Immunology and Pathology in Ocular Drug Development

Abstract

Clear vision is dependent on features that protect the anatomical integrity of the eye (cornea and sclera) and those that contribute to internal ocular homeostasis by conferring hemangiogenic (avascular tissues and antiangiogenic factors), lymphangiogenic (lack of draining lymphatics), and immunologic (tight junctions that form blood–ocular barriers, immunosuppressive cells, and modulators) privileges. The later examples are necessary components that enable the eye to maintain an immunosuppressive environment that responds to foreign invaders in a deviated manner, minimizing destructive inflammation that would impair vision. These conditions allowed for the observations made by Medawar, in 1948, of delayed rejection of allogenic tissue grafts in the anterior chamber of mouse eye and permit the sequestration of foreign invaders (eg, Toxoplasma gondii) within the retina of healthy individuals. Yet successful development of intraocular drugs (biologics and delivery devices) has been stymied by adverse ocular pathology, much of which is driven by immune pathways. The eye can be intolerant of foreign protein irrespective of delivery route, and endogenous ocular cells have remarkable plasticity when recruited to preserve visual function. This article provides a review of current understanding of ocular immunology and the potential role of immune mechanisms in pathology observed with intraocular drug delivery.

International consortium for innovation and quality: An industry perspective on the nonclinical and early clinical development of intravitreal drugs

“…This includes a limited lymphatic and blood vasculature, the BOB, and an array of immunomodulatory mechanisms optimized to protect ocular tissues against collateral damage of an inflammatory response to daily insults. 19,88,89 The BOB comprises the tight junctions among epithelial cells of the RPE, iris, and ciliary body, and among endothelial cells of the non-fenestrated vasculature of the retina, optic nerve, and iris. The BOB protects the eye from penetration by pathogens and foreign material, enables homeostasis through the regulation of fluid and solutes passage, and cell trafficking.…”

“…As a “path of least resistance,” the peripheral margins of the VB and vitreous‐retinal interface are sites for expulsion of drug delivery devices and depot formulations. This is also the place where inflammatory cells accumulate 19 …”

“…All authors wish to thank J. Brassard 19 (AbbVie, California) and J. Sherman 107 (SUNY College of Optometry, NY) for their permission to reprint their figures, and K. Juturu (Novartis Healthcare Private Limited, India) for his assistance with figure montage.…”

“…An ensemble of anatomic and immunological parameters collectively creates an immune‐privileged environment critical to the protection of ocular tissues lacking regenerative capacity. This includes a limited lymphatic and blood vasculature, the BOB, and an array of immunomodulatory mechanisms optimized to protect ocular tissues against collateral damage of an inflammatory response to daily insults 19,88,89 …”

“…Pharmaceutical companies often F I G U R E 1 Structures and compartments of the eye. 19 Hematoxylin-eosin-stained section of a whole dog eye. The anterior segment is divided into the anterior and posterior chambers, which are anatomically delineated by the AH; cornea, sclera, and conjunctiva; ICA; the ciliary processes, and iris body.…”