rheumatoid arthritis that does not interfere with host defence against infection. Furthermore, animals treated with XPro1595 retain their ability to respond effectively to Listeria monocytogenes,Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and M. tuberculosis. The aim here was to determine the efficacy of XPro1595 in the treatment of experimental autoimmune uveitis (EAU).
EAU was analysed by topical endoscopic fundus imaging (TEFI) to assess clinical disease, flow cytometry to determine the number and phenotype of infiltrating cells and histological analysis to assess structural damage, leukocyte infiltration and nitrite (NO) production. The Greiss reagent was used to quantify nitrite production by bone marrow-derived macrophages (BMDM) and ELISAs were used to quantify TNFα and IL-6.
Systemic administration of XPro1595 can suppress EAU in mice, inhibiting onset and also suppressing disease if used as a treatment after onset. Treatment with XPro1595 results in lower clinical disease as assessed by TEFI, with fewer CD4+ and CD11b+ cells in the retina compared to control. In contrast, intravitreal administration of XPro1595 did not suppress EAU. In vitro, both sTNFR-Ig and XPro1595 can inhibit LPS-induced TNF production by BMDM. However, sTNFR-Ig can also suppress LPS-induced IL-6 production, which XPro1595 does not. Unlike sTNFR-Ig, XPro1595 did not inhibit IFNγ-induced NO production by WT BMDM.
Systemic, but not local, administration of XPro1595 can significantly suppress EAU. It has potential to be used as a treatment for uveitis where there is high risk of activation of latent tuberculosis.
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