# Natural Killer Cell Functions in Lymphangioleiomyomatosis

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $399,950

## Abstract

Project Summary. Lymphangioleiomyomatosis (LAM) is a rare lung disease of women in which abnormally
proliferating smooth muscle cells carrying acquired mutations in the TSC1 or TSC2 genes metastasize from
an unknown source and infiltrate the lung. The proliferating smooth muscle cells lead to destruction of
surrounding lung tissue, cystic remodeling, and organ failure. Unfortunately, physicians typically diagnose
LAM after significant disease progression. We reported key findings regarding immune function [specifically,
natural killer (NK) cells] at this stage of disease in LAM patients, but there is still an unmet need to further
define the role of these cells in advanced disease as well as early stages of disease. Early events can be
effectively studied using animal models that best reflect the pathological processes leading to LAM. Our
preliminary data examining LAM patients and a mouse model of LAM featuring leiomyoma formation and
Tsc2-null nodules in the lungs demonstrate the existence of organ-specific alterations in NK cell function that
likely contribute to LAM pathogenesis. Specifically, unique subsets of NK cells exist in circulation and lung
tissue that are characterized as “hyperresponsive” in terms of cytotoxicity and cytokine responsiveness. We
also examined earlier stages of disease using a mouse model employing a uterine specific Tsc2 deletion
which develop hallmark features of LAM including leiomyoma formation and accumulation of pulmonary
nodules consisting of smooth muscle cells carrying Tsc2 deletions. We show that the leiomyomas express
high levels of ligands for the NKG2D activating receptor but also elaborate high levels of soluble ligands that
likely downregulate NKG2D expression and impaired NK cell function. The preliminary data demonstrates a
dynamic shaping of NK cell phenotype and function throughout the arc of pathogenesis. The goal of this
proposal is to define the phenotype, function, and role of NK cells and NKG2D in LAM using both LAM patient
samples and animal models. Towards this goal, we will 1) Define the functional significance of unique NK cell
populations in LAM. 2) Define the mechanism of VEGFD-amplified NK cell activation. 3) Define the function
of NK cells and Nkg2d in the initiation and progression of LAM. And 4) Define the efficacy and benefits of
therapeutic inhibition of circulating soluble Nkg2d ligands. The successful completion of these studies is likely
to have a high impact on our understanding of LAM pathogenesis. The role of cytotoxic lymphocytes such as
NK cell are clear in terms of the multiple stages of disease such as the control of tumor growth and tissue
remodeling. We will identify the role of these cells at multiple stages of disease, identify mechanisms of NK
cell responsiveness and breakdown of immune surveillance, and examine the potential for therapeutic
intervention targeting soluble NKG2D ligands. Several therapeutics aimed at modulating NK cell function are
in development for ...

## Key facts

- **NIH application ID:** 10075307
- **Project number:** 5R01HL141236-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Michael Borchers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,950
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075307

## Citation

> US National Institutes of Health, RePORTER application 10075307, Natural Killer Cell Functions in Lymphangioleiomyomatosis (5R01HL141236-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10075307. Licensed CC0.

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