(from abstract): Giant cell arteritis (GCA) is an ophthalmic emergency with a high risk for permanent vision loss. If diagnosed promptly, GCA responds well to glucocorticoids but therapy is associated with a high rate of side effects and no improvement in disease management has been made in the last 25 years. The PI has succeeded in establishing a novel model for this vasculitis by engrafting human temporal arteries into SCID mice. Studying the artery-SCID chimeras holds the promise to approach pathomechanisms, design new therapies and directly test them in the chimeras. The goal of this proposal is to investigate mechanisms of vaso-occlusion which are critical in causing ischemic optic neuropathy. She proposes that the initial events in GCA relate to the recognition of antigen by CD4+ T cells and the induction of IFN- production. Tissue damage, including intimal hyperplasia is likely a downstream effect regulated through mediators released by resident cells and by infiltrating macrophages. A correlation exists between anatomical structures of the artery and functional differentiation of macrophages. Accordingly, one macrophage subset produces IL-1B , IL-6, and TGF-B 1 a second subset releases metalloproteinases and a third subset is specialized in synthesizing inducible nitric oxide synthase. The PI has already demonstrated that variations in the lesional cytokine pattern correlate with the absence or presence of clinical ischemia. Experiments proposed here are designed to identify cells and mediators directly involved in stimulating intimal proliferation and ischemic complications. The contribution of individual cell subsets and cytokines will be explored by correlating the tissue expression of growth factors, metalloproteinases, inducible nitric oxide synthase, angiotensin converting enzyme and endothelin with intimal proliferation and with clinical evidence for reduction in ocular blood flow in a cohort of GCA patients. GCA-SCID chimeras will be treated with glucocorticoids to explore beneficial and detrimental effects on intimal thickening and arterial occlusion. To establish the connection between the immunological injury and the vascular response, the PI will modulate IFN-production in arterial xenografts and thus test IFN-y directed interventions for their therapeutic potential. The PI will also explore whether TGF-B 1 is a second key cytokine in the disease and whether neutralization of TGF-B 1 in the SCID chimeras inhibits chemotaxis as well as effector mechanisms leading to arterial occlusion. Pathways involved in causing ischemic disease with subsequent blindness should represent premier targets for new therapeutic strategies in GCA.
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