# Molecular and cellular mechanisms of the FVIII immune response

> **NIH NIH U54** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $1,389,453

## Abstract

Overall Program-Abstract
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 application assembles a cross-disciplinary team of investigators with
appropriate track records, research interests and synergistic expertise to address unanswered mechanistic
questions related to FVIII immunogenicity. Our innovative scientific program is well-integrated, tests new
hypotheses and brings novel innovative technologies and investigators from a wide range of background to
better understand FVIII immunogenicity Project 1 (Arruda/Milone): Characterization of the functional
repertoire and ontogeny of FVIII humoral response across species. Studies using immunoproteomics and
genomics to help rigorously determine the ontogeny of the inhibitor producing cells in HA patients. They will
define the B cell repertoires responsible for the inhibitors in these patients and in longitudinal studies in HA
dogs with inhibitors. Moreover, the will define the emerging role of B cell survival cytokine in the context of
FVIII inhibitors. Project 2 (Herzog): In vivo Mechanism of Immune Response to Factor VIII. Utilizing
innovative strategies, including in vivo visualization techniques to define which antigen presenting cells (APCs)
are required for MHC II presentation to CD4+ T cells 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. Project 3 (Lillicrap): Influence of the host microbiome on the
mechanism of FVIII immunogenicity. Innovative preliminary observations linking elements of the gut
microbiome in determining the FVIII-specific immune response. Employing animal studies to investigate the
modulatory role of the host gut microbiome on the immune response to FVIII. 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 (Camire/Krishnaswamy): Factor VIII Immunogenicity-Biology and Structure.
This project centers on the role of various 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. A major hypothesis to be pursued
under this project relates to the role played by the interaction between FVIII and vWF as a modulator of
inhibitor formation. The multi-pronged approach contained in this integrated proposal derives from the
established areas of expertise of the participating investigators and provides a comprehensive investigation
into the multiple biological mechanisms underlying the immunogenicity of FVIII.

## Key facts

- **NIH application ID:** 10406331
- **Project number:** 5U54HL142012-05
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Rodney M Camire
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,389,453
- **Award type:** 5
- **Project period:** 2018-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406331

## Citation

> US National Institutes of Health, RePORTER application 10406331, Molecular and cellular mechanisms of the FVIII immune response (5U54HL142012-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10406331. Licensed CC0.

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