A variety of mechanisms contribute to "immune privilege" in the eye. Failure to adequately suppress occular immune responses often leads to disease, including autoimmune keratitis, which can develop either as a secondary symptom in individuals with an existing autoimmune disease, as a consequence of prior infection or injury, or spontaneously on its own. A mouse model for autoimmune keratitis would be useful in developing a better understanding of inflammatory processes in the cornea, and in devising potential ways of treating the disease. In this proposal, we introduce two new mouse models for autoimmune keratitis: B10.TCR?-/- and B10.TCR?-/- female mice, which lack ?? and ?? T cells, respectively. These mice develop keratitis spontaneously at a very high rate. Numerous publications have indicated roles for both ?? and ?? T cells in establishing and maintaining ocular immune privilege. We hypothesize that in the B10.TCR?-/- and B10.TCR?-/- mouse strains, the lack of particular immunoregulatory T cells renders their eyes, especially those of the females, exceptionally vulnerable to autoimmune attack. We plan to further characterize the disease that develops in these mice, and test our hypothesis, via the following specific aims: Specific Aim 1. To determine how keratitis arises in B10.TCR?-/- mice. We will examine whether female hormones predispose B10.TCR?-/- mice to develop keratitis, and whether as is often found in human keratitis, B10.TCR?-/- keratitic mice show a concomitant reduction in corneal sensitivity. We will also characterize the autoaggressive ?? T cells in B10.TCR?-/- keratitic mice that lead to keratitis. In addition, we will characterize the specific resident ?? T cell population normally present in the limbus of the eye, and determine whether these ?? T cells play an immunoregulatory role which prevents the development of keratitis. Finally, we will examine whether antibodies that recognize molecules in the cornea play a role in the development or persistence of keratitis in B10.TCR?-/- females. Specific Aim 2. To determine how keratitis arises in B10.TCR?-/- mice. B10.TCR?-/- females are as keratitis-susceptible as B10.TCR?-/- females, although their disease differs in some details. We hypothesize that inflammatory cells, induced by autoaggressive ?? T cells, promote corneal inflammation in B10.TCR?-/- mice, which does not resolve due to their lack of regulatory (Treg) ?? T cells. In this aim, we plan to determine whether ?? T cells in B10.TCR?-/- females are autoaggressive, and if so, to characterize these cells. We will also test whether repletion of these mice with Treg-like cells can reduce or prevent disease. This proposal is submitted in response to PA07-336, "Development of Animal Models and Related Biological Materials for Research," and because it investigates both regulatory T cells and the immunity of the eye, is pertinent to research supported by both the NIAID and NEI.

R21EY019328

2010-04-01

2013-03-31