The survival rate of corneal allografts in "high risk" vascularized corneal bed recipients is poor due to immune rejection. Our hypothesis is that these grafts are similar to the fate of other solid organ vascularized allogeneic grafts that require aggressive systemic immune-suppression to improve survival. The rejection of allografts is mediated through the coordinated recruitment and infiltration of allo-specific T cells. Most recently, studies investigating the immunological rejection of solid vascularized organ allotransplants have shown that the early induction of selective chemokines at the site of transplantation after surgery is required for the optimal recruitment of T cells into rejecting allografts. Our data shows that recruitment of T cells into the graft is also critical in rejection of high risk vascularized corneal allografts. This correlates to the early production of the neutrophil chemoattractant CXCL1/KC and late up-regulation of the T cell chemoattractants: CXCL9/Mig (monokine induced by IFN-3) and CXCL10/IP10 (IFN-3-inducible protein). Although the in vivo neutralization of CXCL1/KC results in increased graft survival, our recent data shows that neutralization of CXCL10/IP10 causes a faster and robust rejection. In this application we will test the hypothesis that a high risk vascularized cornea behaves like a vascularized solid organ transplant. The early production of CXCL1/KC is crucial to the late induction of T cell chemoattractants necessary for the recruitment of allo-specific effector or regulatory CD4 T cells into the graft. The overall goal of the experiments proposed in this application is to understand how the vascularized corneal environment regulates early CXC chemokine production and the recruitment of primed allo-specific effector and regulatory T cells into the graft to mediate rejection reactions.
In Aim 1, we will test using a novel system of tracking antigen specific T cells, to monitor allo-specific T cells priming and test this is altered by high risk vascularized corneal allografts in such a way that there are more T cells with a different phenotype optimized for recruitment.
In Aim 2, we will identify the cell source of CXCL1/KC and test how CXCL1/KC induces the late production of T cell chemoattractants by increasing infiltration of CXCR2+ cells that produce IFN-?. Experiments in Aim 3 will use neutralizing antibodies and mice deficient in CXCL/9/Mig to test that this T cell chemoattractant is responsible for the increased recruitment of T cells into the graft. We will also utilize novel animal models with fluorescently labeled effector and regulatory T cells to test how intragraft chemokines alter their recruitment and graft outcome. The results from experiments described in this proposal will identify targets for the development of novel therapeutic reagents and strategies to inhibit T cell infiltration into high risk allografts. This will ultimately improve graft survival while decreasing the dependence on the generalized and debilitating immunosuppressive regimens currently available.
The main treatment for blindness caused by severe corneal scarring is corneal transplantation. Unfortunately, in patients where corneal scarring is associated with blood vessel formation, the rejection rate of the transplant is high. The experiments proposed in this application will examine how the recruitment of immune cells by chemokine signals is responsible for graft rejection. We believe that the local neutralization of these chemokines will be a novel form of therapy to keep corneal transplants clear and improve the visual outcome in patients with vascularized scarred corneas.
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