Th1 responses are more susceptible to infliximab-mediated immunosuppression than Th17 responses

Treatment with infliximab, a chimeric anti-tumor necrosis factor (TNF)-α antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-α and induces the apoptosis of transmembrane TNF-α-positive macrophages and T cells in the gut. Recently, T helper (Th)17, as well as Th1, responses have been implicated in the pathogenesis of IBD.

To clarify the effects of infliximab on Th1 and Th17 responses in vitro.

Naive CD4(+) T cells isolated from the peripheral blood of healthy volunteers were stimulated under Th1- or Th17-inducing conditions in the presence of 10 μg/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-γ, interleukin (IL)-17, and TNF-α in the culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Th1 and Th17 cells were immunostained with infliximab or control IgG1 and transmembrane TNF-α-positive cells were analyzed by flow cytometry. Annexin V staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays were conducted in order to analyze the percentage of apoptotic cells.

Both Th1 and Th17 cells expressed soluble and transmembrane TNF-α abundantly. Although infliximab suppressed IFN-γ secretion by Th1 cells and IL-17 secretion by Th17 cells, the level of the former was more profound than the latter. Infliximab increased annexin V- and TUNEL-positive apoptotic cells under Th1-inducing conditions, but not under Th17-inducing conditions.

Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-γ production by Th1 cells was more profoundly suppressed than IL-17 secretion by Th17 cells. Th1 responses were more susceptible to infliximab-mediated apoptosis than Th17 responses. Our results clarify a new mechanism of action of infliximab.