Cracking TRALI: targeting the membrane attack complex Free

In this issue of Blood, Chen et al have identified the membrane attack complex (MAC) as a key mediator in anti-CD36-mediated murine transfusion-related acute lung injury (TRALI),¹ opening the door to new therapeutic strategies targeting late complement activation.

TRALI remains a major cause of transfusion-associated mortality, marked by sudden hypoxemia and noncardiogenic pulmonary edema following transfusion.^2,3 Despite its clinical burden, effective treatment options remain elusive, and no targeted treatment exists to date.

Antibody-mediated TRALI has long been linked to leukocyte antibodies and Fc receptor-dependent mechanisms. Indeed, Looney et al have previously showed that FcγR-deficient BALB/c mice failed to develop antibody-mediated TRALI.⁴ In addition, other studies have established that alloantibodies targeting HLAs or human neutrophil antigens (HNAs) can initiate TRALI through Fc-mediated complement activation.^5,6 However, the role of complement activation remained controversial.

The study by Chen et al provides compelling experimental evidence that the terminal complement complex C5b-9, known as the MAC, is a critical effector in murine TRALI triggered by anti-CD36 and anti-major histocompatibility complex (MHC) I antibodies. Using a murine 2-hit TRALI model, the authors show that C5-deficiency (C5⁻/⁻) protected mice from anti-CD36-induced TRALI. Similarly, wild-type mice receiving anti-C5 antibodies were rescued as well. However, strikingly, mice lacking the C5a receptor (C5aR1⁻/⁻) remained susceptible to TRALI, and C5a receptor antagonism PMX53 failed to confer protection. These findings strongly suggest an alternative downstream effector of C5 cleavage, namely C5b-9. Indeed, Chen et al observed increased MAC deposition in lung tissue and bronchoalveolar lavage fluid of TRALI mice. Importantly, pharmacologic inhibition of MAC formation using an antiC7 monoclonal antibody alleviated lung injury in both anti-CD36 and anti-MHC I–mediated TRALI models. Preventative and therapeutic administration of anti-C7 also significantly improved survival, normalized lung wet-to-dry weight ratios, and reduced inflammatory markers. The study further refined the role of C5a receptor signaling: C5aR1 appeared dispensable, whereas the activation of the alternative receptor C5aR2 by the selective ligand P32 eased lung injury, suggesting a modulatory or protective role for this pathway.

This study convincingly reframes our understanding of complement-mediated injury in TRALI (see figure). Although previous models emphasized the role of anaphylatoxin-like C5a in recruiting and activating immune cells,⁷ Chen et al highlight the MAC as a direct cytolytic and proinflammatory effector, capable of inducing endothelial damage and monocyte activation. These effects are particularly relevant given the observed protection in C5⁻/⁻ but not C5aR1⁻/⁻ mice and the reduction of TRALI symptoms with anti-C7 therapy.

These major findings have broad therapeutic implications. C7 blockade represents a targeted approach to dampen complement effector function without fully abrogating upstream complement activity, a potential safety advantage in maintaining host defense. Furthermore, the observed efficacy across 2 distinct antibody models (anti-CD36 and anti-MHC I) supports the widespread applicability of MAC inhibition in antibody-mediated TRALI.

Of note, these findings align with recent data supporting complement inhibition as a general strategy in acute lung injury and extend the data to transfusion medicine. Although the translation of murine findings to humans warrants caution, the mechanistic clarity and robustness of this study provide a strong rationale for further clinical investigation. Several outstanding questions remain: will MAC inhibition be effective across the broader spectrum of TRALI triggers? What is the precise role of MAC in endothelial vs leukocyte activation in this context? How can complement diagnostics be integrated to identify candidates for such targeted therapies? The exact mechanism by which MAC induces lung injury, whether through endothelial cell death, cytokine release, or both, needs clarification. How can our understanding of biological response modifier (BRM)-mediated TRALI, particularly soluble CD40 ligand, be improved? What about other contributing factors? For example, how does the gastrointestinal microbiota contribute to the development of murine TRALI,⁸ and what is the potential involvement of the pancreas and other organs, besides the lungs, in the pathogenesis of TRALI?⁹ 

In summary, Chen et al deliver a paradigm-shifting insight into TRALI pathogenesis, identifying MAC as a critical mediator and therapeutic target. Their findings pave the way for complement-based interventions in transfusion-related complications. Their work opens new avenues for complement-targeted therapy, offering hope for one of transfusion medicine’s most intractable challenges. Human studies will be critical to validate these murine findings, particularly regarding the safety and pharmacokinetics of anti-C7 antibodies. Furthermore, TRALI is heterogenous in pathophysiology; understanding whether MAC deposition correlates with severity or the triggering mechanism in human patients could refine patient stratification and inform therapeutic trials.

Conflict-of-interest disclosure: The authors declare no competing financial interests.