Preventing murine transfusion‐related acute lung injury by expansion of CD4⁺CD25⁺FoxP3⁺ Tregs using IL‐2/anti‐IL‐2 complexes

Abstract

BACKGROUND Transfusion‐related acute lung injury (TRALI) is one of the most serious adverse events following transfusion, and there is no specific treatment in clinical practice. However, regulatory T cells (Tregs) have been suggested to play a potential role in the treatment of TRALI. This study investigated whether interleukin (IL)‐2 or IL‐2/anti‐IL‐2 complexes (IL‐2c), which are mediators of Treg expansion, can modulate the severity of antibody‐mediated TRALI in vivo. STUDY DESIGN AND METHODS This study utilized a mouse model of the “two‐hit” mechanism: BALB/c mice were primed with lipopolysaccharide (LPS) as the first hit, and then TRALI was induced by injecting major histocompatibility complex Class I antibodies. Mice injected with LPS only or LPS combined with isotype control antibodies served as controls. For the Treg‐depleted groups, mice were infused with anti‐mouse IL‐2Rα first and then subjected to the same treatments as the TRALI group. Regarding IL‐2‐ and IL‐2c‐treated mice, recombinant murine IL‐2 or IL‐2c was intraperitoneally administered to mice for 5 consecutive days before induction of the TRALI model. Samples were collected 2 hours after TRALI induction. RESULTS Prophylactic administration of IL‐2 or IL‐2c to mice prevented the onset of edema, pulmonary protein levels, and proinflammatory factors that inhibited polymorphonuclear neutrophil aggregation in the lungs. Furthermore, the percentage of CD4 + CD25 + FoxP3 + Tregs was expanded in vivo using IL‐2 and IL‐2c compared to TRALI mice, as was confirmed through analysis of the spleen, blood, and lung. CONCLUSION This study validates that the protective mechanisms against TRALI involve CD4 + CD25 + FoxP3 + Tregs, which can be expanded in vivo by IL‐2 and IL‐2c. This results in increased IL‐10 levels and decreased IL‐17A, thereby prophylactically preventing antibody‐mediated murine TRALI.