# Utilizing Dendritic Cell Biology to Characterize the Innate Immune Response to Blood Coagulation Proteins

> **NIH NIH K99** · STANFORD UNIVERSITY · 2024 · $202,500

## Abstract

Project Summary
Inherited deficiencies of blood coagulation glycoproteins factor VIII (FVIII) or factor IX (FIX) result in the
bleeding disorders hemophilia A and B, respectively. These individuals require intravenous infusions of
exogenous factor to treat and prevent bleeding events. However 30% of patients with severe hemophilia A and
1-3% of patients with hemophilia B will form neutralizing antibodies called inhibitors against FVIII and FIX
respectively. Although the immune response to FVIII and FIX are both dependent on CD4+ T cell responses,
inhibitors to FIX can induce allergic IgE-mediated hypersensitivity responses and nephrotic syndrome due to
immune complex deposition, which are rarely seen in patients with FVIII inhibitors. Antigen presenting cells
(APCs), including dendritic cells (DCs), B cells, and macrophages, are essential for sensing antigens and
directing adaptive immune responses towards immunity or tolerance. DCs have an enhanced ability to capture
and process antigens for presentation on MHC complexes to naïve T cells. There is limited understanding of
the underlying mechanisms and critical cellular components that mediate innate immunity to FVIII and FIX. The
main objective of this work is to characterize the role of DCs in the innate immune response to FVIII and FIX.
This proposal consists of 3 specific aims: 1) Evaluate the role of conventional DCs in CD4+ T cell dependent-
antibody formation in murine models of hemophilia A and B, 2) Identify the mechanisms of FVIII and FIX
recognition and internalization by conventional DCs, and 3) Determine the properties of FVIII and FIX that
mediate DC activation and co-stimulatory signaling. In Aim 1, T cell responses and antibody formation will be
measured after targeted depletion of APC subsets in mice immunized with FVIII, FIX, or ovalbumin. The role of
phagocytosis, macropinocytosis, and receptor-mediated endocytosis through C-type lectin receptors DCIR2
and Dectin-2 in FVIII and FIX uptake under normal conditions and with inflammation will be evaluated to
determine the mechanism of factor recognition and internalization by DCs in Aim 2. In Aim 3, the effect of
increasing concentrations of FVIII and FIX on DC activation in vitro will be measured. Additionally, the effect of
inhibiting DC co-stimulatory signals on T cell activation, antibody responses, and complement activation in
hemophilia A and B mice immunized by intravenous, subcutaneous, or intraperitoneal injections of FVIII and
FIX will be evaluated. A fundamental understanding of these mechanisms will be important for evaluating
immunologic changes in hemophilia patients during early factor exposure and for the development of strategies
that prevent and eradicate inhibitors. The career development plan outlined will address training in
immunology, molecular biology laboratory techniques, and translational research to ensure successful
transition to research independence.

## Key facts

- **NIH application ID:** 10988970
- **Project number:** 7K99HL150595-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Glaivy Batsuli
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $202,500
- **Award type:** 7
- **Project period:** 2024-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988970

## Citation

> US National Institutes of Health, RePORTER application 10988970, Utilizing Dendritic Cell Biology to Characterize the Innate Immune Response to Blood Coagulation Proteins (7K99HL150595-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10988970. Licensed CC0.

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