Disappearance of inhibitor to factor VIII in HIV‐infected hemophiliacs with progression to AIDS or severe ARC

Abstract

The spontaneous disappearance of the inhibitor to factor VIII (FVIII) was observed in two human immunodeficiency virus (HIV)-infected men with hemophilia A. Both men had end-stage HIV infection, one with acquired immune deficiency syndrome (AIDS) and one with severe AIDS-related complex (ARC). Loss of the inhibitor was associated with a fall in T4 helper lymphocytes to less than 100 per mm3 in both patients. Subsequent spontaneous and traumatic hemorrhages were treated successfully with standard doses of FVIII concentrate, resulting in adequate FVIII:C levels and good hemostasis. The mechanism by which the anti-FVIII inhibitor disappears is not known, but it is likely to be related to a quantitative decline in T4 cell number.

CD4+ T-cell epitopes associated with antibody responses after intravenously and subcutaneously applied human FVIII in humanized hemophilic E17 HLA-DRB1*1501 mice

“…6,7 The identification of CD4 ϩ T-cell epitopes of FVIII has therefore been the subject of previous studies in mice and humans. [11][12][13][14][15][16][17][18] We used humanized E17 HLA-DRB1*1501 mice to identify CD4 ϩ T-cell epitopes of FVIII in the context of HLA-DRB1*1501.…”

“…4,5 In line with this perception, several lines of evidence have supported the involvement of CD4 ϩ T cells in the generation of antibody responses against FVIII in patients with hemophilia A and in murine hemophilia models. 6,7 CD4 ϩ T cells express T-cell receptors that recognize antigen-derived peptides (CD4 ϩ T-cell epitopes) presented by MHC class II molecules, which are expressed on specialized antigen-presenting cells. 8 Structural features of both the MHC class II molecule and the peptide determine the specificity of CD4 ϩ T cells that can bind to the MHC class II-peptide complex.…”

A role for thrombin in the initiation of the immune response to therapeutic factor VIII

“…The immune response to FVIII is T-cell dependent in humans [8][9][10][11] and mice. 12,13 A typical T cell-dependent antibody response begins when an immature antigen-presenting cell (APC; eg, dendritic cell) encounters a "danger" signal.…”

Factor VIII brand and immunogenicity

“…2,3 Evidence pointing in the same direction has come from comparisons of ALL at diagnosis and relapse, where microdeletions and mutations present only at relapse have been backtracked to minor subclones in the corresponding diagnostic sample. 4,5 Genetic heterogeneity at diagnosis may be one of the underlying factors when the leukemia relapses, because small subclones may survive the treatment that eradicates the main diagnostic clone and subsequently lead to disease recurrence.…”

“…3 The inhibitor alloantibody binds to infused (foreign) factor VIII, neutralizes its activity, and disrupts normal hemostasis. For an affected patient, the burden of disease is significant: uncontrolled bleeding results in twice the hospitalizations 4 and 10 times the cost.…”