Identification of host cellular immune mechanisms responsible for the initiation and/or modulation of Transfusion Related Acute Lung Injury (TRALI)

Transfusion-related acute lung injury (TRALI) denotes lung injury soon after a patient receives a blood transfusion. With a death rate of 5-14%, TRALI has recently been ranked as the leading cause of transfusion-related death; recent clinical studies have also suggested that approximately 3-5% of all deaths in cardiac surgery patients are due to TRALI-like lung complications. The mechanisms of how TRALI occurs are not completely clear, but substances within the blood product are thought to be the main factors involved. It appears that the majority (approximately 85%) of cases of TRALI are associated with the transfusion of antibodies that react with cells within the patient's lungs. This interaction causes the cells to become activated and release substances that damage the lung tissue. Perhaps more intriguing is that many units that cause TRALI in one recipient do not cause lung injury in others indicating that recipient factors also play a role. We have developed a mouse model of antibody-mediated TRALI to study these recipient factors and have found that one of the initial primary recipient initiating mechanisms for TRALI induction are circulating monocytes. It appears that the transfused antibodies bind to monocytes and cause their activation which leads to the secretion of chemokines (MIP-2) that facilitate pulmonary neutrophil accumulation. The pulmonary neutrophils subsequently are activated in an Fc-dependent manner that leads to pulmonary capillary leakage and lung damage. Perhaps more importantly, we have discovered that blocking chemokine receptors is an effective treatment to prevent TRALI induction. We will use these results to design experimentation and tests to determine the exact role that recipient immune factors play in initiating or modulating TRALI reactions. Understanding these factors may lead to the identification of recipients at risk of developing TRALI and lead to novel therapies for the treatment of TRALI.

SEMPLE, John

St. Michael's Hospital

Canadian Blood Services-CIHR Partnership Operating Grant Program

Ontario

398982.0