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Review
. 2014 Sep;13(9):909-16.
doi: 10.1016/j.autrev.2014.05.003. Epub 2014 May 12.

Immunotherapeutic strategies in autoimmune uveitis

Affiliations
Review

Immunotherapeutic strategies in autoimmune uveitis

Pedro Henrique Papotto et al. Autoimmun Rev. 2014 Sep.

Abstract

Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab' antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results.

Keywords: Autoimmune uveitis; CD28 antagonists; Costimulation blockade; Experimental autoimmune uveitis; Immune modulation.

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Figures

Fig. 1
Fig. 1
Summarizes the preliminary data from our group showing that in an autoimmune uveitis B10.RIII model, treatment with a murine analog of FR104 (Effimune) protects against severe disease when compared to untreated mice. Moreover, this effect seems to be associated with higher frequencies of naïve T cells infiltrating the eyes of the treated mice, suggesting that the CD28 blockade by this novel Fab′ ´CD28 antagonist prevents a full activation of T cells, rendering them in a naïve state. Furthermore, this effect appears to be associated with a dampened memory formation. Thus, the T cells from treated mice infiltrate the eyes but cannot induce a potent inflammatory response, restoring immune equilibrium in the eyes and protecting against disease progression.

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