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Anti-factor VIII antibodies of hemophiliac patients are frequently directed
towards nonfunctional determinants and do not exhibit isotypic restriction
JG Gilles, J Arnout, J Vermylen and JM Saint-Remy
Allergy and Clinical Immunology Unit, Universite Catholique de Louvain,
Brussels, Belgium.
A significant proportion of hemophilia A patients receiving transfusions of
factor VIII (FVIII) develop a specific antibody response towards FVIII.
These antibodies are usually detected by assays in which they inhibit the
function of the molecule, such as the Bethesda clotting test. We have
prepared anti-FVIII antibodies by specific immunoadsorption from the plasma
of four hemophiliacs with stable inhibitor levels. The isotypic
distribution of such antibodies was determined and their capacity to bind
to insolubilized FVIII was compared with their inhibitory activity in two
functional assays, namely, the Bethesda assay and a chromogenic assay. In
addition, the FVIII epitope specificity was determined by competition with
monoclonal antibodies for the binding to insolubilized FVIII. We show here
that (1) anti-FVIII antibodies are not isotypically restricted; thus, a
significant proportion of specific IgG2 was found; (2) antibodies are
frequently directed towards epitopes of FVIII that are not directly
involved in the function of the molecule and therefore escape detection in
the Bethesda method or chromogenic assay; and (3) each patient shows a
unique pattern of FVIII epitope recognition. We conclude that evaluation of
anti-FVIII antibodies by a functional method does not provide an accurate
evaluation of the specific antibody response. These findings have important
implications for the comparison of the immunogenicity of FVIII molecules
produced by different technologies and for the development of methods to
control anti-FVIII antibody production.
Volume 82,
Issue 8,
pp. 2452-2461,
10/15/1993
Copyright © 1993 by The American Society of Hematology
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