Projects

Project 1: Characterization of the Functional Repertoire and Ontogeny of FVIII Humoral Response Across Species

Project Leader: Valder Arruda and Michael Milone

Location: CHOP

Define the clonal repertoire and epitope specificity of circulating anti-FVIII antibodies in patients with HA.
Define the FVIII antibody repertoire and its dynamics in canine HA inhibitor models.
Investigate the role of B cell survival cytokines in inhibitor formation, epitope diversity and eradication.

Project Leader: Roland Herzog

Location: Indiana University

Define the mechanism of in vivo MHC II presentation of FVIII antigen to CD4+ T cells.
Define the mechanism of in vivo activation of FVIII-specific CD4+ T cells and B cells.
Determine the effects of signals derived from innate immune sensing and the microbiome on B and T cell activation against FVIII.

Project Leader: David Lillicrap

Location: Queens University

To evaluate the influence of modifications of the host gut microbiome on FVIII immunogenicity through antibiotic therapy, and changes in nutrient and microbiome metabolite content.
To characterize the mechanisms of FVIII immunogenicity in germ-free HA mice and in germ-free HA mice whose gut microbiome has been selectively repopulated with microbial subpopulations and distinct fecal transplants.
To determine the mechanisms of FVIII immunogenicity of orally administered FVIII.

Project Leader: Rodney Camire and Sriram Krishnaswamy

Location: CHOP

Evaluate and characterize the immune response to homologous coagulation factors V and VIII.
Determine whether distinct physiologic forms of FVIII differentially stimulate the immune response.
Use structural approaches to study the mechanism of inhibition of FVIII by inhibitors and vWF.

Skills Development Core Directors: Dr. Valder Arruda and Dr. Rodney M. Camire

Writing and Publications Director: Ronald Herzog and David Lillicrap