ALBERT

Description: Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion and has been ranked as one of the leading causes of transfusion-related fatalities. Nonetheless, many details of the immunopathogenesis of TRALI, particularly with respect to recipient factors are unknown. We used a murine model of antibody-mediated TRALI in an attempt to understand the role that recipient lymphocytes might play in TRALI reactions. Intravenous injection of an IgG2a antimurine major histocompatibility complex class I antibody (34-1-2s) into BALB/c mice induced moderate hypothermia and pulmonary granulocyte accumulation but no pulmonary edema nor mortality. In contrast, 34-1-2s injections into mice with severe combined immunodeficiency caused severe hypothermia, severe pulmonary edema, and approximately 40% mortality indicating a critical role for T and B lymphocytes in suppressing TRALI reactions. Adoptive transfer of purified CD8+ T lymphocytes or CD4+ T cells but not CD19+ B cells into the severe combined immunodeficiency mice alleviated the antibody-induced hypothermia, lung damage, and mortality, suggesting that T lymphocytes were responsible for the protective effect. Taken together, these results suggest that recipient T lymphocytes play a significant role in suppressing antibody-mediated TRALI reactions. They identify a potentially new recipient mechanism that controls the severity of TRALI reactions.

Description: Abstract 641 Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion and has been ranked as the leading cause of transfusion-related fatalities. The majority (approx. 80%) of TRALI reactions are associated with and probably initiated by donor alloantibodies recognizing recipient granulocytes and/or human leukocytes antigens (HLA). Nonetheless, many details of the immunopathogenesis of TRALI are unknown. Previous studies have shown that a murine anti-MHC (H-2Kd) class I antibody (clone 34-1-2s) can induce TRALI in mice (Looney et al J Clin Invest. 116:1615,2006) and we utilized this model in an attempt to understand the role that recipient lymphocytes might play in TRALI reactions. BALB/c (H-2d) mice were injected iv with titrations of 34-1-2s and body temperature, morbidity/mortality, pulmonary granulocyte accumulation and serum levels of MIP-2 (the murine analog of human neutrophil chemokine IL8) were measured at various time points. Results showed that when BALB/c mice were administered 34-1-2s, a significant drop (N=20) in rectal body temperature indicating shock occurred within 30 min post-infusion, with evidence of recovery beginning at 1 hour post-infusion. Visible signs of breathing difficulty were apparent but there was no mortality observed. A significant granulocyte accumulation (N=20) within the lungs was also observed by 30 min post-infusion, which continued on to the end of the experiment (2 hours post-infusion). Serum MIP-2 levels were also significantly elevated concurrently with the granulocyte accumulation. To determine the role of recipient lymphocytes on these responses, BALB/c mice with severe combined immunodeficiency (SCID; lacking T and B lymphocytes) were infused with 34-1-2s. Compared with the BALB/c recipients, the decreases in rectal temperatures in the SCID mice were significantly greater (N=18) and there was a 66% mortality rate (N=18) with symptoms of severe respiratory distress and tracheal edema with 30 minutes after infusion of 34-1-2s. In addition, there was a significantly greater accumulation of pulmonary granulocytes in the SCID mice at lower doses of 34-1-2s and the antibody stimulated the production of significantly higher serum levels of MIP-2. These findings were also seen in 34-1-2s-infused SCID mice that were first depleted of natural killer cells suggesting that NK cells play no role in the enhanced severity of the antibody-mediated TRALI reaction. Taken together, these results suggest that recipient T and B lymphocytes have a protective role in suppressing antibody-mediated TRALI reactions perhaps by modulating recipient chemokine production. They identify a potentially new recipient mechanism that controls the severity of antibody-mediated TRALI. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1112 Background & Aims: Transfusion-related acute lung injury (TRALI) is a predominant cause of transfusion-related morbidity and mortality, however the mechanism underlying its development remains undefined. We have previously demonstrated that heat-treated supernatant from stored (day 5) human whole blood platelet components (d5-PLT-S/N) cause TRALI in lipopolysaccharide (LPS) treated sheep (Tung et al. Vox Sang 2010). This two-event in-vivo model was used to further investigate TRALI due to heat-treated supernatant from stored (day 42) human red cells (d42-PRBC-S/N), and a comparison of the two models is reported here. Methods: Sheep were infused with LPS (15μg/kg; to model a first event of clinical infection), and then transfused with either d5-WB-PLT-S/N or d42-PRBC-S/N (10% of estimated blood volume; second event), with saline and supernatant from fresh blood components as controls. Microarray techniques were used to analyze cytokine and chemokine expression levels in both the supernatants. A range of hemodynamic and respiratory parameters were recorded with continuous in-line monitoring. This data was then analyzed using non-linear mixed effects modelling. TRALI was defined by both hypoxemia during or within 2 hours of transfusion and histological evidence of pulmonary edema. Results & Discussion: TRALI developed in 80% of LPS-treated sheep following transfusion with either d5-WB-PLT-S/N (n=5) or d42-PRBC-S/N (n=5), with significantly lower (P