Ex Vivo Overactivation of Lymphocyte Subsets in Fibrotic Hypersensitivity Pneumonitis Is Blunted by a Sphingosine-1-Phosphate Receptor Ligand

Lymphocytes are central to the pathogenesis of hypersensitivity pneumonitis and a strong body of evidence supports that lymphocytes are modulated by sphingosine-1-phosphate receptor-modifying drugs. This exploratory study aimed to determine if a pharmacological sphingosine-1-phosphate receptor ligand interfered with the activation of lymphocytes obtained from fibrotic hypersensitivity pneumonitis patients. Peripheral blood mononuclear cells of 12 patients and 10 control subjects were submitted to CD3/CD28 stimulation, isolated B cells were incubated with a TLR9 ligand; and we tested how these stimulations were impacted by ozanimod, a sphingosine-1-phosphate receptor ligand. T cell and B cell subsets from patients overexpressed CD69 and cytokines such as TNF and IL-4 in response to CD3/CD28 stimulation, compared to controls. In patients with fibrotic hypersensitivity pneumonitis, ozanimod alleviated CD3/CD28 induction of CD69, IL-4, and TNF in CD8, but not CD4 T cells. In isolated B cells stimulated with a TLR9 ligand, ozanimod reduced cell surface expression of CD69, CD86, and CD40, as well as TNF and IL-6 accumulation in supernatant. We conclude that lymphocyte subsets are functionally impacted in patients with fibrotic hypersensitivity pneumonitis and that ozanimod can interfere ex vivo with the overactivation of B cells and CD8 T cells in response to specific stimuli.