Th1 Responses Are More Susceptible to Infliximab-Mediated Immunosuppression Than Th17 Responses

Background Treatment with infliximab, a chimeric anti-tumor necrosis factor (TNF)-alpha antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-alpha and induces the apoptosis of transmembrane TNF-alpha-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. Aims To clarify the effects of infliximab on Th1 and Th17 responses in vitro. Methods 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 mu g/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-gamma, interleukin (IL)-17, and TNF-alpha 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-alpha-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. Results Both Th1 and Th17 cells expressed soluble and transmembrane TNF-alpha abundantly. Although infliximab suppressed IFN-gamma 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. Conclusions Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-gamma 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.