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S. Wang, Z.F. Boonman, M.J. Jager, R.E. Toes, H. Li, Y. He, E. Mayhew, J.Y. Niederkorn; Role of Interferon-Gamma and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in the Immune Rejection of Syngeneic Intraocular Tumors . Invest. Ophthalmol. Vis. Sci. 2003;44(13):761.
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Purpose:Immunogenic tumors can breach ocular immune privilege and undergo immune rejection in the eye. We have previously demonstrated that an adenovirus-induced tumor (Ad5E1) undergoes a non-phthisical, CD4+ T cell-dependent immune rejection in the eyes of syngeneic C57BL/6 mice. Rejection can occur in mice deficient in: B cells; NK cells; perforin; CD8+ T cells; FasL; or TNF. Accordingly, we examined the roles of interferon-gamma (IFN-gamma) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the CD4+ T cell-dependent rejection of intraocular Ad5E1 tumors. Methods:Ad5E1 tumors were transplanted intracamerally into C57BL/6 IFN-gamma knockout (IFN-KO) mice and wild-type C57BL/6 mice. CD4+ T cells were enriched by selection with immunomagnetic beads. Expression of TRAIL, TRAIL receptors, and cytoplasmic IFN-gamma was detected by flow cytometry. Apoptosis of tumor cells was determined using Annexin V and caspase 3 assays. Results: Intraocular tumors underwent a non-phthisical rejection in normal C57BL/6 mice, but grew progressively in IFN-gamma KO hosts. Flow cytometric analysis revealed that the tumor cells expressed TRAIL-R2. In vitro studies using recombinant murine IFN-gamma and purified TRAIL indicated that tumor cells were only weakly susceptible to IFN-gamma induced apoptosis (<7%), but underwent significant TRAIL-induced apoptosis (40%). Pretreatment with IFN-gamma further enhanced the tumor cells susceptibility to TRAIL-induced apoptosis (P<0.05). In vitro assays demonstrated that CD4+ T cells induced apoptosis of 80% of the Ad5E1 tumor cells (P<0.05). This apoptosis was reduced by 50% in the presence of anti-TRAIL antibody. IFN-gamma treatment induced a significant increase in the expression of TRAIL on CD4+ T cells (25% TRAIL+). By contrast, IFN-gamma KO mice expressed feeble amounts of TRAIL (<2% TRAIL+) and failed to kill tumor cells in vitro. Conclusions:These findings suggest that the CD4+ T cell-dependent and IFN-gamma-dependent rejection of intraocular Ad5E1 tumors correlates with IFN-gamma upregulation of TRAIL expression on CD4+ T cells and the capacity of IFN-gamma to increase the tumor cells susceptibility to TRAIL-induced apoptosis.
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