INHIBITION OF TUMOR-NECROSIS-FACTOR ACTIVITY MINIMIZES TARGET ORGAN DAMAGE IN EXPERIMENTAL AUTOIMMUNE UVEORETINITIS DESPITE QUANTITATIVELY NORMAL ACTIVATED T-CELL TRAFFIC TO THE RETINA

Recent studies demonstrated that administration of a p55-tumor necrosi s factor (TNF) receptor IgG-fusion protein (TNFR-IgG) prevented the cl inical onset of experimental autoimmune encephalomyelitis but did not alter the number or tissue distribution of autoantigen-specific CD4(+) effector T cells which trafficked into the central nervous system. To determine whether specific target tissues of autoimmune damage remain intact after TNFR-IgG treatment despite the presence of inflammatory cells within the tissues, we examined rats with experimental autoimmun e uveoretinitis (EAU), as in this model, the main target of autoreacti ve CD4(+) T cells, the retinal rod outer segments (ROS), can be examin ed readily by light microscopy. As judged by direct ophthalmoscopy, th e onset of inflammation in the anterior chamber of the eye in EAU foll owing administration of TNFR-IgG was delayed by 6 days compared to unt reated controls, but the magnitude of the response was only slightly l ess than controls. Histological examination of the retinae and direct assessment of retinal inflammation revealed a disproportionate sparing of ROS in the TNFR-IgG-treated animals despite a level of retinal inf lammation not substantially less than controls in which ROS damage was marked. Analysis of retinal leukocytes by immunofluorescence microsco py and now cytometry indicated that approximately equal numbers of CD4 (+)alpha beta TCR(+) lymphocytes were present in treated and control r etinae, more than 30% of CD4(+) cells in both experimental groups expr essed the CD25 or MRC OX40 activation markers and most cells, which wo uld include the CD4(+)T lymphocytes, were activated as evidenced by MH C class II expression. Fewer activated macrophages and granulocytes we re present in the treated retinae, possibly reflecting the lower level of tissue damage and subsequent accumulation of these inflammatory ce lls. The results demonstrate directly that a tissue specifically targe ted for autoimmune destruction can be protected despite the influx of fully activated CD4(+) T cells.