Immunological factors in the pathogenesis and treatment of age-related macular degeneration

Abstract

Recent findings indicate that immunological factors are involved not only in the pathogenesis of age-related macular degeneration (AMD), but also in its treatment. Earlier data showing the presence of inflammatory cells in affected areas of AMD retinas support this statement. Although a possible role for autoimmunity was initially suggested, it has never reached general acceptance. Microorganisms have also been implied in the pathogenesis of AMD. Both serum antibacterial antibody levels and positive DNA tests from neovascular membranes have pointed to a possible role for Chlamydia pneumoniae in the pathogenesis of AMD. New data is providing evidence for the hypothesis that deposits between Bruch's membrane and the retinal pigment epithelium (RPE) cell layer may act as a stimulus for the local activation of the complement system. This may lead to a further growth of the deposits due to the strong chemotactic activity of certain complement activation products (such as C5a) with an influx of inflammatory cells. The buildup of cells and extracellular deposits may lead to local ischemia resulting in the activation of RPE cells. These activated RPE cells are thought to release angiogenic stimuli leading to choroidal neovascularization, which is the most serious complication of AMD. The fact that immunosuppressive drugs such as triamcinolone acetonide and anecortave acetate are capable of inhibiting choroidal neovascularization is consistent with an inflammatory component in the pathogenesis of AMD. Specific immunotherapy directed at certain cytokines or growth factors is now being investigated at both the animal and patient levels. Various clinical trials involving engineered antibodies are now being applied to block angiogenic factors such as the vascular endothelial growth factor (VEGF). An approach using gene therapy to influence angiogenesis by inducing the production of the pigment epithelium-derived factor (PEDF) was able to block neovascularization in an experimental murine model. Besides trying to block ongoing processes in AMD, retinal transplantation is now also being investigated as a treatment option. The fact that the retina is possibly an immunoprivileged tissue in combination with experimental data showing that the subretinal space is an immunoprivileged site is an indication that transplantation would not suffer from the rejection process. A larger obstacle is the question whether transplanted retinal tissue will regain its functional properties.