Emerging roles for complement in lung transplantation
Hrishikesh S. Kulkarni, … , John A. Belperio, Carl Atkinson
Hrishikesh S. Kulkarni, … , John A. Belperio, Carl Atkinson
Published October 1, 2025
Citation Information: J Clin Invest. 2025;135(19):e188346. https://doi.org/10.1172/JCI188346.
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Review Series

Emerging roles for complement in lung transplantation

Abstract

The complement system is an evolutionarily conserved host defense system that has evolved from invertebrates to mammals. Over time, this system has become increasingly appreciated as having effects beyond purely bacterial clearance, with clinically relevant implications in transplantation, particularly lung transplantation. For many years, complement activation in lung transplantation was largely focused on antibody-mediated injuries. However, recent studies have highlighted the importance of both canonical and noncanonical complement activation in shaping adaptive immune responses, which influence alloimmunity. These studies, together with the emergence of FDA-approved complement therapeutics and other drugs in the pipeline that function at different points of the cascade, have led to an increased interest in regulating the complement system to improve donor organ availability as well as improving both short- and long-term outcomes after lung transplantation. In this Review, we provide an overview of the when, what, and how of complement in lung transplantation, posing the questions of: when does complement activation occur, what components of the complement system are activated, and how can this activation be controlled? We conclude that complement activation occurs at multiple stages of the transplant process and that randomized controlled trials will be necessary to realize the therapeutic potential of neutralizing this activation to improve outcomes after lung transplantation.

Authors

Hrishikesh S. Kulkarni, John A. Belperio, Carl Atkinson

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Figure 2

Proposed scenarios and consequences of local complement activation in lung transplantation.

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Proposed scenarios and consequences of local complement activation in lu...
(A) Antibody-mediated rejection. Antibodies against HLA antigens and neoepitopes activate the classical complement pathway. Antibodies also activate immune cells, promoting cytotoxicity. Recent studies suggest that complement component deposition in the endothelium and signaling through the C3a and C5a receptors (especially C5aR1) can disrupt the integrity of the endothelial barrier and increase recruitment of immune cells. Additionally, signaling through noncomplement receptors can affect endothelial proliferation and thrombosis and promote resistance to complement-mediated damage. (B) Primary graft dysfunction. Local complement activation can damage the donor tissue, resulting in acute lung injury. Sources of complement proteins can include the tissue-resident cells, such as epithelial cells, fibroblasts, endothelial cells, and myeloid cells, but these proteins can also be sourced from the circulation in the setting of alveolar-capillary barrier disruption. (C) Chronic lung allograft dysfunction. Complement activation in donor lung contributes to persistent inflammation and immune dysregulation, culminating in CLAD. The effects of complement in CLAD can be attributed to the effects of activation fragments influencing B cells and/or ongoing inflammation resulting in the downregulation of regulatory proteins. For example, increased TGF-β in the lung downregulates CD46 and CD55 in the epithelium. CD59 can also be cleaved, in addition to being downregulated. MAC, membrane attack complex.