Mechanisms that maintain ocular immune privilege may contribute to ocular tumor progression by inhibiting tumoricidal immune responses. to preserve immune privilege by minimizing ocular immunopathology may hasten the outgrowth of tumor escape variants which contributes to ocular tumor progression. via immunosuppressive cell surface molecules. For example iris/ciliary ZSTK474 body PE express CD86 and CE cells express programmed death ligand-1 (PD-L1) which engages cytotoxic T-lymphocyte antigen 4 (CTLA4) or PD-1 respectively on activated T cells to induce the generation of CD4+FoxP3+Treg.(28) Hence effector function may be inhibited as activated T cells extravasate from vessels in the iris/ciliary body into the a.c. by conversion of T effectors into Treg. A similar phenomenon may occur in the retina as retinal PE cells express PD-L1 which inhibits T-cell activation.(29) Ocular cell surface expression of PD-L1/PD-L2(30) and the CD95 ligand (FasL)(31) can also induce ZSTK474 apoptosis of the activated T cells. The significance of these death-inducing molecules in maintaining immune privilege is well established in corneal transplantation as mice that are deficient in either of these molecules reject corneal allografts at a higher frequency than their wild-type counterparts.(30 32 Moreover T-cell apoptosis is demonstrable in accepted corneal allografts whereas rejecting grafts are heavily infiltrated by CD4+ T cells. ACAID Mice harboring progressively growing ocular tumors expressing minor MHC antigen differences with their host display prolonged acceptance of skin grafts sharing the same Igfbp2 haplotype as ocular tumors whereas major and minor MHC antigen-disparate skin grafts are rejected with normal kinetics.(33) Tolerance to these ZSTK474 semi-allogeneic skin grafts was associated with inhibited CD4+ T-cell-mediated delayed type hypersensitivity (DTH) responses specific for minor antigens(34) while tumor-specific CD8+ CTL responses(35) and antibody production(4) were unimpaired. These data indicate that the immune system responds to ocular antigens but is clearly deviated from the response evoked by the same antigens encountered at extraocular sites. Hence Streilein and Niederkorn proposed the term a.c. associated immune deviation (ACAID) to describe this phenomenon.(36) ACAID has been primarily characterized by the suppression of ZSTK474 CD4+ T-cell mediated DTH responses to ocular antigens and is a ZSTK474 complex process involving the spleen thymus and the sympathetic nervous system.(37) The current paradigm suggests that F4/80+ APC from the eye traffic via the bloodstream to the thymus and the marginal zone of the spleen where they directly present antigens as well as indirectly present antigens to B cells that function as APC for thymus-derived NK T cells and γδ T cells via nonclassical MHC molecules. Coordinate interactions of these cell populations along with the expression of interleukin-10 (IL-10) and inhibited IL-12 production culminate in the generation of CD4+ and CD8+ Treg which inhibit the induction and expression of DTH responses. IMMUNE PRIVILEGE AND OCULAR TUMOR DEVELOPMENT Immune suppressive mechanisms which maintain ocular immune privilege should favor ocular tumor development and persistence. However ocular tumors are very rare. The prevalence of the most common intraocular malignancy UMs is over 30 times lower than cutaneous melanoma.(38 39 One explanation for this paradox is that the eye compensates for an absence of immune surveillance by expressing death receptors that target transformed cells for apoptosis. For example tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) targets several different transformed cell lines for apoptosis (40) and P815 tumor cells transduced to express TRAIL receptor DR5 failed to develop into ocular tumors when injected into the a.c. of mice where TRAIL is constitutively expressed.(41) Moreover UM cell lines that express Fas(42) and retinoblastoma cell lines that express Fas and TRAIL receptors (DR4 and DR5)(43) are resistant to apoptosis induced by respective death receptors which is consistent with the hypothesis that apoptosis induction in the eye and in general must be prevented for ocular tumors to develop. Immunosurveillance and immunoediting: shaping tumor phenotype through antitumor immunity In the early 20th century Paul Erlich proposed that a major function of the immune system was to detect and eliminate tumors from the host.(44) Thomas and Burnet.