Hypothesis for the control of clotting factor VIII inhibitory antibodies by decreasing potency of helper T-cell-recognized epitopes in factor VIII.
The study of the immunobiology of FVIII inhibitors may lead to new therapies for this potentially severe complication of haemophilia A and to new principles for the use of therapeutic proteins. In order to characterize the idiotype-anti-idiotype networks regulating FVIII inhibitors, we developed rabbit anti-idiotypic sera to 7 murine inhibitors and found at least 12 independent FVIII loci to which inhibitors could be raised. Rabbit antisera to the FVIII peptide, Ser1687-Thr1695, characterized one functional site to which about 46% of patients' inhibitor sera reacted. The multiplicity of inhibitor-recognized epitopes in FVIII makes it impractical, at the present time, to develop clinically useful specific anti-idiotypic therapies for FVIII inhibitors. Alternatively, one might induce genomic mutations in recombinant FVIII molecules to decrease immunogenicity of epitopes recognized by T helper cells. Methods to design such altered therapeutic proteins are presented, based on changing the longitudinal hydrophobic strip-of-helix which is in or near many T-cell-presented epitopes.
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000939:Epitopes; D005169:Factor VIII / Q000037:antagonists & inhibitors* / Q000276:immunology*; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D051379:Mice; D011817:Rabbits; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D000939:Epitopes; D007106:Immune Sera; D005169:Factor VIII