# The Role of Type I Interferons in Factor VIII Inhibitor Formation

> **NIH NIH K08** · EMORY UNIVERSITY · 2022 · $151,092

## Abstract

Project Summary/Abstract
 Anti-factor VIII (FVIII) alloantibodies, known as inhibitors, develop in 20-30% of patients with severe
hemophilia A following therapy with FVIII infusion. This, in turn, makes bleeding difficult to control and prevent,
resulting in increased morbidity and mortality, increased cost of care and decreased quality of life. Despite the
negative consequences of inhibitor formation, no prophylactic therapy is currently available to predict or prevent
inhibitor development. This largely stems from a fundamental lack of understanding regarding key pathways that
initiate this process. In order to effectively understand risk factors that may predict the likelihood of inhibitor
development and then prevent this process in at-risk patients, our long-term goal is to identify the mechanisms
that initiate and then orchestrate inhibitor formation, in order to predict and then prevent the development of anti-
FVIII alloantibodies in patients with hemophilia A. This is in line with a key priority identified by the NHLBI to
identify key immune targets that may be used to prevent inhibitor formation.
 Addressing these pertinent clinical problems, recent data in a pre-clinical model shows that both depletion
of marginal zone (MZ) B cells and genetic deletion of type I IFN receptors (IFNRs) significantly reduces
alloantibody formation following FVIII exposure. Thus, MZ B cells and type I IFNs represent key initiating
pathways for inhibitor development. The hypothesis moving forward is that type I interferons (IFNs) directly
enhance the ability of FVIII-specific MZ B cells to generate anti-FVIII antibodies, traffic antigen to the B cell
follicle, and directly activate CD4 T cells following FVIII exposure and that patients with inhibitors display an
enhanced type I IFN gene signature. Using both a clinical and pre-clinical model, the first aim is to define the
role of type I IFNs on MZ B cell-mediated antibody formation following FVIII exposure and determine the type I
IFN signature in patients with hemophilia A with and without inhibitors. The second aim focuses on defining the
role of type I IFNs on MZ B cell antigen trafficking and activation of CD4 T cells. These studies possess the
capacity to not only provide new insight into key aspects of inhibitor formation, but may also provide an important
framework to develop rational approaches to prophylactically predict and prevent inhibitor development in
patients with hemophilia A.
 In addition to the important research aims outlined above, this proposal will allow for advanced instruction
in immunology relevant to the field of hematology as well as training in novel research techniques including RNA
sequencing and human sample processing. This will take place in the environment of a prestigious academic
institution with many opportunities for collaboration and mentorship. Completion of the outlined research and
career development goals will facilitate successful advancement to a career as an i...

## Key facts

- **NIH application ID:** 10482349
- **Project number:** 5K08HL151962-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Patricia Elizabeth Zerra
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $151,092
- **Award type:** 5
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10482349

## Citation

> US National Institutes of Health, RePORTER application 10482349, The Role of Type I Interferons in Factor VIII Inhibitor Formation (5K08HL151962-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10482349. Licensed CC0.

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