title: Rejection of intraocular tumors by CD4(+) T cells without induction of phthisis.
abstract: Immune privilege of the eye protects against sight-threatening inflammatory events, but can also permit outgrowth of otherwise nonlethal immunogenic tumors. Nonetheless, ocular tumor growth can be controlled by cellular immune responses. However, this will normally result in phthisis of the eye, in case tumor rejection is mediated by a delayed-type hypersensitivity response orchestrated by CD4(+) T cells. We now show that intraocular tumors can be eradicated by CD4(+) Th cells without inducing collateral damage of neighboring ocular tissue. Injection of tumor cells transformed by the early region 1 of human adenovirus type 5 in the anterior chamber of the eye leads to intraocular tumor formation. Tumor growth is transient in immunocompetent mice, but lethal in immunodeficient nude mice, indicating that T cell-dependent immunity is responsible for tumor clearance. Tumor rejection has all the characteristics of a CD8(+) T cell-mediated immune response, as the tumor did not express MHC class II and only tumor tissue was the subject of destruction. However, analysis of the molecular and cellular mechanisms involved in tumor clearance revealed that perforin, TNF-alpha, Fas ligand, MHC class I, and CD8(+) T cells did not play a crucial role in tumor eradication. Instead, effective tumor rejection was entirely dependent on CD4(+) Th cells, as CD4-depleted as well as MHC class II-deficient mice were unable to reject their intraocular tumor. Taken together, these observations demonstrate that CD4(+) T cells are able to eradicate MHC class II-negative tumors in an immune-privileged site without affecting surrounding tissues or the induction of phthisis.
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: L R
authors.initials: LR
authors.lastname: Schurmans
authors.forename: L
authors.initials: L
authors.lastname: Diehl
authors.forename: A T
authors.initials: AT
authors.lastname: den Boer
authors.forename: R P
authors.initials: RP
authors.lastname: Sutmuller
authors.forename: Z F
authors.initials: ZF
authors.lastname: Boonman
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.forename: E I
authors.initials: EI
authors.lastname: van der Voort
authors.forename: J
authors.initials: J
authors.lastname: Laman
authors.forename: C J
authors.initials: CJ
authors.lastname: Melief
authors.forename: M J
authors.initials: MJ
authors.lastname: Jager
authors.forename: R E
authors.initials: RE
authors.lastname: Toes
mesh_terms: D017498:Adenovirus E1 Proteins / Q000494:pharmacology; D000818:Animals; D000867:Anterior Chamber / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002461:Cell Line, Transformed; D005128:Eye Diseases / Q000276:immunology*; D005134:Eye Neoplasms / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein; D007249:Inflammation / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
chemical_list: D017498:Adenovirus E1 Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin