Modelling experimental uveitis: barrier effects in autoimmune disease.

OBJECTIVE AND DESIGN: A mathematical analysis of leukocytes accumulating in experimental autoimmune uveitis (EAU), using ordinary differential equations (ODEs) and incorporating a barrier to cell traffic. MATERIALS AND SUBJECTS: Data from an analysis of the kinetics of cell accumulation within the eye during EAU. METHODS: We applied a well-established mathematical approach that uses ODEs to describe the behaviour of cells on both sides of the blood-retinal barrier and compared data from the mathematical model with experimental data from animals with EAU. RESULTS: The presence of the barrier is critical to the ability of the model to qualitatively reproduce the experimental data. However, barrier breakdown is not sufficient to produce a surge of cells into the eye, which depends also on asymmetry in the rates at which cells can penetrate the barrier. Antigen-presenting cell (APC) generation also plays a critical role and we can derive from the model the ratio for APC production under inflammatory conditions relative to production in the resting state, which has a value that agrees closely with that found by experiment. CONCLUSIONS: Asymmetric trafficking and the dynamics of APC production play an important role in the dynamics of cell accumulation in EAU.

The dynamics of leukocyte infiltration in experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) serves as an animal model for human uveitis. EAU is inducible in animals by peripheral immunization with proteins found in the retina that triggers an immune response which leads to tissue damage. This is coordinated by autoantigen specific CD4(+) T cells whose activation is accompanied by the infiltration of a wide range of other leukocytes into the retina. Infiltrating macrophages and granulocytes cause destruction by the release of reactive oxygen and nitrogen species but these and other leukocytes also regulate inflammation. This review will describe the dynamics of leukocyte infiltration in EAU from the initial systemic activation of T cells following immunization, through their traffic into the eye causing a peak of infiltration, and ending with a phase of secondary regulation in which, although clinical disease has resolved, the leukocyte composition of the eye remains altered.

Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations.

Experimental autoimmune uveoretinitis (EAU) is an animal model for human intraocular inflammatory disease. EAU is induced in B10.RIII mice by immunization with RBP-3 161-180 peptide and intraperitoneal pertussis toxin and is mediated by CD4(+) T cells that generate a clinically monophasic disease peaking approximately 2 weeks post-immunization. Collagenase digestion of retinal tissue allowed the quantification and characterization of leukocytes in the inflamed retina during disease progression. Using this method we identified three stages of disease. Initially there is a prodromal phase where we found significant changes in the number of leukocytes in the eye as early as 5 days post-immunization. This effect was, in part, non-antigen specific as a small increase in retinal leukocytes was also observed following immunization with OVA peptide. Following the prodrome there is a primary peak of infiltration including both CD4(+) T cells and CD11b(+) cells. This coincides with an early influx of neutrophils and is associated with a peak in IL-17-producing T cells. The neutrophils in the eye are CD11b(+) and Gr1(+) but can be distinguished from other myeloid cells by their high expression of Ly6G. The remaining CD11b(+)Gr1(+) cells can suppress proliferation and are analogous to myeloid derived suppressor cells which are found in tumors. The inflamed eye also contains a considerable proportion of FoxP3(+) regulatory cells. Following peak disease, the retina does not return to its pre-disease phenotype. Instead, fluctuations in infiltrating leukocyte numbers and changes to their relative composition continue, indicating that clinical recovery does not equate to the restoration of a normal retinal leukocyte population.