Recognition of coagulation factor VIII by CD4+ T cells of healthy humans

Abstract

Summary. Hemophilia A patients treated with coagulation factor (F)VIII may develop an anti-FVIII immune response. Anti-FVIII antibodies may occur also in healthy subjects. To understand the extent to which an immune response to FVIII occurs in healthy subjects, we investigated the proliferative response of blood CD4 T cells from 90 blood donors to FVIII and to pools of overlapping synthetic peptides spanning the sequences of individual FVIII domains (A1±A3, C1±C2). Most subjects responded to FVIII and several FVIII domains. Men had stronger responses to FVIII than women, and older subjects than younger subjects. The domain-induced responses were weaker than the FVIII-induced responses, yet their intensity in individual subjects correlated with that of the response to FVIII. We examined whether Th1 and/or Th2 cells responded to FVIII in 68 subjects, by determining the CD4 T cells that secreted interferon-g (IFN-g) or interleukin (IL)-5 after stimulation with FVIII: 25 subjects had FVIII-speci®c IFN-g-secreting cells, and seven of them had also FVIIIspeci®c IL-5-secreting cells. None had only IL-5-secreting cells. Thus, a CD4 T cell response to FVIII, which ®rst involves Th1 cells, is common among subjects with a normal procoagulant function.

Quantitation of anti–factor VIII antibodies in human plasma

“…The incidence of autoantibodies in the healthy population examined by our assay is at the low end of reported frequency (0%-36%) for healthy individuals. [41][42][43][44][45][46] The high incidence of antibodies in healthy donors reported by others might arise due to the lack of nonspecific binding controls in the detection assays used to analyze the samples. Inclusion of a binding control in our assay largely eliminates from analyses signals from the nonspecific binding of plasma proteins.…”

CD4 T cells specific for factor VIII are present at high frequency in healthy donors and comprise naïve and memory cells

“…[12][13][14] However, no clear difference was found in terms of intensity of the anti-FVIII response or epitope specificity between T cells from healthy individuals and patients with HA who had developed anti-FVIII alloantibodies. 12,14 To shed some light on the mechanisms underlying T-cell tolerance to FVIII under physiological conditions, we quantified and characterized naturally occurring FVIII-specific CD4…”

Recombinant and plasma-derived factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A mice

“…Our findings support the results obtained by Hu et al and Sasgary et al and indicate that rFVIII induces the production of IL-2, IL-10, and IFN-␥ by CD4 ϩ T cells. 26,28,29 We further investigated the importance of IFN-␥ on the formation of FVIII inhibitors by pretreating hemophilic mice with neutralizing anti-IFN-␥ antibodies before and after the 4 weekly 2-IU rFVIII treatments. The anti-IFN-␥-treated mice showed a 30% reduction in FVIII inhibitor formation in comparison to isotype controltreated mice (data not shown).…”