# The Immunobiology of Factor VIII

> **NIH NIH U54** · EMORY UNIVERSITY · 2021 · $373,686

## Abstract

Summary/Abstract (Project 2)
Anti-factor VIII (fVIII) alloantibodies (inhibitors), which can develop in patients with hemophilia A, limit the
therapeutic options for these patients, and can increase morbidity and mortality. Unlike most immunogens
encountered by a host, fVIII possesses no canonical innate immune ligands known to activate host immunity.
Despite this, nearly 30% of patients develop inhibitors following fVIII exposure. The inability to prevent inhibitor
formation largely stems from a fundamental lack of understanding regarding key features of fVIII that are
responsible for engaging and then activating host immunity. Our long-term goal is to define key features of fVIII
that initiate and then enhance inhibitor formation following subsequent fVIII exposures, in order to reduce or
prevent inhibitor development. Our central hypothesis is that key glycan signatures on fVIII facilitate initial host
recognition and response to fVIII, followed by the formation of anti-fVIII specific antibodies that in turn impact the
immunological outcome of subsequent fVIII exposures. Our hypothesis is formulated based on our recent
discovery that different fVIII products not only possess unique glycan signatures and distinct abilities to induce
inhibitors, but also that fVIII engagement by distinct anti-fVIII antibodies differentially impacts host immune cell
interactions. Thus, fVIII glycans and early anti-fVIII antibodies may represent key early regulators that
dictate the ultimate immune outcome of fVIII exposure. As unique glycan structures can differentially engage
distinct innate immune receptors, these results strongly suggest that individual fVIII glycoforms may differentially
impact host recognition and inhibitor development. Furthermore, the ability of distinct anti-fVIII antibodies to
differentially impact fVIII uptake by antigen presenting cells strongly suggests that the nature and epitope
specificity of early anti-fVIII antibodies likely shape the immunological consequence of subsequent fVIII exposure.
Finally, as non-human glycan epitopes present on certain fVIII products can be recognized by naturally occurring
anti-αGal antibodies, anti-αGal antibodies (stimulated by distinct microflora) may likewise bind fVIII and impact
the likelihood of inhibitor formation. We will use a complementary approach of biochemical analyses and in vivo
studies to define key features of fVIII responsible for inhibitor formation by testing the following specific aims:
Aim 1: Define the role of fVIII glycans on inhibitor formation. Aim 2: Define the role of anti-fVIII antibodies on fVIII
immune complex formation and inhibitor development. Aim 3: Define the impact of microbiota on anti-αGal
antibody development and subsequent inhibitor formation. We believe that successful completion of these aims
not only possesses the capacity to define key features of fVIII that regulate inhibitor formation, but may also
establish an important framework to develop rational appr...

## Key facts

- **NIH application ID:** 10147149
- **Project number:** 5U54HL141981-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sean R Stowell
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,686
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147149

## Citation

> US National Institutes of Health, RePORTER application 10147149, The Immunobiology of Factor VIII (5U54HL141981-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10147149. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*