Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A
Nature Medicine, Volume 19, No. 10, Year 2013
Notification
URL copied to clipboard!
Description
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. © 2013 Nature America, Inc. All rights reserved.
Authors & Co-Authors
Pandey, Gouri Shankar
United States, Bethesda
Fda Center for Biologics Evaluation and Research
Yanover, Chen
United States, Seattle
Fred Hutchinson Cancer Research Center
Israel, Haifa
Ibm Research - Haifa
Miller-Jenkins, Lisa M.
United States, Rockville
National Cancer Institute Nci
Garfield, Susan H.
United States, Rockville
National Cancer Institute Nci
Cole, Shelley A.
United States, San Antonio
Texas Biomedical Research Institute
Curran, Joanne E.
United States, San Antonio
Texas Biomedical Research Institute
Moses, Eric Keith
United States, San Antonio
Texas Biomedical Research Institute
Australia, Perth
The University of Western Australia
Rydz, Natalia
Canada, Kingston
Queen’s University
Simhadri, Vijaya
United States, Bethesda
Fda Center for Biologics Evaluation and Research
Kimchi-Sarfaty, Chava
United States, Bethesda
Fda Center for Biologics Evaluation and Research
Lillicrap, David P.
Canada, Kingston
Queen’s University
Viel, Kevin R.
United States, Atlanta
Histonis Inc.
Przytycka, Teresa M.
United States, Bethesda
National Library of Medicine Nlm
Pierce, Glenn F.
United States, Los Angeles
Va Greater Los Angeles Healthcare System
United States, Los Angeles
Keck School of Medicine of Usc
United States, Los Angeles
David Geffen School of Medicine at Ucla
Howard, Tom E.
United States, Bethesda
Fda Center for Biologics Evaluation and Research
Sauna, Zuben E.
United States, Cambridge
Biogen Inc.
Lusher, Jeanne
United States, Detroit
Wayne State University
Chitlur, Meera B.
United States, Augusta
Medical College of Georgia
Ameri, Afshin
United States, Augusta
Medical College of Georgia
Natarajan, Kavita
United States, Jackson
University of Mississippi Medical Center
Iyer, Rathi V.
United States, Evanston
Northwestern University
Thompson, Alexis A.
United States, Birmingham
The University of Alabama at Birmingham
Watts, Raymond G.
United States, Atlanta
Emory University
Kempton, Christine L.
United States, Washington, D.c.
Georgetown University
Kessler, Craig M.
United States, Richmond
Virginia Commonwealth University
Barrett, John C.
United States, Richmond
Virginia Commonwealth University
Martin, Erica J.
United States, Richmond
Virginia Commonwealth University
Key, Nigel S.
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Kruse-Jarres, Rebecca
United States, New Orleans
Tulane University
Lessinger, Cindy
United States, New Orleans
Tulane University
Pratt, Kathleen P.
United States, Seattle
Puget Sound Blood Center
Josephson, Neil C.
United States, Seattle
Puget Sound Blood Center
McRedmond, Kevin
United States, Columbia
Palmetto Health
Withycombe, Janice
United States, New York
Mount Sinai
Walsh, Christopher E.
United States, Seattle
Seattle Children's Hospital
Matthews, Dana
South Africa, Johannesburg
University of the Witwatersrand
Mahlangu, Johnny Ndoni
South Africa, Congella
King Edward Viii Hospital
Krause, Amanda
South Africa, Congella
King Edward Viii Hospital
Schwyzer, Rosemary
South Africa, Congella
King Edward Viii Hospital
Thejpal, Rajendra
South Africa, Bloemfontein
University of the Free State
Rapiti, Nadine
South Africa, Bloemfontein
University of the Free State
Goga, Yasmin
South Africa, Bloemfontein
University of the Free State
Coetzee, Marius
United States, Burlington
University of Vermont
Stones, David
United States, Burlington
University of Vermont
Mann, Kenneth G.
United States, San Antonio
Texas Biomedical Research Institute
Butenas, Saulius
United States, San Antonio
Texas Biomedical Research Institute
Almasy, Laura A.
United States, Los Angeles
University of California, Los Angeles
Blangero, John C.
United States, Los Angeles
University of California, Los Angeles
Carless, Melanie A.
United States, Los Angeles
University of California, Los Angeles
Raja, Rajalingam
United States, Los Angeles
University of California, Los Angeles
Reed, Elaine F.
United States, Los Angeles
University of California, Los Angeles
Statistics
Citations: 60
Authors: 51
Affiliations: 32
Identifiers
Doi:
10.1038/nm.3270
ISSN:
10788956
e-ISSN:
1546170X
Research Areas
Genetics And Genomics
Study Design
Cross Sectional Study