Determining the Role of Lymphocytes in Glaucoma

Stuart McKinnon, MD, PhD
Duke University (Durham, NC)
Year Awarded:
2014
Grant Duration:
July 1, 2014 to June 30, 2016
Disease:
Glaucoma
Award Amount:
$50,000
Grant Reference ID:
G2014076
Award Type:
Standard
Award Region:
US Southeastern

This grant is made possible in part by a bequest from the John A. Beaty Trust.

Neuroinflammation: The Role of Lymphocytes In Glaucoma

Summary

In glaucoma, permanent vision loss and blindness occur when retinal ganglion cells (RGCs) that make up the optic nerve are lost. Increasing evidence points to a central role of the immune system in the death of RGCs in glaucoma. This project will test that hypothesis by determining whether specific populations of lymphocytes are required for RGC death in glaucoma, and whether blocking the movement of those lymphocytes from the bloodstream into ocular tissue in a mouse model of glaucoma serves to rescue RGCs. Data supporting or refuting the roles of lymphocytes in glaucomatous RGC death would represent a significant advance for the field because it might set the stage for new therapies aimed at modulating the immune system to protect against vision loss and blindness in human glaucoma patients

Details

In glaucoma, permanent vision loss and blindness occur when retinal ganglion cells (RGCs) that make up the optic nerve are lost. Increasing evidence points to a central role of the immune system in the death of RGCs in glaucoma. We have recently shown the surprising finding that in an experimental mouse model of glaucoma, a severely immunodeficient transgenic mouse that lacks T- and B-lymphocytes (Rag1 knockout) is robustly protected against optic nerve damage due to chronic exposure to elevated intraocular pressure (IOP). These transgenic mice lack expression of Rag1, a protein essential to the generation of mature T- and B-lymphocytes, and are thus immunodeficient. This finding generates the novel hypothesis that immune system events involving lymphocytes are necessary for RGC cell death and optic nerve axon loss in glaucoma.

This project will test that hypothesis by determining whether specific populations of lymphocytes are required for RGC death in glaucoma, and whether blocking lymphocyte extravasation into ocular tissues (diapedesis) rescues RGCs in a mouse glaucoma model. We will isolate T- or B-cells using standard immunology techniques and transfer these cells to Rag1 knockout mice to reconstitute this portion of the mouse immune system. We will then utilize our well-established mouse glaucoma model to determine if either T- or B-cells are necessary for RGC axon loss. Lymphocytes migrate from the bloodstream to tissues by the process of diapedesis, which requires the expression of a4 integrin protein on vascular endothelium. We will induce glaucoma in transgenic mice that carry a point mutation in a4 integrin to determine if blocking lymphocyte diapedesis is neuroprotective in our mouse glaucoma model. We will also test whether pharmacological blockage of a4 integrin-mediated diapedesis with a murine version of natalizumab (Tysabri, Biogen, Inc.) is neuroprotective in our mouse glaucoma model.

If T- or B-cells are necessary for glaucoma damage, further research will be designed to determine whether specific lymphocyte subpopulations (e.g. CD4+, CD8+, etc.) can be identified as crucial to RGC axon loss in glaucoma. Given the existing literature, data supporting or refuting the roles of lymphocytes in glaucomatous RGC death would represent a significant advance for the field because therapies could be designed to modulate the immune system to protect against vision loss and blindness in our human glaucoma patients.

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.