Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A

Gouri Shankar Pandey, Chen Yanover, Lisa M. Miller-Jenkins, Susan Garfield, Shelley A. Cole, Joanne E. Curran, Eric K. Moses, Natalia Rydz, Vijaya Simhadri, Chava Kimchi-Sarfaty, David Lillicrap, Kevin R. Viel, Teresa M. Przytycka, Glenn F. Pierce, Tom E. Howard*, Zuben E. Sauna, Jeanne Lusher, Meera Chitlur, Afshin Ameri, Kavita NatarajanRathi V. Iyer, Alexis A. Thompson, Raymond G. Watts, Christine L. Kempton, Craig Kessler, John C. Barrett, Erica J. Martin, Nigel Key, Rebecca Kruse-Jarres, Cindy Lessinger, Kathleen P. Pratt, Neil Josephson, Kevin McRedmond, Janice Withycombe, Christopher Walsh, Dana Matthews, Johnny Mahlangu, Amanda Krause, Rosemary Schwyzer, Rajendra Thejpal, Nadine Rapiti, Yasmin Goga, Marius Coetzee, David Stones, Kenneth Mann, Saulius Butenas, Laura Almasy, John Blangero, Mel Carless, Rajalingam Raja, Elaine Reed

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


Neutralizing antibodies (inhibitors) to replacement factor VIII (FVIII, either plasma derived or recombinant) impair the effective management of hemophilia A. Individuals with hemophilia A due to major deletions of the FVIII gene (F8) lack antigenically cross-reactive material in their plasma ("CRM-negative"), and the prevalence of inhibitors in these individuals may be as high as 90%. Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-positive, and their overall prevalence of inhibitors is <10% (ref. 2). Individuals with the F8 intron 22 inversion (found in ∼50% of individuals with severe hemophilia A) have been grouped with the former on the basis of their genetic defect and CRM-negative status. However, only ∼20% of these individuals develop inhibitors. Here we demonstrate that the levels of F8 mRNA and intracellular FVIII protein in B lymphoblastoid cells and liver biopsies from individuals with the intron 22 inversion are comparable to those in healthy controls. These results support the hypothesis that most individuals with the intron 22 inversion are tolerized to FVIII and thus do not develop inhibitors. Furthermore, we developed a new pharmacogenetic algorithm that permits the stratification of inhibitor risk for individuals and subpopulations by predicting the immunogenicity of replacement FVIII using, as input, the number of putative T cell epitopes in the infused protein and the competence of major histocompatibility complex class II molecules to present such epitopes. This algorithm showed statistically significant accuracy in predicting the presence of inhibitors in 25 unrelated individuals with the intron 22 inversion.

Original languageEnglish
Pages (from-to)1318-1324
Number of pages7
JournalNature Medicine
Issue number10
StatePublished - Oct 2013
Externally publishedYes


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