Glaucoma is one of the most common causes of irreversible vision loss and blindness world wide. The disease affects a large number of veterans and degrades their quality of life. Loss of vision is ultimately due to the degeneration of retinal ganglion cells (RGC) which are required to convey visual information from the retinal photoreceptors to the visual centers of the brain. It is currently unclear what initially causes the damage to RGC. It has been well established that the degeneration of the RGC is accompanied by retinal neuroinflammation characterized by microglial activation, expression of proinflammatory molecules, upregulation of MHC II molecules, and retinal synthesis of components of the complement cascade. Preliminary data included in this application demonstrate that glaucomatous RGC degeneration also elicits a cellular autoimmune response in mouse models of the disease. Adoptive transfer of splenocytes or T cells, but not B cells, from glaucomatous mice into healthy, normotensive recipients elicits slow and progressive loss of RGC. Other cell types of the retina do not appear to be affected. Importantly, we further demonstrate that transfer of immune cells from human glaucoma patients into immune deficient mice also leads to specific RGC loss in the recipient mice. This was invariably the case when material from patients with disc hemorrhages (a clinical sign of ongoing glaucomatous degeneration) was used. Material from patients with glaucoma, but without a disk hemorrhage, causes RGC loss in mice to a varying degree. Transfer of cells from healthy controls causes no damage. We hypothesize that the amount of RGC loss in the mouse is correlated to the vision loss that will be experienced by the donating patient in the coming months. Thus, transfer of immune cells from human patients to the mouse is a predictor of future damage and can serve to identify those patients who would benefit from aggressive clinical interventions. Early and maximal treatment could serve to prevent loss of vision and decline of quality of life in affected veterans. This proposal will test this hypothesis by obtaining blood derived immune cells from veterans with primary open angle glaucoma. These cells will be transferred to the mice, and the resulting damage will be quantitated. Patients will be re-examined after two years and the degree of vision loss and decline of quality of life will be correlated to RGC loss in the mouse model. Additional experiments are proposed to further define the type of immune cell mediating this phenomenon. Finally we will determine if immune modulation in the recipient mouse can prevent RGC loss. If successful these data might point out new approaches to prevent progressive vision loss in glaucoma patients. The concept of a T cell based autoimmune response associated with vision loss in glaucoma is very innovative and has potentially significant clinical ramifications. The development of a predictive assay based upon this response would provide clinicians with a new tool to identify those patients most at risk for the slow but steady decline in vision noted in too many veterans.
This proposal is based preliminary data demonstrating the very novel concept that glaucomatous degeneration in human patients is associated with the development of a cellular autoimmune response that can be detected and quantitated in vivo by transferring the patients' immune cell to immune deficient mice. We hypothesize the magnitude of the observed reaction in the mouse is predictive of future loss of vision and quality of life of the donating patient. Early identification of patients at high risk to develop vision loss allows aggressive treatment before the damage occurs. The development of a predictive assay would provide ophthalmologists with a valuable tool and preserve the quality of life for veterans.
