title: Effect of factor VIII concentrate on antigen-presenting cell (APC)/T-cell interactions in vitro: relevance to inhibitor formation and tolerance induction.
abstract: Inhibitor formation in patients with haemophilia receiving factor VIII (FVIII) concentrate is a common problem requiring tolerance induction therapy. Immune tolerance is dependent on defective T cell/antigen-presenting cell (APC) interactions and inhibitor antibody formation is associated with effective T-cell/B-cell interaction. We studied the expression of the cell-surface molecules involved with these interactions using multiparameter flow cytometry and a whole blood stimulation assay-phytohaemaglutinin (PHA) to activate T cells and Escherichia coli lipopolysaccharide (LPS) to activate monocytes and B cells. Up-regulation of T-cell co-stimulatory receptors CD11a, CD40 ligand (CD40L) and CTLA4 were inhibited in a dose-dependent manner by plasma-derived (pd)FVIII, but CD28 was unchanged. Up-regulation of monocyte and B-cell co-stimulatory ligands CD4O, B7-1 (CD80) and B7-2 (CD86) were also inhibited in a dose-dependent manner by pdFVIII, but LFA-3 (CD58) was unchanged. The combined inhibitory effect of prednisolone, an immunosuppressive agent used in several tolerance induction protocols, with pdFVIII on co-stimulatory molecules, was additive. There was no significant alteration in T-cell/APC adhesion or co-stimulatory molecules noted in the presence of recombinant (rh)FVIII concentrate. The inhibitory effect of pdFVIII on molecules involved in interaction between T cells and APCs may result in immune tolerance in recipients of pdFVIII concentrate. The inhibitory effect of pdFVIII on CD40/CD40L up-regulation may result in defective antibody formation. We now provide evidence that the use of pdFVIII, through interfering with APC/T-cell interactions, may be more appropriate than rhFVIII for tolerance induction.
authors.affiliation: Haematology Department, Women's and Children's Hospital, North Adelaide, South Australia. hodgeg@mail.wch.sa.gov.au
authors.forename: G
authors.initials: G
authors.lastname: Hodge
authors.forename: P
authors.initials: P
authors.lastname: Han
mesh_terms: D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology*; D015703:Antigens, CD; D001402:B-Lymphocytes / Q000276:immunology; D051940:B7-2 Antigen; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D006467:Hemophilia A / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D011239:Prednisolone / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; C497964:CD86 protein, human; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D005169:Factor VIII; D011239:Prednisolone