Giant cell arteritis (GCA) is an immune-mediated vasculopathy with granulomatous inflammation of the arterial wall leading to lumenal obstruction and ischemia. The most common ophthalmic manifestation of GCA is anterior ischemic optic neuropathy causing acute visual loss in one or both eyes. Over the last decade, we have systematically deciphered the immunopathogenesis of GCA providing the conceptual framework for the current application. We hypothesize that dendritic cells (DC) indigenous to the artery initiate and sustain vasculitis by attracting, stimulating and instructing disease-relevant T cells. Whereas vascular DC in healthy arteries prevent immune stimulation, DC in GCA are hyperresponsive and compromise the artery's immunoprivilege. We have developed experimental systems which recapitulate the microenvironment in human arteries; human artery-SCID chimeras and bioengineered 3-D constructs resembling medium-sized human vessels. The current proposal presents three specific aims designed to mechanistically examine DC-T cell interactions leading to either desired T cell tolerance or pathological vascular inflammation.
Aim 1 examines the hypothesis that CD28-CD86 interactions are critical in initiating vasculitis. Preliminary studies in GCA-resistant human arteries suggest selective repression of CD86 as a tolerance mechanism. Applying artery-SCID chimeras and tissue-engineered arteries, we will explore the role of CD86 by silencing this costimulatory ligand in DC or blocking with a soluble decoy receptor (CTLA4-Ig). Conversely, we will attempt to break tolerance by forced CD86 expression through epigenetic manipulation.
Aim 2 examines the hypothesis that GCA development reflects defective coinhibitory signals, leading to unopposed T cell activation. Building on preliminary data showing overrepresentation of a low-expresser PD-L1 promoter allele and insufficient PD- L1 induction on DC from GCA patients, we will characterize mechanisms underlying defective PD-L1 signaling. We will continue preclinical studies aimed at developing a novel therapy for GCA by replenishing PD-L1 in the vasculitic lesions.
Aim 3 will examine how vascular DC determine T cell effector functions mediating vasculitis. Specifically, we will search for molecules regulating T cell tissue-invasiveness, a prerequisite for the transmural progression of vasculitis.
. GCA remains a sight-threatening disease and represents an ophthalmic emergency as blindness is preventable by prompt diagnosis and immunosuppressive therapy. This proposal examines how products from bacteria and viruses drive sentinel cells (so-called dendritic cells) in human arteries to become highly stimulatory and attract inflammatory lymphocytes. Receptor-ligand pairs utilized by inflammatory cells are examined with the hope that disruption of dendritic cell-lymphocyte interactions can be exploited for novel therapeutic strategies of this vision-threatening disease. ? ? ?
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