Th17 and Th1 T-Cell Responses in Giant Cell Arteritis

Abstract

Background-In giant cell arteritis (GCA), vasculitic damage of the aorta and its branches is combined with a syndrome of intense systemic inflammation. Therapeutically, glucocorticoids remain the gold standard because they promptly and effectively suppress acute manifestations; however, they fail to eradicate vessel wall infiltrates. The effects of glucocorticoids on the systemic and vascular components of GCA are not understood. Methods and Results-The immunoprofile of untreated and glucocorticoid-treated GCA was examined in peripheral blood and temporal artery biopsies with protein quantification assays, flow cytometry, quantitative real-time polymerase chain reaction, and immunohistochemistry. Plasma interferon-␥ and interleukin (IL)-17 and frequencies of interferon-␥-producing and IL-17-producing T cells were markedly elevated before therapy. Glucocorticoid treatment suppressed the Th17 but not the Th1 arm in the blood and the vascular lesions. Analysis of monocytes/macrophages in the circulation and in temporal arteries revealed glucocorticoid-mediated suppression of Th17-promoting cytokines (IL-1␤, IL-6, and IL-23) but sparing of Th1-promoting cytokines (IL-12). In human artery-severe combined immunodeficiency mouse chimeras, in which patient-derived T cells cause inflammation of engrafted human temporal arteries, glucocorticoids were similarly selective in inhibiting Th17 cells and leaving Th1 cells unaffected. Conclusions-Two Clinical Perspective on p 915Glucocorticoids remain the gold standard of therapy; attempts to introduce steroid-sparing agents, including antitumor necrosis factor blockers, have not been successful. 3,4 Methotrexate may have minor benefits when given over prolonged periods. 5 In a double-blind, placebo-controlled study employing glucocorticoid pulse therapy, patients pulsed at diagnosis had fewer disease flares and discontinued therapy earlier than patients without initial pulse therapy. However, benefits of pulse glucocorticoids were delayed until 12 to 18 months into treatment. 6 Acetylsalicylic acid has a role as adjuvant therapy, partially by inhibiting inflammation and partially through antiplatelet effects. 7,8 Steroid withdrawal after Ͼ2 years of therapy is often accompanied by recurrence of inflammatory markers, and vascular inflammation persists despite glucocorticoid treatment. 9 -11 In essence, despite their prompt, impressive therapeutic effects, glucocorticoids fail to abrogate vasculitis. Improved disease management and avoidance of severe glucocorticoid side effects will require a better understanding of underlying immune abnormalities.Both the innate and adaptive immune system contribute to GCA pathogenesis. 12 Granulomatous inflammatory infiltrates composed of CD4 T cells, activated macrophages, and multinucleated giant cells induce intimal hyperplasia and luminal compromise. 13 In cell-depletion studies, dendritic cells (DCs) have emerged as the predominant antigen-presenting cell. 14,15 DCs are now recognized as an indigenous cell

Tocilizumab for the Treatment of Patients With Refractory Takayasu Arteritis

“…In GCA, the vascular infl ammation is primarily evoked by pro-inflammatory IL-17-secreting Th17 cells, which have been proven to be activated in active GCA patients. 29) Th17 lymphocytes infi ltrate large and medium-sized vessels by the chemotactic guidance of dendritic cells within the vascular walls.…”

“…29) IL-17 stimulates macrophages and vascular resident cells within the vascular walls such as fi broblasts, endothelial cells, and smooth muscle cells to produce pro-infl ammatory cytokines, including IL-6. This signaling circuit, mediated by IL-6 and Th17 cells, constitutes a positive feedback loop which could be a major potential target of TCZ in patients with GCA.…”

New insights into the pathogenesis of giant cell arteritis

“…These pleiotropic functions are achieved through the differentiation of naive CD4 + T cells in effector and/or memory cells of specialized phenotypes such as TH1, Th2, Th9 and Th17 cells [74]. In particular, compared with control subjects, patients with GCA show a massive artery infiltration by IFN-γ-secreting Th1 [75,76], IL-9-secreting Th9 [77] and IL-17-secreting Th17 lymphocytes [75][76][77]. IFN-γ levels in the GCA arteries are correlated with neo-angiogenesis and the outgrowth of the hyperplastic intima [78].…”

“…The receptor for IL-9 activates endothelial cells, induces the expression of mast cell proteases and activates neutrophils [77]. Recent data suggest that changes in the composition of the T-cell infiltrate allow the distinction of the arteritis into early and late GCA [75,76]. Th1 cells and Th17 cells seem in fact to predominate in early phases of GCA [76].…”

Nagyérvasculitisek korszerű kezelése

“…A patogén vascularis gyulladás kialakulásához aktivált T-sejtek szükségesek [52]. A citotoxikus T-lymphocytaasszociált fehérje-4 (cytotoxic T-lymphocyte-associated protein 4 -CTLA-4) a T-helper sejtek felszínén expreszszálódik és az antigén-prezentáló sejteken (antigen-presenting cell -APC) a CD80/CD60-hoz kompetitíven kötődve csökkenti az immunválaszt.…”