Intravenous Gammaglobulin (IVIg) Therapy Prevents Antibody-Mediated Transfusion Related Acute Lung Injury (TRALI) by Directly Inhibiting Recipient Neutrophil Activation in a Murine Model

Abstract 42

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-related fatalities and most TRALI reactions are thought to be caused by donor antibodies. Because intravenous gammaglobulin (IVIg) therapy has been shown to be beneficial in many antibody-mediated disorders, we hypothesized that IVIg would be effective in treating antibody-mediated TRALI. TRALI was induced in CB.17 SCID mice by injection of an anti-murine major histocompatibility complex (MHC) class I antibody (34-1-2s). The mice were treated with doses of IVIg either prophylactically 18 hours before TRALI induction or after the first symptoms of TRALI were observed (within 3 minutes after 34-1-2s injection). Body temperatures, lung edema, mortality and neutrophil activation were assessed. In IVIg non-treated mice, injection of 34-1-2s caused significantly reduced body temperatures indicating systemic shock within 2 minutes post injection. Pulmonary neutrophil accumulation and mortality occurred within 1 hour post 34-1-2s injection and mortality reach 25% by 2 hours post administration. When bone marrow neutrophils were purified after 34-1-2s administration, they produced significantly more reactive oxygen species compared with 34-1-2s non-treated mice. In contrast, if the mice were pre-treated with either 1 or 2 g/kg IVIg 18 hours before 34-1-2s-TRALI induction, they were completely protected from systemic shock, lung edema and mortality. The prophylactic in vivo IVIg treatment also significantly reduced 34-1-2s-induced neutrophil ROS production. IVIg's effect on ROS production appeared to be due to a direct contact mechanism as titrations of IVIg significantly inhibited the ability of neutrophils to produce ROS in vitro. In mice treated with IVIg 2–3 minutes after 34-1-2s-TRALI induction (when symptoms were first observed), there was also significant protection against the lung damage and mortality. In contrast, IVIg treatment was not as effective against acute lung injury induced by acid inhalation. The results suggest that the treatment of antibody-mediated TRALI reactions with IVIg can effectively prevent pulmonary reactions and mortality and it does so by directly interfering with 34-1-2s-induced neutrophil activation.