The matrix metalloproteinase inhibitor BB-1101 prevents experimental autoimmune uveoretinitis (EAU)

Abstract

EAU is characterized by breakdown of the blood-retinal barrier and extravasation of leucocytes into retinal tissue leading to destruction of photoreceptor cells. Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7, to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of clinical disease. When administered from day 7 until day 21, EAU was completely abrogated. A quantitative polymerase chain reaction (PCR) assay showed an increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with naive controls. These enzymes are produced by activated leucocytes and act on components of the basement membrane. These results therefore implicate these MMP as integral to the development of pathology in EAU.

Fig. 1

EAU was induced in Lewis rats (n = 12) by inoculation with 50 μg bovine retinal S-antigen in Hunter's adjuvant. •, BB-1101, 10 mg/kg body wt per day, was given from day 0 to day 14; ▪, control group given vehicle only (n = 5). Results are expressed as cumulative clinical disease scores for all animals in the group. *P > 0.01, Mann–Whitney test.

Fig. 2

Histological study. (a) BB-1101-treated rat showing intact retina and no leucocyte infiltration and no tissue damage. (b) Control EAU animal showing retinal, choroidal and vitreous leucocyte infiltration and complete destruction of the photoreceptor cell layer.

Fig. 3

EAU was induced as in Fig. 1. BB-1101 was given from day 0 or day 7 to day 14; ▪, control group given vehicle only (n = 5); •, BB-1101, 2.5 mg/kg body wt per day, given from day 0; ▴, BB-1101, 2.5 mg/kg body wt per day, given from day 7. Results are expressed as cumulative clinical disease scores for all animals in the group.

Fig. 4

EAU was induced as in Fig. 1. BB-1101 was given from day 0 or day 7 to day 21. ▪, Control group given vehicle only (n = 5); •, BB-1101 2.5 mg/kg body wt per day, given from day 0 (n = 10); ▴, BB-1101, 2.5 mg/kg body wt per day, given from day 7 (n = 10). Results are expressed as cumulative clinical disease scores for all animals in the group. *P > 0.01, Mann–Whitney test.

Fig. 5

Matrix metalloproteinase (MMP) mRNA expression in EAU and normal retinas determined by quantitative polymerase chain reaction. Relative expression of converted cDNA compared with β-actin. □, Control; ▪, uveitis.