# Complement driven innate and adaptive autoreactivity in lung transplantation

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $451,162

## Abstract

Abstract: Obliterative bronchiolitis (OB) is the leading cause of late death after lung transplantation (LTx) and
the principle unmet obstacle to improved long-term outcomes. Increasing evidence indicates a role for recipient
autoimmunity in the pathogenesis of graft rejection. Emphysema, a principle indication for LTx, has been
shown to express a wide-spectrum of extracellular matrix autoreactive antibodies and T cells directed towards
collagen, elastin, and decorin, the impact of which on post-Tx outcomes is unknown. Here we will utilize mouse
models of emphysema, and orthopic LTx, to investigate LTx outcomes in a clinically relevant scenario. The
scientific premise of these studies is to determine if pre-transplant autoreactive immunity induced by
emphysema, promotes post-Tx injury that leads to exacerbated ischemia reperfusion injury (IRI) and OB.
The earliest injury to the LTx occurs as a consequence of IRI, the severity of which is thought to lead to
accelerated onset OB. Ischemic insult followed by reperfusion leads to the exposure of neoepitopes expressed
on stressed/injured cells recognized by natural self-reactive IgM Abs, which bind and activate the C system,
resulting in inflammation and injury. We have identified annexin IV as an injury-specific neoepitope expressed
in ischemic transplant grafts, and have shown that this neoepitope binds natural IgM, activates C and promotes
IRI. By means of an anti-annexin IV single chain Ab (B4scFv), we have validated annexin IV as a target for the
therapeutic delivery of C inhibition to murine allografts. There are a number of therapeutic benefits of this
neoepitope targeting approach for protection against IRI in a LTx recipient: 1. It will target the proximal event in
complement activation, 2. The targeting vehicle itself contributes to therapeutic activity by blocking the binding
of complement activating antibodies, and 3. Will inhibit C activation locally, which will impair T cell activation.
Our working hypothesis is that pre-transplant autoreactivity to extracellular matrix targets exacerbates early
graft injury, thus promoting early onset OB. We propose that neoepitope IgM graft-targeted C inhibitors will
synergize to inhibit adaptive autoantibody effector functions, and reduce intragraft autoreactive T cell activity.
We propose the following specific, independent, but interrelated aims. 1. Determine the complement-mediated
effector functions that contribute to extracellular matrix autoreactive immunity induced acute lung graft injury.
Here we will determine the isotype and phenotype of autoreactive antibodies and T cells that promote injury
post transplantation and further dissect the complement effector functions that induce graft damage, and 2. In
a murine model of OB, determine whether cigarette smoke-induced autoimmunity exacerbates IRI and chronic
rejection following transplantation in a complement-dependent manner. We will transplant lungs into
emphysematous mice (induced by cigarett...

## Key facts

- **NIH application ID:** 9953828
- **Project number:** 5R01HL140470-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Carl Atkinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,162
- **Award type:** 5
- **Project period:** 2018-07-16 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953828

## Citation

> US National Institutes of Health, RePORTER application 9953828, Complement driven innate and adaptive autoreactivity in lung transplantation (5R01HL140470-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9953828. Licensed CC0.

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