CHOP Center

The formation of inhibitory antibodies to infused factor VIII (FVIII) remains one of the most challenging complications of protein replacement therapy in hemophilia A (HA) patients and it is associated with increase morbidity and mortality. This U54 The Children’s Hospital of Philadelphia (CHOP) Factor VIII center application assembles a cross-disciplinary team of investigators with the research interests and synergistic expertise to address unanswered mechanistic questions related to FVIII immunogenicity. The (CHOP) program tests new hypotheses and brings novel innovative technologies and investigators from a wide range of background to better understand FVIII immunogenicity.

• Project 1 (Drs. Arruda and Milone): Characterization of the Functional Repertoire and Ontogeny of FVIII Humoral Response across Studies using immunoproteomics and genomics to help rigorously determine the ontogeny of the inhibitor producing cells in HA patients will be conducted. The B cell repertoires responsible for the inhibitors in these patients and in longitudinal studies in HA dogs with inhibitors will be defined. Moreover, this study will characterize the emerging role of B cell survival cytokine in the context of FVIII inhibitors.
• Project 2 (Dr. Herzog): In vivo Mechanism of Immune Response to Factor VIII. In vivo visualization techniques will be employed to define antigen presenting cells (APCs) that are required for MHC II presentation to CD4+ T cells. Additionally, how these APCs interact to prime FVIII-specific CD4+ T cells, which subsets of CD4+ T cells are induced to promote B cell activation, and how innate immune signaling and the microbiome may alter these events will be investigated.
• Project 3 (Dr. Lillicrap): Influence of the Host Microbiome on the Mechanism of FVIII Immunogenicity. Preliminary observations linking elements of the gut microbiome in determining the FVIII-specific immune response have been made. Animal models to investigate the modulatory role of the host gut microbiome on the immune response to FVIII will be employed. This novel line of investigation is proposed to reveal a critical link between environmental factors and variability in the development of inhibitory antibodies to FVIII.
• Project 4 (Drs. Camire and Krishnaswamy): Factor VIII Immunogenicity-Biology and Structure. This project centers on the role of molecular species relevant to the biological life cycle of FVIII in regulating the immune response and inhibitor development using biochemical and structural biological approaches to focus on the properties of FVIII driving the immune response. The role played by the interaction between FVIII and vWF as a modulator of inhibitor formation will be investigated. 

Public Health Relevance

Pathogenic antibody formation against infused factor VIII in hemophilia A patients is a major complication. This U54 provides a comprehensive investigation of the multiple facets of the immune response to factor VIII. This will be achieved by investigators with diverse and complementary areas of expertise.