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T. G. Coursey, P. W. Chen, J. Y. Niederkorn; Role of TNF- and iNOS in CD4+ T Cell-Mediated Immune Responses That Reject Intraocular Tumors but Destroy the Eye. Invest. Ophthalmol. Vis. Sci. 2010;51(13):845.
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© ARVO (1962-2015); The Authors (2016-present)
Intraocular tumors undergo immune rejection by one of two pathways. In one pathway, the architecture of the eye is preserved. A second pathway leads to extensive necrosis and culminates in phthisis. This study explored the mechanisms of phthisical intraocular tumor rejection.
Ad5E1 tumor cells (C57BL/6 origin) that undergo phthisical rejection were injected into the anterior chamber (AC) of C57BL/6, NOD-SCID, clodronate-liposome treated, interferon-γ (IFN-γ) KO, iNOS-depleted, and tumor necrosis factor-α (TNF-α) KO mice. Macrophage-mediated killing of tumor cells was evaluated in vitro. M1 macrophages were identified by quantifying nitric oxide synthetase-2 (NOS2) expression in intraocular tumors by qPCR. Mice were treated with the iNOS inhibitor L-NAME to determine if tumor rejection and phthisis were nitric oxide-dependent.
Ad5E1 tumors were not rejected in NOD-SCID or clodronate-treated mice indicating that T cells and macrophages were required tumor rejection. Rejecting tumors had a 40-fold increase in NOS2 expression suggesting that classically activated (M1) macrophages were involved in tumor rejection. Inhibition of iNOS abolished 90% of the macrophage-mediated tumor cell killing in vitro. NOS was essential for controlling the intraocular tumors, as administration of the iNOS inhibitor L-NAME prevented rejection. Participation of M1 macrophages was also supported by progressive tumor growth in mice deficient in IFN-γ, a key activator of M1 macrophages. TNF-α was required for phthisis, but not tumor rejection, as 80% of the TNF-α-deficient mice rejected their tumors, yet the affected eyes did not undergo phthisis.
Rejection of intraocular Ad5E1 tumors requires M1 macrophages and the generation of NO, as disabling either of these prevents tumor rejection. By contrast, TNF-α is not required for tumor rejection, but is needed for the development of phthisis. Thus, TNF-α plays a deleterious role in phthisical intraocular tumor rejection. This model demonstrates that it is possible to modify the host’s response such that the immune system eliminates the intraocular tumor while preserving the integrity of the eye.
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