Center for the Investigation of Factor FVIII Immunogenicity



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The Center for the Investigation of Factor VIII Immunogenicity at CHOP is part of a concerted multidisciplinary effort funded by a U54 grant award from the National Heart, Lung, and Blood Institute (NHLBI) to overcome the serious challenge of the formation of FVIII inhibitors in patients with congenital hemophilia. The collaborators’ goal is gain new insights from diverse areas of science — structural biology, immunology, genomics, and cancer immunotherapy — to answer the question: Why is FVIII so immunogenic? CHOP’s center is leading four projects to broaden researchers’ understanding of why 20 percent to 30 percent of patients with hemophilia A recognize infused FVIII as a foreign protein, which prevents the replacement therapy from working.

Research Project Highlights

Project one: New high definition technologies will help researchers to identify which specific parts of the FVIII protein are more or less immunogenic, and they will compare their findings in studies of a naturally occurring mutation of FVIII in dogs to see if humans and canines recognize the protein as foreign in the same way. In addition, researchers will build upon preliminary studies that suggest a protein needed for B cell survival, called B cell activating factor (BAFF), could be a new therapeutic target for hemophilia.

Project two: Using in vivo visualization techniques to track where the immune response that triggers B and T cell activation against FVIII takes place and innate immune responses, scientists want to pinpoint ways to block immune signaling.

Project three: Environmental factors may influence the development of inhibitory antibodies to FVIII, so researchers are studying possible connections between the gut microbiome and the immune response to FVIII.

Project four: Researchers are collaborating to better understand the molecular characterization and properties of the FVIII protein driving the immune response. They also are comparing their findings with the inhibitor formation to a similar, not identical, protein called factor V.

The investigators will share their progress and findings with two other FVIII centers that the NHLBI designated, Emory University and Temple University, in order to gain new insights and inspire collaboration. CHOP and Penn investigators participating in the projects include: Valder Arruda, MD, PhD; Michael Milone, MD, PhD; Benjamin Samelson-Jones, MD, PhD; Bhavya Doshi, MD; Vijay Bhoy, MD; Rodney Camire, PhD; Sriram Krishnaswamy, PhD; Lindsey George, MD; and Shekar Kumar, PhD.