Interleukin 17A as an Effective Target for Anti-inflammatory and Antiparasitic Treatment of Toxoplasmic Uveitis

Abstract

Toxoplasmosis is the most common cause of posterior uveitis in immunocompetent subjects. The requirement of limiting both parasite multiplication and tissue destruction suggests that the balance between T-helper (Th) 17 and T-regulatory cells is an important factor in toxoplasmosis-induced retinal damage. In a prospective clinical study of acute ocular toxoplasmosis, we assessed the cytokine pattern in aqueous humors of 10 affected patients. To determine the immunological mechanisms, we evaluated intraocular inflammation, parasite load, and immunological responses using messenger RNA and protein levels in a mouse model. Anti-interleukin 17A (IL-17A) monoclonal antibodies (mAbs) were administered with the parasite to evaluate the role of IL-17A. Severe ocular inflammation and cytokine patterns comparable to human cases were observed, including IL-17A production. Neutralizing IL-17A decreased intraocular inflammation and parasite load in mice. Detailed studies revealed up-regulation of T-regulatory and Th1 pathways. When interferon γ (IFN-γ) was neutralized concomitantly, the parasite multiplication rate was partially restored. Local IL-17A production by resident cells plays a central role in the pathology of ocular toxoplasmosis. The balance between Th17 and Th1 responses (especially IFN-γ) is crucial for the outcome of infection. This data reveals new in vivo therapeutic approaches by repressing inflammatory pathways using intravitreal injection of IL-17A mAbs.