Immune-Mediated Mechanisms of Phthisical and Non-Phthisical Intraocular Tumor Rejection

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Title: Immune-Mediated Mechanisms of Phthisical and Non-Phthisical Intraocular Tumor Rejection
Author: Coursey, Terry Glenn, II
Abstract: Although intraocular tumors reside in an immunoprivileged site where immune responses are suppressed , some tumors are rejected nonetheless . An example of this is the syngeneic adenovirus -induced (Ad5E1 ) tumor model . Intraocular tumors are rejected in one of two pathways : one that maintains normal architecture and function of the eye and one that causes gross destruction leading to necrosis or phthisis . Ad5E1 tumor cell lines were created from single cell clones that are consistently rejected in a phthisical manner or non -phthisical manner . The first objective sought to characterize non -phthisical intraocular tumor rejection . I demonstrated that this form of rejection is dependent on T cells . Rejection was also found to be dependent on M1 macrophages that mediate cytotoxicity ; however , iNOS was not required . An unidentified soluble factor was determined to be responsible for macrophage -mediated killing . My results indicated that T cells and M1 macrophages were required for phthisical rejection of intraocular Ad5E1 clone 2 .1 . In addition , in vitro inhibition of iNOS abolished most of the macrophage -mediated killing of the tumor cells , and in vivo results indicated that iNOS was essential for controlling the growth of the intraocular tumors . Studies in tumor necrosis factor (TNF ) -deficient mice revealed that although TNF -alpha was not necessary for tumor rejection , it was required for phthisis . Thus , 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 . The last aim sought to determine the mechanisms of IFN -gamma -independent tumor rejection . Although phthisically -rejected Ad5E1 tumors were not rejected when transplanted into the eyes of IFN -gamma KO mice , they were rejected following subcutaneous transplantation (SC ) . Thus , outside of the eye , Ad5E1 tumors elicit a form of tumor immunity that is IFN -gamma -independent . SC tumor rejection required IL -17 , which was produced by CD4+ T cells in response to tumor antigens (TAs ) . Additionally , depletion of IL -17 decreased CTL activity against Ad5E1 tumor cells . However , this does not occur in the eye . IL -6 production within the eye is severely reduced , which is consistent with the failure to induce Th17 cells within the intraocular tumors . Therefore , IFN -gamma -independent tumor rejection is excluded from the eye and may represent a newly recognized form of ocular immune privilege .
URI: http : / /hdl .handle .net /2152 .5 /937
Date: 2011-12-12


Immune-Mediated Mechanisms of Phthisical and Non-Phthisical Intraocular Tumor Rejection. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /937 .

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