Session Title: ACR Plenary Session II: Discovery 2013
Session Type: Plenary Sessions
Background/Purpose: In giant cell arteritis (GCA), CD4 T cells, macrophages and multinucleated giant cells form granulomatous lesions in the walls of medium and large arteries. A plethora of innate and adaptive cytokines are produced within the vasculitic infiltrates, but it is not known whether a hierarchy of cytokines exists that initiates and sustains vessel wall damage, drives intimal hyperplasia and promotes persistent immune activation. Most cytokines function by triggering JAK/STAT signaling pathways in target cells to regulate gene programs that drive cellular activation, differentiation, and survival, all critical in the maladaptive response of the inflamed artery and the acute phase response underlying systemic inflammation.
Methods: To induce experimental GCA, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (NSG) mice were engrafted with human medium-sized arteries and reconstituted with PBMC from patients with biopsy-proven GCA. Following induction of vasculitis, chimeras were treated with either dexamethasone (15 mg/kg) or tofacitinib (4 mg/kg) or both for 5 days. Explanted artery grafts or temporal artery biopsies from patients with GCA were analyzed for gene expression profiles by RT-PCR. Plasma was harvested from GCA patients and from untreated or treated reconstituted chimeras and cytokines were quantified by ELISA.
Results: To identify signaling pathways involved in vasculitis, we screened temporal artery biopsy samples and plasma from GCA patients for induction of signal transducer and activator of transcription (STAT) activity. STAT-1 transcripts were abundantly expressed in tissue lesions. The major inducer cytokine of STAT-1, IFN-γ, was 10-fold higher in GCA patients than in age-matched controls. To examine the relevance of STAT-1 signaling, we compared the effects of two classes of immunosuppressive agents (corticosteroids and the JAK/STAT-inhibitor tofacitinib, CP-690,550, a potent kinase inhibitor for JAK3 > JAK1 > JAK2) in experimentally induced vasculitis in 7 independent experiments. Dexamethasone primarily suppressed innate immunity with inhibition of dendritic cell activation (P = 0.005), IL-6 and IL-1β expression in the vascular lesions. Conversely, dexamethasone spared adaptive immunity and left IFN-γ-producing TH1 unaffected (P = 0.98). The kinase inhibitor effectively prevented T cell accumulation in the vessel wall and suppressed IFN-γ production (P = 0.03) and signaling. JAK/STAT inhibition reduced blood levels of IFN-γ in the chimera mice by 65% (P = 0.004). The underlying mechanism involved a reprogramming of T cell trafficking, barring vasculitic T cells from arterial wall infiltration.
Conclusion: STAT-1 signaling is a key pathogenic pathway in GCA, is sustained by excessive activity of the adaptive cytokine IFN-γ and persists despite suppression of innate immunity. Retention of vasculitic T cells in the vessel wall is a major determinant of vasculitic activity and emerges as a novel therapeutic target.
M. H. Weisman,
K. J. Warrington,
J. J. Goronzy,
C. M. Weyand,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-stat1-signaling-pathway-in-giant-cell-arteritis/