| Summary: | Inflammation contributes to major causes of visual loss. Both intraocular inflammatory disease (uveitis) and immune-mediated retinal degenerative disorders such as agerelated macular degeneration account for the majority of visual impairment in the adult population in developed countries. Non-infectious uveitis is considered an autoimmune disease initiated by a loss of immune tolerance to retinal proteins, mediated and characterized by infiltration of leukocytes, including T cells and tissuedamaging macrophages. Glucocorticoids remain the first-line treatment of choice, however, despite up to a third of patients failing to achieve disease control at tolerable systemic doses in addition to adverse side-effects. As a preclinical model of human uveitis, experimental autoimmune uveoretinitis (EAU) provides a platform for dissection of the mechanisms responsible for immune-mediated tissue damage, as well as permitting assessment of immunotherapeutic efficacy. The purpose of this thesis was to investigate whether targeted approaches to modulate macrophage responses in EAU could impact disease severity and offer future therapeutic potential. The data presented demonstrates that harnessing CD200 receptor (CD200R) signaling; a homeostatic regulatory mechanism that contributes to the immune health of the normal retina is a viable approach which can suppress macrophage-mediated tissue damage. Specifically, when a CD200R agonist monoclonal antibody (mAb), DX109 is administered either systemically or locally (via intravitreal injection) inflammatory responses and disease severity are suppressed. Triggering of the receptor via DX109 binding delivers a negative signal, and thus mimicking the normal effect of the cognate ligand CD200 to deactivate and tonically suppress macrophage responses. Inappropriate complement activation resulting either from dysregulated para-inflammatory responses or autoimmune inflammation is implicated in ocular tissue damage. By targeting the complement component C5 and preventing generation of the potent pro-inflammatory anaphylatoxin C5a, macrophage responses and tissue damage in the retina can also be suppressed. The results demonstrate that selective blockade with an anti-C5 mAb via both systemic and local routes of administration can be exploited therapeutically. In the final approach, I utilised an S1 P receptor-1 agonist (Fingolimod) to prevent the influx of antigenspecific T cell infiltrate and the subsequent recruitment and activation of macrophages cells, which results in suppression of overt inflammatory responses, and ultimately protects the tissue. Furthermore, employing clinically relevant doses of Fingolimod can acutely suppress active intraocular inflammation, maintain disease remission and support the vascular barrier integrity of the eye.
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