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Lack of IFN- Synthesis in Aqueous Humor during Corneal Graft Rejection Correlates with Suppressed Nitric Oxide Production by Macrophages

¹From the School of Medical Sciences and ²Bristol Eye Hospital, Academic Unit of Ophthalmology, Department of Clinical Science at South Bristol, Bristol, United Kingdom.

PURPOSE. To investigate cytokine production by leukocytes in aqueous humor (AH) during corneal graft rejection and nitric oxide (NO) production by macrophages as a potential mediator of graft damage.

METHODS. Rats received corneal allotransplants and were killed during acute rejection. Leukocytes in AH that expressed tumor necrosis factor (TNF)-, interferon (IFN)-, and interleukin (IL)-10 were quantified by flow cytometry. Isograft and further allograft recipients were killed, and sectioned corneas with conjunctivae were examined by histology for production of inducible nitric oxide synthase (iNOS), NO, and nitrotyrosine (NT).

RESULTS. Between 80% and 90% of T cells, NK cells, and macrophages in AH expressed TNF-, and at least 20% expressed IL-10. However, IFN- was undetectable unless cells were first stimulated in vitro with PMA and ionomycin, which yielded IFN- in 25% of cells. iNOS⁺ macrophages were identified in donor cornea and AH, correlating precisely with rejection. Cells producing low levels of NO (NO^dim cells) were found in donor stroma, but NT⁺ cells were rare. Both NT⁺ and NO⁺ cells were rare in the anterior chamber (AC) or attached to corneal endothelium. NT⁺ macrophages that were also NO^bright were associated with sutures in allograft and isograft recipients and within conjunctivae, either scattered or in leukocyte aggregates.

CONCLUSIONS. IFN- synthesis is lacking in the AC during rejection, correlating with lack of NO but not of iNOS expression. NO does not appear to mediate endothelial cell death. NT and high levels of NO production are associated with nonspecific inflammatory cells.