Regulatory T Cells Control Uveoretinitis Induced by Pathogenic Th1 Cells Reacting to a Specific Retinal Neoantigen

Abstract

In many clinical cases, uveitis develops secondary to an infection. This could result from peripheral activation followed by ocular penetration and reactivation of T cells specific for microbial Ags expressed in the retina. To gain insights into the pathophysiology of uveitis, we developed a new mouse model based on stable retinal expression of influenza virus hemagglutinin (HA) neoantigen by adeno-associated virus-mediated gene transfer. One month thereafter, we adoptively transferred HA-specific T cells, which were activated in vitro or in vivo. Intraocular inflammation was clinically and histologically observed in all animals within 15 days. The ocular infiltrate was composed mostly of macrophages and HA-specific T cells with a proinflammatory cytokine profile. Depletion of CD4+CD25+ regulatory T cells exacerbated the disease, whereas HA-specific CD4+CD25+ T cells given i.v. controlled the disease. This novel model should allow to better study the pathophysiology and therapeutic of uveitis.

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

“…21 We studied 3 different conditions of adoptive transfer in BALB/c mice in the presence or absence of IVIg infusion: CFSE-labeled HA-specific CD4 ϩ CD25 Ϫ Tconv alone, CD4 ϩ CD25 ϩ T cells alone (Treg), and a mixture of CD4 ϩ CD25 Ϫ T cells (90%) with CD4 ϩ CD25 ϩ T cells (10%; Tconv ϩ Treg). Cell transfer was followed by immunization with HA 126-138 peptide in CFA.…”

Treatment of Uveitis by In Situ Administration of Ex Vivo–Activated Polyclonal Regulatory T Cells

“…In this model, we previously showed that i.v. injection of HA-specific Treg (HA-Treg) cells controlled uveitis (13). In this study, we analyzed the therapeutic efficacy of these HA-Treg cells after in situ injection (2 3 10 5 cells injected in the vitreous) versus systemic injection (2 3 10 6 cells injected in the blood).…”

“…We assessed the therapeutic potential of Treg cells in uveitis in a mouse model that we have described previously (13). Briefly, the disease was induced by transferring effector T (Teff) cells specific for the HA model Ag (HA-Teff cells) into mice that stably expressed HA in the retina.…”

“…The viral particles were purified by double cesium chloride gradient centrifugation and titrated by quantitative PCR. Subretinal injection of this AAV vector was performed under direct retinoscopy using a binocular microscope (Wild M3B; Leica) in mice anesthetized by ketamine (50 mg/kg) and xylazine (10 mg/kg), as described preciously (13). Briefly, a 33-gauge needle (Hamilton) was brought into focus between the retina and retinal pigment epithelium and 2 ml viral supernatant (6 3 3 10 8 viral genome/ml) was injected in the two eyes, visualized by retinal detachment.…”

International progress in cancer gene therapy

“…Another example was experimental uveitis in mice. Terrada et al 75 showed that Treg depletion exacerbates uveitis whereas Treg injection controls it. Tregs are also particularly important in chronic infections such as leishmanosis and malaria and are also involved in inhibiting immune responses against cancer.…”