Immune inflammation and transplantation rejection processes are reduced and sometimes profoundly suppressed in the eye. This phenomenon has been recognized for over a century and is termed "immune privilege". Immune privilege can have an important impact on the function of the eye and vision. Immune privilege accounts for the extraordinary success of corneal transplants and also protects tissues in the eye from immune-mediated injury. This is particularly important as corneal endothelial cells and retina cells are crucial for vision and have limited or no regenerative capacities. It is noteworthy that three major causes of infectious blindness - trachoma, river blindness, and HSV keratitis - are immune-mediated diseases and represent loss of ocular immune privilege. However, in some circumstances it is beneficial to abrogate immune privilege to ensure survival. Immune rejection of intraocular tumors is an example of how circumvention of immune privilege is desirable. The proposed studies will use two clones derived from a parental tumor cell line that circumvents immune privilege in the mouse eye. Both tumor clones undergo immune rejection, but with remarkably different consequences. Clone 2.1 undergoes a form of immune rejection that destroys both the eye and tumor (phthisical rejection). The other tumor (clone 4.0) also undergoes immune rejection, but leaves the eye anatomically and functionally intact (pristine rejection). Studies in mice will characterize the mechanisms for both forms of immune rejection and seek to convert the phthisical form of immune rejection to a pattern of rejection that rids the eye of the tumor while preserving ocular integrity and vision. This project will also test a novel hypothesis which proposes that the phthisical form of necrotizing immune rejection is caused by an inflammatory protein called HMGB-1 that is produced by tumor cells in response to immune molecules that are produced by T lymphocytes that encounter tumor cells in the eye. Experiments will determine if blocking this inflammatory pathway will prevent phthisis of the eye without preventing tumor rejection. Other investigations will identify the mechanisms whereby IL-17-producing T cells are excluded from or silenced within the tumor-bearing eye.
of the present project rests on the notion that it is feasible to circumvent immune privilege to rid the eye of a tumor without altering the anatomical integrity of the eye or jeopardizing vision. Understanding immune regulation and immune privilege in the eye has important implications in the management of immune- mediated diseases of the eye such as uveitis and in maintaining immune homeostasis within the eye.
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