AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells

Abstract

AS101 is an organotellurium compound with multifaceted immunoregulatory properties that is remarkable for its lack of toxicity. We tested the therapeutic effect of AS101 in experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis. Unexpectedly, treatment with AS101 elicited Treg generation in vivo in otherwise unmanipulated mice. Mice immunized for EAU with the retinal antigen IRBP and treated with AS101 developed attenuated disease, as did AS101-treated recipients of retina-specific T cells activated in vitro. In both settings, eyeinfiltrating effector T cells were decreased, whereas regulatory T (Treg) cells in the spleen were increased. Mechanistic studies in vitro revealed that AS101 restricted polarization of retinaspecific T cells towards Th1 or Th17 lineage by repressing activation of their respective lineagespecific transcription factors and downstream signals. Retina-specific T cells polarized in vitro towards Th1 or Th17 in the presence of AS101 had impaired ability to induce EAU in naïve recipients. Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis.

The tellurium-based immunomodulator, AS101 ameliorates adjuvant-induced arthritis in rats

“…The non-toxic immunomodulator AS101 provides a beacon of hope and is currently under clinical investigation for the treatment of cervical cancer and age-related macular degeneration. AS101 has been previously shown to exhibit profound anti-inflammatory properties in various experimental inflammatory/autoimmune diseases, owing to its Te(IV) redox chemistry [17,18,[20][21][22][23]. The ability of AS101 to react with vicinal thiols results in the functional inhibition of inflammatory integrins such as α4β1 (VLA-4) and α4β7, and the prevention of inflammatory/autoreactive lymphocytes (α4β1 and α4β7-expressing T cells and macrophages) extravasation into the relevant sites of inflammation.…”

“…Much of the biological activity of AS101 has been linked to its chemical redox reaction with vicinal thiols in the exofacial domain of very late antigen‐4 (VLA‐4) + [16]. AS101 has been shown to modulate acquired drug resistance in acute myelogenous leukemia [16] and to ameliorate experimental autoimmune encephalomyelitis [17] and experimental autoimmune uveitis [18]. The redox modulating activities of AS101 ultimately results in a variety of beneficial biological effects [19].…”

Immune Privilege: The Microbiome and Uveitis

“…Caspi's initial studies in mice confirmed the importance of minor antigens in murine susceptibility to induction of EAU (51). Further studies defined the roles of a range of innate immune genes such as TLR, C-type lectins, and genes regulating the inflammasome and IL1 production (103,(155)(156)(157)(158). Indeed, an essential role for IL1 in EAU induction has been shown (159).…”

Immunological Insights in Equine Recurrent Uveitis

“…Detection of IL-6, IL-17, and IL-23 in cell infiltrates of the ciliary body and iris, on the other hand, indirectly suggests that a Th17 mediated immune reaction might also present in ERU eyes (42). In rodent models, EAU can develop either as a Th1 or a Th17 response depending on the model and the antigen used for induction, showing the importance of both T cell subpopulations in disease pathogenesis (41,(101)(102)(103)(104). In ERU, on the other hand, the important role of Th1 lymphocytes as effector cells is well known (2,3,36), the exact impact of Th17 cells on disease pathogenesis, however, merits further investigations.…”