A Negative Immune Regulator Controls Wet AMD

Abnormal blood vessel growth is a major cause of irreversible vision loss in age-related macular degeneration (AMD) patients. Currently there is no effective treatment to prevent or slow the blood vessel proliferation in wet AMD patients. This work aims to investigate a novel negative-immune regulator that may suppress inflammation-induced abnormal vessel growth in AMD by altering immune-vascular crosstalk. Novel activators of this immune regulator will be evaluated in a pre-clinical animal model of AMD to determine if treatment is effective in preventing or slowing development of AMD-like pathologies, and findings from this work will identify new treatments to prevent or treat wet AMD.

Our studies aim to determine the root causes of new blood vessel formation (neovascularization) in wet AMD by targeting an immune regulator to modulate immune-vascular crosstalk using both genetical and pharmacological approaches. Abnormal new blood vessels lead to neuronal cell death and eventually cause blindness, however current treatments to block new blood vessels are only effective in 50% of wet AMD patients and cause serious side effects that affect the health of normal blood vessels and retinal nerve cells. Understanding the primary drivers of neovascularization is critical and urgent. Our goal is to determine the drivers and identify new, effective, and safe treatments to prevent and treat wet AMD.

Choroidal neovascularization affects 10% of AMD patients but accounts for up to 90% of vision loss associated with AMD. Immune-vascular crosstalk is a critical pathogenetic pathway in AMD. We will address the fundamental problems of immune dysfunction and inflammatory changes that lead to choroidal neovascularization development. Immune cells, especially myeloid cells, play a key role in linking innate and adaptive immunity, primarily through antigen presentation and recruitment of adaptive immune cells. Choroidal circulation brings to the eye a large number of immune cells, specifically those of myeloid origin, which play important roles in retinal and choroidal vascular pathology. In response to chronic insults, such as those occurring in AMD, myeloid cells become activated and release inflammatory mediators (such as growth factors, matrix metalloproteinases, interleukins, and chemokines) that stimulate ocular neovascularization. A number of chemokines attract immune cells to invade and infiltrate ocular tissues and furthermore stimulate the secretion of more trafficking molecules utilized by migrating immune cells. Increasing evidence shows that inflammatory changes in immune cells influence pathological angiogenesis, but the specifics are still unknown as to how immune cells strongly influence pathological vascular formation. Therefore, analyzing inflammatory mediators and the degree of myeloid cell activation and infiltration around choroidal neovascularization is necessary to understand how the innate inflammatory response contributes to choroidal neovascularization onset and progression. There is a lack of effective approaches to control immune/inflammation, needed to suppress choroidal neovascularization.

We aim to fill this gap by investigating a novel immune regulator that can control immune-vascular crosstalk and that may be targeted pharmacologically to suppress choroidal neovascularization in AMD. Our study is innovative in that it applies novel approaches (activation of a unique immunoregulator in immune cells) to suppress choroidal neovascularization, to prove the concept that pathological choroidal neovascularization formation is controlled by immune cells. The contribution of our research is expected to be conceptual advances on how inflammatory factor in immune cells controls pathological blood vessel growth via modulation of immune-vascular crosstalk. This contribution of our studies will be significant because it will provide a novel target for developing therapeutic strategies that have broad translational importance in the prevention and treatment of AMD. For translation to the clinic, we will evaluate pharmacological activators of immune regulators in the AMD mouse model for new strategies with which to treat and prevent neovascular AMD. Successful completion of the aims will broaden the field of retinal vascular biology research to include modulation of immune-vascular crosstalk via a novel immune regulator to prevent pathological blood vessel growth.