Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients

HaemophiliaA patients treated with human factorVIII (fVIII) may develop antibody (Ab) inhibitors to fVIII. FVIII-specific CD4(+)T cells are common in haemophilia A patients, but also in healthy subjects who do not have a sustained anti-fVIII Ab response. Here, we examined the fVIII-induced IFN gamma-, IL-4- and TGF-beta 1-producing CD4(+) T blasts by culturing peripheral blood mononuclear cells (PBMC) from controls and patients with recombinant fVIII. FVIII exposure significantly increased IFN gamma- and IL-4-, but not TGF-beta I -producing CD4(+)T blasts in patients with inhibitors. Patients without inhibitors had fVIII-induced IFN gamma and TGF-beta 1-,but not IL-4-producing CD4(+)T blasts. Controls did not have IL-4-producing CD4(+) T blasts. However, controls whose PMBC proliferated in response to fVIII had fVIII-induced CD4(+) T blasts that produced IFN-gamma, the number of which correlated with the intensity of the proliferative response to fVIII of their PMBC, whereas controls whose PMBC did not proliferate to fVIII had predominantly fVIII-induced CD4(+)T blasts that producedTGF-beta 1. The presence in controls and patients without inhibitors of fVIII-induced IFN-gamma-producing CD4(+)T cells, but not IL-4-producing CD4(+)T cells,which are abundant in inhibitor patients, suggests a role of Th1 cells in initiating the immune response to fVIII, and ofTh2 cells in the development of strong inhibitor production. The polarized high ratios of Th3/Th1 and Th3/Th2 in controls and patients without inhibitors suggest that a preponderance of Th3 cells in the response to fVIII may help to maintain tolerance to fVIII.