Polysialinsäure zur Immunmodulation im Tiermodell der feuchten altersabhängigen Makuladegeneration (AMD)

Zusammenfassung

Hintergrund Die chronische Reaktivität des angeborenen Immunsystems zählt zu den pathophysiologisch hoch relevanten Mechanismen bei der Entstehung und Progression der altersabhängigen Makuladegeneration (AMD). Sowohl zelluläre Prozesse, getrieben vor allem durch aktivierte mononukleäre Phagozyten, als auch humorale Immunmechanismen, vermittelt durch ein autoreaktives Komplementsystem, tragen zum degenerativen Geschehen in der Netzhaut bei. Neuste Ergebnisse weisen auf einen direkten Zusammenhang zwischen Immunzellaktivierung, Komplementaktivierung, Schädigung der Bruch-Membran, Fehlfunktion des retinalen Pigmentepithels, Photorezeptordegeneration und choroidaler Neovaskularisierung (CNV) hin. Neben der antiangiogenen Therapie bietet das Immunsystem Ansatzpunkte für komplementäre Therapieoptionen bei der AMD. Der vorliegende Artikel stellt die beispielhafte Anwendung der Polysialinsäure im Mausmodell der feuchten AMD dar.

Material und Methoden Zur Simulation der feuchten AMD wurde das Mausmodell der laserinduzierten CNV verwendet. Polysialinsäure wurde intravitreal appliziert und die Mikrogliaaktivität mittels Iba1-Immunfärbung von Flachpräparaten der Netzhaut und RPE/Aderhaut bestimmt. Gefäßleckage wurde mittels Fluoresceinangiografie bestimmt.

Ergebnisse Die intravitreale Injektion von Polysialinsäure bei der laserinduzierten CNV der Maus führte zu einer verminderten läsionsassoziierten Mikrogliaaktivität sowohl in der Netzhaut als auch dem RPE. Die Gefäßleckage der Laserherde war ebenfalls bei Polysialinsäurebehandlung vermindert.

Schlussfolgerung Die lokale retinale Immunmodulation mittels Polysialinsäure könnte ein vielversprechendes Konzept zur Behandlung der inflammatorischen Komponenten der feuchten AMD darstellen.

Abstract

Background Chronic activation of the innate immune system is a hallmark of retinal degenerative diseases, including age-related macular degeneration (AMD). Overt microglia and macrophage reactivity, as well as dysregulation of the alternative complement system, trigger and sustain retinal degeneration. It is now accepted that there exists a vicious cycle of mononuclear phagocyte reactivity, abnormal intrinsic complement activation, damage of Bruchʼs membrane, dysfunction of the retinal pigment epithelium, photoreceptor degeneration and choroidal neovascularization (CNV). Targeting the innate immune system may, therefore, be a complementary approach to anti-angiogenic therapy. This article presents data from polysialic acid treatment experiments in the laser-induced mouse model of wet AMD.

Material and Methods The laser-CNV mouse model was used to simulate events of neovascular AMD. Polysialic acid was applied by intravitreal injection and microglia activity was assessed with Iba1 staining of retinal and RPE/choroidal flat mounts. Neovascular leakage was determined by fluorescein angiography.

Results Intravitreal injection of polysialic acid reduced retinal and RPE/choroidal lesion-associated microglia activity in the laser-induced mouse model of AMD. Polysialic acid treatment also diminished vascular leakage at laser spots in this model.

Conclusion Local retinal immunomodulation with polysialic acid presents a novel concept for treatment of inflammatory conditions related to neovascular AMD.

Schlüsselwörter

AMD - Netzhautdegeneration - Immunsystem - Mikroglia

Key words

AMD - retinal degeneration - immune system - microglia

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