Blocking GM-CSF receptor α with mavrilimumab reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with giant cell arteritis

Abstract

BackgroundEffective and safe therapies are needed for the treatment of patients with giant cell arteritis (GCA). Emerging as a key cytokine in inflammation, granulocyte-macrophage colony stimulating factor (GM-CSF) may play a role in promoting inflammation in GCA.ObjectivesTo investigate expression of GM-CSF and its receptor in arterial lesions from patients with GCA. To analyse activation of GM-CSF receptor-associated signalling pathways and expression of target genes. To evaluate the effects of blocking GM-CSF receptor α with mavrilimumab in ex vivo cultured arteries from patients with GCA.MethodsQuantitative real time PCR, in situ RNA hybridisation, immunohistochemistry, immunofluorescence and confocal microscopy, immunoassay, western blot and ex vivo temporal artery culture.ResultsGM-CSF and GM-CSF receptor α mRNA and protein were increased in GCA lesions; enhanced JAK2/STAT5A expression/phosphorylation as well as increased expression of target genes CD83 and Spi1/PU.1 were observed. Treatment of ex vivo cultured GCA arteries with mavrilimumab resulted in decreased transcripts of CD3ε, CD20, CD14 and CD16 cell markers, and reduction of infiltrating CD16 and CD3ε cells was observed by immunofluorescence. Mavrilimumab reduced expression of molecules relevant to T cell activation (human leukocyte antigen-DR [HLA-DR]) and Th1 differentiation (interferon-γ), the pro-inflammatory cytokines: interleukin 6 (IL-6), tumour necrosis factor α (TNFα) and IL-1β, as well as molecules related to vascular injury (matrix metalloprotease 9, lipid peroxidation products and inducible nitric oxide synthase [iNOS]). Mavrilimumab reduced CD34 + cells and neoangiogenesis in GCA lesions.ConclusionThe inhibitory effects of mavrilimumab on multiple steps in the GCA pathogenesis cascade in vitro are consistent with the clinical observation of reduced GCA flares in a phase 2 trial and support its development as a therapeutic option for patients with GCA.

Advances in the Treatment of Giant Cell Arteritis

“…Interestingly, MAV decreased intimal thickness, T-cell infiltration, and neo-vessel formation in a human artery-SCID (severe combined immunodeficiency) chimera model [ 105 ]. In this line, Corbera-Bellalta et al have recently demonstrated that MAV reduces infiltrating cells, pro-inflammatory markers and neoangiogenesis in ex vivo cultured arteries from patients with GCA [ 106 ]. In fact, MAV reduced the expression of molecules relevant to T-cell activation (HLA-DR) and Th1 differentiation (IFN-γ), the pro-inflammatory cytokines IL-6, TNFα and IL-1β, as well as molecules related to vascular injury (MMP-9, lipid peroxidation products and inducible nitric oxide synthase).…”

“…In fact, MAV reduced the expression of molecules relevant to T-cell activation (HLA-DR) and Th1 differentiation (IFN-γ), the pro-inflammatory cytokines IL-6, TNFα and IL-1β, as well as molecules related to vascular injury (MMP-9, lipid peroxidation products and inducible nitric oxide synthase). Furthermore, MAV reduced CD34+ cells and neoangiogenesis in GCA lesions [ 106 ].…”

Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial

“…Current medications for GCA (eg, glucocorticoids and tocilizumab) target primarily the CD4 + T h 17 immune response, possibly leaving residual CD4 + T h 1 pathway activity, which may explain why a sizeable proportion of patients flare with these treatments. In contrast, GM-CSF blockade with mavrilimumab may address the pathogenic mechanisms of GCA more comprehensively via its demonstrated suppressive effects on macrophages, CD4 + T h 17 cells, and CD4 + T h 1 cells, including downregulation of IFNγ expression 22 23. However, further mechanistic research linked to clinical outcomes is needed before firm conclusions can be drawn.…”

“…Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional cytokine that modulates the biology of dendritic cells, CD4 + T-cells and macrophages 18. Preclinical research has implicated GM-CSF in the pathogenesis of GCA 19–22. GM-CSF, its receptor, and downstream signalling molecules are expressed by immune and endothelial cells in temporal arteries from patients 19–22.…”

“…[19][20][21][22] GM-CSF, its receptor, and downstream signalling molecules are expressed by immune and endothelial cells in temporal arteries from patients. [19][20][21][22] Furthermore, GM-CSF receptor blockade in cultured temporal arteries resulted in decreased expression of dendritic cell, T-cell, and macrophage markers along with downregulation in transcription of genes associated with the T h 1 and T h 17 immune responses (eg, interferon-γ and interleukin-6). 20 22 In a mouse model of vascular inflammation, GM-CSF inhibition was associated with reduced arterial inflammation and remodelling.…”