title: Abrogating TNF-α expression prevents bystander destruction of normal tissues during iNOS-mediated elimination of intraocular tumors.
abstract: Although intraocular tumors reside in an immune privileged site, some tumors are rejected nonetheless. For example, intraocular adenovirus-induced (Ad5E1; adenovirus type 5 early region 1) tumors are rejected in syngeneic C57BL/6 mice by one of two pathways. One pathway leads to extensive necrosis of innocent bystander cells and culminates in destruction of the eye, a condition called phthisis. The second pathway is characterized by piecemeal tumor cell death that rids the eye of the tumor while preserving the architecture and function of the eye. To study the mechanisms of phthisical tumor rejection, we isolated a cell clone-designated clone 2.1 that consistently undergoes rejection in a phthisical manner. CD4(+) T cells and macrophages were required for phthisical rejection of intraocular clone 2.1 tumors and M1 macrophages were involved in mediating tumor rejection. In vitro and in vivo inhibition of iNOS (inducible nitric oxide synthase) abolished macrophage-mediated killing of tumor cells and rejection of intraocular tumors. A role for M1 macrophages was further supported by investigations showing that intraocular tumors grew progressively in IFN-γ KO (knockout) mice. Studies in mice deficient in TNF-α, TNF receptor-1, or TNF receptor-2 revealed that although TNF-α was not needed for tumor rejection, it was required for the development of necrotizing inflammation and phthisis of tumor-bearing eyes. Together, our findings suggest new strategies to successfully eliminate ocular tumors while preserving the integrity of the eye.
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. jerry.niederkorn@utsouthwestern.edu
authors.forename: Terry G
authors.initials: TG
authors.lastname: Coursey
authors.forename: Peter W
authors.initials: PW
authors.lastname: Chen
authors.forename: Jerry Y
authors.initials: JY
authors.lastname: Niederkorn
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017498:Adenovirus E1 Proteins / Q000235:genetics; D000818:Animals; D002472:Cell Transformation, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005134:Eye Neoplasms / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D017498:Adenovirus E1 Proteins; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D019331:NG-Nitroarginine Methyl Ester