Title:
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Targeting myeloid cells as a therapeutic approach to intraocular inflammation
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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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