PROJECT SUMMARY/ABSTRACT The innate immune system is comprised of cells and molecules that make up non-antigen specific responses to injury and infection, and includes macrophages, dendritic cells, and PMNs. Innate immune responses in the CNS, represented in part by microglia, have been shown to affect the outcome of neural injuries based on evidence for neuroprotective roles, as well as roles in neurodegeneration and pathology. It is likely that innate immunity plays similar roles in retina. The innate immune response promotes adaptive immune responses, and can be regulated by the adaptive, antigen specific arm of immunity, raising the possibility that these two facets of immunity could be exploited to control the neural tissue response to injury. The possibility of producing more favorable outcomes to neural injuries has received significant attention since the late 1990s when it was proposed that T cells with specificity for neural self-antigens were an important part of neuroprotection. The idea is attractive for several reasons, including the possibility to promote neuroprotection in chronic diseases of the eye that have enormous health impacts on the retina (glaucoma, macular degeneration, diabetes, etc.). However, definitive evidence on how the immune system and nervous system interface remains elusive, and key hypotheses still require experimental validation. Further, new hypotheses are being developed that may change these paradigms. We have been using transgenic and knockout mice for studies related to retinal autoimmunity and immunologic tolerance, and found a new component in the response to retinal injury. These mice and strategies could be rapidly applied to the study of neuroprotection, and used to examine the role of immunity in retinal homeostasis and response to injury, separate from experimental autoimmune disease. The mice bring a fresh opportunity to define the role of immunity in neuroprotection/neurodegeneration. The questions in this proposal are based on preliminary results that suggest the early participation of dendritic cells following injury to retinal ganglion cells. The experiments concentrate on the possible contributions of dendritic cells of innate immunity to neurodegenerative disease/protection, and test their role in focusing retinal antigen specific T cells on neuroprotection, rather than disease. Using the optic nerve crush model for retinal ganglion cell death in glaucoma, the first Aim tests our hypothesis that dendritic cells contribute to retinal homeostasis. We ask: 1) if dendritic cells, rather than microglia, are the first critical responders to retinal injury, 2) do they contribute to neuroprotection, and 3) how they communicate with injured retinal ganglion cells. Since dendritic cells are important antigen presenting cells, the second Aim examines recruitment of an adaptive immune response into neuroprotection, and asks: 1) do the dendritic cells recruit T cells to the injury, 2) what population of T cells is important to retinal ganglion cell survival or loss, and 3) does the Ag- specificity of the T cells matter.

PROJECT NARRATIVE Injuries and diseases that lead to neurodegeneration afflict an ever-growing portion of the human population. The outcomes of these neurodegenerative processes range from mildly debilitating to deadly and include glaucoma, age-related macular degeneration, diabetic retinopathy, Alzheimer's disease, stroke, traumatic injuries, infectious diseases, and many other less common causes. Since aging is a factor in many of these diseases, their impact will increase, as the average age of the population increases. Progress toward understanding the fundamental mechanisms of neuroprotection is critical.