# Pathogenesis of lung injury mediated by lung-restricted antibodies

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $613,633

## Abstract

PROJECT SUMMARY
Lung-restricted antibodies (LRA) against non-polymorphic lung self-antigens, collagen type V (COLV) and K-
alpha1 tubulin (KAT), are present in over a third of patients undergoing lung transplantation. Since these self-
antigens are expressed in all humans, pre-existing LRA in the recipient can bind to cognate antigens exposed
in the freshly transplanted lungs. Indeed, LRA have emerged as the predominant risk factor for the
development of primary graft dysfunction, the principal cause of early mortality following lung transplantation.
In murine models, LRA are causally linked to severe lung allograft injury, and in patients they are associated
with development of donor specific alloimmune responses. However, the mechanisms underlying their
pathogenicity have not been elucidated. Given the high prevalence of LRA and their causal association with
allograft injury, delineating these mechanisms should lead to relevant strategies to improve lung transplant
survival. We have reported that LRA mediated allograft injury is associated with the deposition of complement
and neutrophil infiltration. However, we do not understand the mechanisms by which LRA drive complement
deposition or neutrophil recruitment, nor whether either is necessary for LRA-mediated injury. Since these lung
self-antigens are located in the interstitial spaces, it is also unclear how circulating LRA gain access to these
antigens. We have recently reported that spleen-derived Ly6ChighCCR2+ classical monocytes (CM) are
recruited to the lungs following ischemia-reperfusion injury where they are necessary to open endothelial tight
junctions by activating IL1β receptors (IL1R). Consistent with these findings, our preliminary data shows that
syngeneic or allogeneic lung grafts from Il1r-/- donors are protected from LRA-mediated lung graft injury. We
have also reported that Ly6ClowCCR2- pulmonary intravascular non-classical monocytes (NCM) are necessary
for neutrophil recruitment into the donor lung. Our new preliminary data suggest that LRA cross-linked to their
cognate antigens can enhance release of the neutrophil chemoattractant CXCL2 from human and murine NCM.
Therefore, we hypothesize that extravasation of LRA into the lung interstitium requires IL1β-dependent
opening of endothelial tight junctions by spleen-derived classical monocytes and, upon binding to cognate
antigens in the interstitium, cross-linked LRA activate complement as well as donor-derived NCM to promote
acute lung allograft injury. Accordingly, we will determine 1) whether splenic CM allow passage of LRA into the
lungs by opening endothelial tight junctions after being educated in the spleen, 2) which complement pathway
is responsible for LRA-mediated injury as well as the mechanisms of complement activation, and 3) whether
toll-receptor independent activation of donor NCM by LRA leads to neutrophil recruitment and lung injury.
Overall goal of these experiments is to provide novel insights into the biol...

## Key facts

- **NIH application ID:** 10372131
- **Project number:** 5R01HL147290-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Ankit Bharat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $613,633
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372131

## Citation

> US National Institutes of Health, RePORTER application 10372131, Pathogenesis of lung injury mediated by lung-restricted antibodies (5R01HL147290-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*