title: Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients.
abstract: Haemophilia A patients treated with human factor VIII (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-beta1-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-beta1-producing CD4(+) T blasts in patients with inhibitors. Patients without inhibitors had fVIII-induced IFN gamma- and TGF-beta1-, 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 produced TGF-beta1. 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 of Th2 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 ofTh3 cells in the response to fVIII may help to maintain tolerance to fVIII.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. huxxx057@umn.edu
authors.forename: Genlin
authors.initials: G
authors.lastname: Hu
authors.forename: Delan
authors.initials: D
authors.lastname: Guo
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Conti-Fine
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis*; D005169:Factor VIII / Q000276:immunology*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000276:immunology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D016207:Cytokines; C508598:IL4 protein, human; D053773:Transforming Growth Factor beta1; D015847:Interleukin-4; D007371:Interferon-gamma; D005169:Factor VIII