Mechanism of the immune response to human factor VIII in murine hemophilia A.
Mice genetically deficient in factor VII (fVIII) are a model of hemophilia A. As a first step to reproduce in this mouse model what occurs over time in hemophilia A patients treated with human fVIII (hfVIII), we have investigated the time course and the characteristics of their immune response to hfVIII, after multiple intravenous injections. Anti-hfVIII antibodies appeared after four to five injections. They were IgG1 and to a lesser extent IgG2, indicating that they were induced by both Th2 and Th1 cells. Inhibitors appeared after six injections. CD4+ enriched splenocytes from hfVIII-treated mice proliferated in response to fVIII and secreted IL-10: in a few mice they secreted also IFN-gamma and in one mouse IL-4, but never IL-2. A hfVIII-specific T cell line derived from hfVIII-treated mice secreted both IL-4 and IFN-gamma, suggesting that it included both Th1 and Th2 cells. CD4+ enriched splenocytes of hfIII-treated mice recognized all hfVIII domains. Thus, hemophilic mice develop an immune response to hfVIII administered intravenously similar to that of hemophilia A patients. Their anti-hfVIII antibodies can be inhibitors and belong to IgG subclasses homologous to those of inhibitors in hemophilic patients; their anti-hfVIII CD4+ cells recognize a complex repertoire and both Th1 and Th2 cytokines, and especially IL-10, may drive the antibody synthesis.
Wu
H
H
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis-St Paul, 55108, USA.
Reding
M
M
Qian
J
J
Okita
D K
DK
Parker
E
E
Lollar
P
P
Hoyer
L W
LW
Conti-Fine
B M
BM
D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000097:blood; D000921:Antibody-Producing Cells / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes / Q000032:analysis; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology; D006467:Hemophilia A / Q000097:blood* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013997:Time Factors
D000906:Antibodies; D016207:Cytokines; D000939:Epitopes; D007074:Immunoglobulin G; D016753:Interleukin-10; D005169:Factor VIII