# Mechanistic insights into factor VIII inhibitor formation and eradication

> **NIH NIH K99** · CHILDREN'S HOSP OF PHILADELPHIA · 2022 · $158,013

## Abstract

PROJECT SUMMARY/ABSTRACT
This K99 Career Pathway to Independence in Blood Science Award details a five-year training program to
advance Dr. Bhavya Doshi’s career goal of becoming an independent translational physician-scientist in
coagulation. The proposed application combines approaches using tissue culture and animal models with
investigations using patient samples to address the current limitations in the understanding of the immune
response to factor VIII (FVIII). Dr. Doshi’s career development and training objectives are geared to foster this
research proposal and her overall career goal of understanding basic mechanisms that drive disease to
develop targeted treatment and prevention strategies. During the award period, Dr. Doshi will engage with a
robust team of scientists in hemostasis and immunology to build her immunologic and translational research
skills, learn genomic skills necessary for her future career aspirations, and continue to develop her expertise in
coagulation and inhibitors. Under the guidance of her mentors, Dr. Rodney Camire and Dr. Michael Milone,
these training objectives will be met by a combination of didactic course work and workshops, participation in
seminar series, hands-on research experience, and mentoring by her advisory committee. Her advisory
committee is composed of world-renowned scientists with extensive mentoring experience and diverse and
complementary scientific expertise. They are all versed in bringing basic research findings to the bedside.
Hemophilia A (HA) is caused by a mutation in the F8 gene leading to dysfunction or deficiency of coagulation
FVIII. The development of neutralizing antibodies (“inhibitors”) to FVIII is the leading cause of morbidity and
mortality in patients with HA. Dr. Doshi’s preliminary studies in HA patients and mice are the first to support
that the cytokine B cell activating factor (BAFF) is potentially a biomarker and/or regulator of the FVIII immune
response. This proposal seeks to probe basic mechanisms in FVIII-specific B cell generation and how BAFF
contributes to this humoral response in order to leverage these findings for therapeutic application. Aim 1
seeks to determine the location, kinetics, and types of B cell responses to FVIII in mice by using a novel
method to identify FVIII-specific B cells and subsequently determine what happens to this compartment with
immunomodulatory strategies, including anti-BAFF. As BAFF is both systemically and locally produced by
fibroblast cells and hematopoietically-derived immune cells, respectively, Aim 2 investigates the source of
BAFF and its effect on the T cell response to FVIII. Finally, Aim 3 assesses whether genetic drivers of cytokine
levels for BAFF or T helper cytokines drive phenotypic changes in T and B cell subsets that lead to inhibitor
generation and/or persistence in HA patients. Together, these studies will inform the immune compartments
that are critical to the FVIII immune response and establish the preclini...

## Key facts

- **NIH application ID:** 10413819
- **Project number:** 5K99HL156073-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Bhavya Sharad Doshi
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $158,013
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413819

## Citation

> US National Institutes of Health, RePORTER application 10413819, Mechanistic insights into factor VIII inhibitor formation and eradication (5K99HL156073-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10413819. Licensed CC0.

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