Individuals lacking CD36 on both platelets and monocytes (type I) are at risk of developing anti-CD36 antibodies after receiving a platelet transfusion or during pregnancy. Anti-CD36 antibodies have been suggested to induce transfusion-related acute lung injury (TRALI) upon blood transfusion, particularly in Asian populations. However, little is known about the pathological mechanism of anti-CD36-mediated TRALI, and potential therapies haven’t yet been identified. Here, we developed a murine model of anti-CD36-mediated TRALI to address these questions. We found that administration of mouse monoclonal antibody against CD36 (mAb GZ1) or human anti-CD36 IgG, but not GZ1 F(ab’)2 fragments, induced severe TRALI in Cd36+/+ male mice. Pre-depletion of recipient monocytes or complement, but not neutrophils or platelets, prevented the development of murine TRALI. Moreover, plasma C5a levels after TRALI induction by anti-CD36 were increased more than 3-fold, implying a critical role of complement C5 activation in the mechanism of Fc-dependent anti-CD36-mediated TRALI. Furthermore, C5−/− mice were protected from anti-CD36–mediated TRALI, not C5aR1−/− mice. C5aR1 and C5aR2 antagonists’ administration did not inhibit TRALI, implying a possible role of C5b-9 (membrane attack complex [MAC]). Accordingly, elevated levels of MAC were detected in bronchoalveolar lavage fluid and lung tissue of mice with anti-CD36 induced TRALI. Administration of GZ1 F(ab’)2, antioxidant (NAC), IVIG, anti- FcγRII/III (mAb 2.4G2), anti-C5 (mAb BB5.1), anti-C7 (mAb 73D1) or anti-C7 F(ab’)2 before TRALI induction completely protected mice from anti-CD36-mediated TRALI. Inhibition of MAC formation by administration of anti-C7 alleviated TRALI in mice, suggesting the critical role of the MAC in the pathology of anti-CD36-mediated TRALI. Although no significant amelioration in TRALI was observed when mice were injected with GZ1 F(ab’)2 after TRALI induction, significant improvement was achieved when mice were treated post-induction with NAC or anti-C5. Importantly, anti-C5, anti-C7 and anti-C7 F(ab’)2 treatment completely rescued mice from TRALI, suggesting the potential role of existing anti-complement drugs in the treatment of patients with TRALI caused by anti-CD36 antibodies. The activation of complement is a rapid cascade reaction, which results in CD36 antibody-mediated TRALI being an acute response. Therefore, monoclonal antibodies directed against complement activation may be the best treatment.
