# Modeling Antibody-induced Immune Responses by NK cells in Mice and Humans (Resubmission 1)

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2020 · $265,607

## Abstract

Project Summary: Natural Killer (NK) cells are lymphocytes of the innate immune system. NK cells defend us
by inducing antibody-dependent cell mediated cytotoxicity (ADCC) where NK cells lyse antibody coated virally-
infected target cells. Recent experiments showed generation of long-lived “memory-like” NK cells, similar to
memory lymphocytes in the adaptive immune system, in mouse and humans challenged by viral infections
(such as cytomegalovirus). These memory NK cells generated a more vigorous ADCC response compared to
their naïve counterparts which make the memory NK cells an attractive candidate for augmenting monoclonal
antibody based immunotherapies against cancer and infectious disease. However, two major issues limit the
use of “memory-like” NK cells for such therapies: 1) A rudimentary understanding of mechanisms underlying
NK cell-mediated ADCC is lacking; and 2) humans and mice show key differences in the NK cell signaling
networks, which regulate ADCC. We address the above challenges by developing computational models with
predictive powers for antibody responses induced by NK cell subsets (from naïve to memory) in humans and
mice by synergistically combining data-driven and mechanistic in silico models (rooted in statistical physics,
nonlinear dynamics, information theory, statistics, and chemical engineering) with single cell mass cytometry
by time of flight (CyTOF) and state-of-the-art wet lab experiments in primary NK cells obtained from human
subjects and genetically modified mice. The objective of the proposal is to quantitatively characterize
mechanisms underlying ADCC in diverse NK cell subsets in humans and mice and then use this quantitative
understanding to develop novel mouse models of ADCC that reflect the situation in humans more accurately.
We will pursue two aims: Aim 1: Modeling ADCC activity in human naïve and memory NK cell subsets. Aim 2:
Modeling ADCC in mouse NK cells. The expected outcome of quantitative characterization of the differences
and synergies in mechanisms of ADCC induced by CD16 and CD32 receptors in different NK cell subsets
(naïve to memory primary NK cells) (Aim 1) will help us generate improved mouse models that more accurately
represent ADCC mediated by human NK cells (Aim 2). This unique framework will provide the scientific
community with a mouse model for ADCC that more accurately reflects the situation in humans, a critical asset
for pre-clinical development of monoclonal antibody therapeutics for cancer and infectious diseases.

## Key facts

- **NIH application ID:** 9972399
- **Project number:** 1R01AI146581-01A1
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Jayajit Das
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,607
- **Award type:** 1
- **Project period:** 2020-02-21 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972399

## Citation

> US National Institutes of Health, RePORTER application 9972399, Modeling Antibody-induced Immune Responses by NK cells in Mice and Humans (Resubmission 1) (1R01AI146581-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972399. Licensed CC0.

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