Inhibition of terminal complement complex formation alleviates murine antibody-mediated TRALI

Area of Science:

• Immunology
• Hematology
• Pathology

Background:

• Transfusion-related acute lung injury (TRALI) is a significant cause of mortality associated with blood transfusions.
• Previous research highlighted the role of Fc-dependent complement activation in anti-CD36-mediated murine TRALI.

Purpose of the Study:

• To investigate the specific role of complement component 5 (C5) and its downstream products, including the membrane attack complex (MAC), in the pathogenesis of anti-CD36-mediated TRALI.
• To evaluate the therapeutic potential of inhibiting MAC formation in antibody-mediated TRALI.

Main Methods:

• Utilized C5 knockout (C5-/-) and C5a receptor 1 knockout (C5aR1-/-) mice models.
• Administered anti-C5 and anti-C7 blocking monoclonal antibodies (mAbs).
• Quantified MAC levels in bronchoalveolar lavage fluid and lung tissue.

Main Results:

• C5-/- mice were protected from anti-CD36-mediated TRALI, while C5aR1-/- mice were not, suggesting a C5-dependent but C5aR1-independent pathway.
• Elevated MAC levels were detected in TRALI-affected mice.
• Administration of anti-C7 mAb significantly alleviated TRALI in anti-CD36-induced and anti-MHC I-induced models.

Conclusions:

• The membrane attack complex (MAC) plays a critical role in the pathology of anti-CD36-mediated TRALI.
• Inhibition of MAC formation, specifically targeting C7, shows therapeutic promise for antibody-mediated TRALI, including anti-MHC I-induced TRALI.
• MAC inhibitors represent a potential treatment strategy for TRALI patients.