Immunology of Uveitis - From Bench to Bedside.

Abstract

Abstract: Autoimmune uveitis is an orphan disease with a prevalence of 0.4% and normally very effectively prevented by the immune privilege of the eye. The immune privilege can be overcome, because an immune response that is activated outside the eye against foreign antigens enables T cells to enter the eye and also recognises intraocular antigens via cross-reactivity (antigenic mimicry) and thus triggers uveitis. This leads to the migration of lymphocytes into the eye, followed by the invasion of inflammatory cells that cause the destruction of intraocular structures. Antigenic mimicry can also be used therapeutically to induce oral tolerance. The discovery of the tolerance-inducing but non-pathogenic mimicry epitope B27PD made it possible to treat therapy-refractory uveitis patients by inducing oral tolerance. All 8 treated patients were able to reduce their steroid therapy, with stable or improved visual acuity, and two have been free of recurrence and therapy since oral tolerance induction 30 years ago. Later, the establishment of two new animal models for spontaneously recurrent and chronic uveitis has provided new insights into the role of different T cell types in the eye and allowed us to develop and test new therapies in ongoing autoimmune reactions, as corresponding to the situation in uveitis patients. These new animal models also enabled the development of a small molecule dihydroorotate dehydrogenase (DHODH) inhibitor PP-001/KIO-100 for the treatment of uveitis, which inhibits lymphocytes but has no toxic effects on intraocular cells (in vivo: rat) and human retinal pigment epithelial cells (RPE, in vitro). This was followed by a successful phase I trial for patients with non-infectious posterior uveitis, by intraocular application of PP-001/KIO-100 - without side effects, but with improvement of visual acuity and reduction in inflammation and CME.