Table 4. Overview of evidence for and... | American Society of Hematology

Table 4.

Overview of evidence for and against the involvement of specific cell types in the pathogenesis of TRALI, based on both TRALI animal models and/or human data

Cell type	Supporting evidence for involvement in TRALI	Evidence against involvement in TRALI	Overall effect in TRALI
PMNs	• PMNs are observed in TRALI lungs upon autopsy^86,87 • In vitro TRALI models have shown PMN-induced endothelial cell damage. Antibody-mediated second hits: anti-HNA-3a antibody,⁷⁴ anti-HLA antibody,⁷⁰ low IgM serum.⁹⁷ Non-antibody–mediated second hits: lyso-PC,⁹⁸ soluble CD40 ligand,⁸⁵ platelet microparticles⁸² • NETs detected in plasma (n = 14) and lungs of TRALI patients and in murine plasma and lung microcirculation of mice undergoing anti-MHC class I antibody–mediated TRALI (upon LPS priming)⁶³ Suggested mechanism: Platelets induce NET formation and NETs induce lung injury via direct toxicity to pulmonary endothelial cells • NET biomarkers found in serum of TRALI patients (n = 5) and in murine lung alveoli using an anti-MHC class I antibody–mediated TRALI model (upon LPS priming)⁷³ Suggested mechanism: NETs formed through direct priming of PMNs by anti-HNA-3a antibodies⁷³ • PMNs were shown to interact with von Willebrand factor via CTL-2, enabling anti-HNA-3a to signal via CD11b/CD18, resulting in PMN-activation and agglutination⁹⁹ • Pulmonary PMN infiltration has frequently been observed in multiple animal models of TRALI, both antibody mediated^{52,56,63,66,68,75,76,99-103} and non-antibody mediated^103,104 • PMN-FcγRs were found to be essential in a murine anti-MHC class I antibody–mediated TRALI model (without LPS priming)⁶⁶ Suggested mechanism: Anti-MHC class I antibody binds to the pulmonary endothelium and sequesters PMNs via their FcγRs, resulting in PMN activation and TRALI induction⁶⁶ • PMN depletion fully prevented TRALI occurrence using murine anti-MHC class I antibody–mediated TRALI models (without LPS priming)^52,66,100 • PMN and ROS are critically required for TRALI induction in a murine model of anti-MHC class I antibody–mediated TRALI (model based on CD4⁺ T-cell depletion and without LPS, using C57BL/6 gp91phox knock-out mice)⁵² • In a 2-event in vivo rat TRALI model, inflammatory priming PMNs induced MHC class II surface expression and pulmonary endothelium activation. Anti-MHC class II antibodies subsequently targeted sequestered PMNs resulting in TRALI⁷¹	• TRALI reported in a neutropenic patient¹⁰⁵ • No alveolar PMN influx observed upon lung tissue histology analysis of 2 TRALI patients¹⁰⁶ • Occurrence of TRALI after PMN depletion in a murine anti-HNA-3a TRALI model (despite a decreased disease severity)⁷⁵ • No dependence on PMNs (and partial independence of FcγRs) but on complement component C5a in a murine anti-MHC class I antibody–mediated TRALI model⁶⁷	Pathogenic
Monocytes and/or macrophages	• Anti-MHC class I antibody–mediated murine (SCID mice, without LPS priming) TRALI induction was completely abrogated upon monocyte depletion (and restored upon repletion with purified monocytes)⁶⁸ Suggested mechanism: Anti-MHC class I antibody binding to monocytes induces the secretion of the PMN-chemoattractant MIP-2 (murine homolog of IL-8), resulting in pulmonary PMN recruitment and TRALI⁶⁸ • Depletion or inactivation of monocytes/macrophages in vivo fully suppressed TRALI in murine model of anti-MHC class I antibody–mediated TRALI (without LPS priming)⁶⁷ Suggested mechanism: Anti-MHC class I antibody binding to endothelial cells activates complement with production of C5a, which then binds to the C5aR on monocytes/macrophages, attracting these cells to the lungs and inducing them to produce ROS, damaging the endothelium and inducing TRALI⁶⁷ • Anti-HLA class II antibodies induce monocyte activation in an ex vivo rodent model of TRALI, which subsequently results in activation of PMNs, which then damage the pulmonary endothelium⁷² • TRALI monocytes were activated in vitro by sera implicated in TRALI, resulting in increased production of TNF-α, IL-1β, and Tissue Factor over a 4-h period compared with control sera¹⁰⁷		Pathogenic
Platelets	• Occurrence of thrombocytopenia in TRALI patients^37-40 • Reported thrombocytopenia in murine anti-MHC class I antibody–mediated TRALI model based on CRP infusion⁵⁶ • Platelet depletion (platelet depleting antibody injected 4 h prior to TRALI induction) protected mice from TRALI in a murine anti-MHC class I–mediated TRALI model (with LPS priming)¹⁰⁰ Suggested mechanism: Platelets induce NET formation (which induce lung injury via direct toxicity to pulmonary endothelial cells) and targeting platelet activation with aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and TRALI⁶³ • Stored platelet-derived vascular endothelial growth factor potentially mediates increased lung vascular permeability in isolated-perfused rat lungs⁷⁹ • Plasma and lipids from stored platelets enable TRALI in an LPS-primed rat model⁷⁸ • Lyso-PC from stored platelets causes pulmonary and systemic coagulopathy in an LPS-primed rat model, via PMN-priming in vitro⁸¹ • Platelet-derived microparticles enable PMN-mediated pulmonary endothelial cell damage in vitro⁸² • Aged platelets induce lung injury via acid sphingomyelinase in an LPS-primed murine TRALI model⁸⁰	• No thrombocytopenia detected in murine model of anti-MHC class I antibody–mediated TRALI (without LPS priming)⁶⁶ • No effect of inducing thrombocytopenia or of pharmacological and genetic targeting of platelet functions, on the development of TRALI in a murine anti-MHC class I antibody–mediated TRALI model (with LPS priming)¹⁰⁸ • Platelet depletion (with platelet depleting antibody injected 24 and 48 h prior to TRALI induction or by injection of neuraminidase) did not suppress TRALI development in a murine model of anti-MHC class I–mediated TRALI (without LPS priming)⁶⁷	Pathogenic? Dispensable?
Red blood cells	• Plasma and lipids from red blood cells and leukoreduced red blood cells primed PMNs and induced ALI in rat model with LPS priming⁸⁴ • Red blood cell–derived microparticles may prime PMNs and enable TRALI in LPS-primed mice⁸³ • Lipids and supernatants from stored red blood cells activate pulmonary endothelium through the BLT2 receptor and protein kinase C activation, and predispose to ALI⁷⁷ • Transfusion of supernatant of aged red blood cells induced lung inflammation and coagulopathy in LPS-primed rats¹⁰⁹ • Injection of anti–red blood cell antibody 1 d before induction of anti-MHC class I antibody–mediated murine TRALI resulted in total suppression of TRALI development in BALB/c mice⁶⁷	• Transfusion of 35-d stored autologous red blood cells in LPS-primed human volunteers (with confirmed sepsis/endotoxemia) did not result in lung injury⁸⁹	Pathogenic
CD4⁺CD25⁺FoxP3 Tregs and dendritic cells	• Depletion of CD4⁺CD25⁺FoxP3⁺ Tregs or of CD11c⁺ dendritic cells resulted in low IL-10 levels, which enabled anti-MHC class I antibody–mediated murine TRALI (protection against anti-MHC class I antibody–mediated TRALI was associated with increased IL-10 levels)⁵² Suggested mechanism: Depletion of CD4⁺CD25⁺FoxP3⁺ Tregs or of CD11c⁺ dendritic cells in mice results in low IL-10 levels, which enables increased anti-MHC class I antibody–mediated plasma MIP-2 levels (murine homolog of IL-8), pulmonary PMN infiltration, ROS production, and TRALI development with impaired lung function⁵²		Protective
CD8⁺ T cells		Depletion of CD8⁺ T cells did not significantly result in the onset of anti-MHC class I antibody–mediated murine TRALI⁵²	No significant involvement
B cells		Depletion of B cells did not significantly result in the onset of anti-MHC class I antibody–mediated murine TRALI⁵²	No significant involvement

Cell type	Supporting evidence for involvement in TRALI	Evidence against involvement in TRALI	Overall effect in TRALI
PMNs	• PMNs are observed in TRALI lungs upon autopsy^86,87 • In vitro TRALI models have shown PMN-induced endothelial cell damage. Antibody-mediated second hits: anti-HNA-3a antibody,⁷⁴ anti-HLA antibody,⁷⁰ low IgM serum.⁹⁷ Non-antibody–mediated second hits: lyso-PC,⁹⁸ soluble CD40 ligand,⁸⁵ platelet microparticles⁸² • NETs detected in plasma (n = 14) and lungs of TRALI patients and in murine plasma and lung microcirculation of mice undergoing anti-MHC class I antibody–mediated TRALI (upon LPS priming)⁶³ Suggested mechanism: Platelets induce NET formation and NETs induce lung injury via direct toxicity to pulmonary endothelial cells • NET biomarkers found in serum of TRALI patients (n = 5) and in murine lung alveoli using an anti-MHC class I antibody–mediated TRALI model (upon LPS priming)⁷³ Suggested mechanism: NETs formed through direct priming of PMNs by anti-HNA-3a antibodies⁷³ • PMNs were shown to interact with von Willebrand factor via CTL-2, enabling anti-HNA-3a to signal via CD11b/CD18, resulting in PMN-activation and agglutination⁹⁹ • Pulmonary PMN infiltration has frequently been observed in multiple animal models of TRALI, both antibody mediated^{52,56,63,66,68,75,76,99-103} and non-antibody mediated^103,104 • PMN-FcγRs were found to be essential in a murine anti-MHC class I antibody–mediated TRALI model (without LPS priming)⁶⁶ Suggested mechanism: Anti-MHC class I antibody binds to the pulmonary endothelium and sequesters PMNs via their FcγRs, resulting in PMN activation and TRALI induction⁶⁶ • PMN depletion fully prevented TRALI occurrence using murine anti-MHC class I antibody–mediated TRALI models (without LPS priming)^52,66,100 • PMN and ROS are critically required for TRALI induction in a murine model of anti-MHC class I antibody–mediated TRALI (model based on CD4⁺ T-cell depletion and without LPS, using C57BL/6 gp91phox knock-out mice)⁵² • In a 2-event in vivo rat TRALI model, inflammatory priming PMNs induced MHC class II surface expression and pulmonary endothelium activation. Anti-MHC class II antibodies subsequently targeted sequestered PMNs resulting in TRALI⁷¹	• TRALI reported in a neutropenic patient¹⁰⁵ • No alveolar PMN influx observed upon lung tissue histology analysis of 2 TRALI patients¹⁰⁶ • Occurrence of TRALI after PMN depletion in a murine anti-HNA-3a TRALI model (despite a decreased disease severity)⁷⁵ • No dependence on PMNs (and partial independence of FcγRs) but on complement component C5a in a murine anti-MHC class I antibody–mediated TRALI model⁶⁷	Pathogenic
Monocytes and/or macrophages	• Anti-MHC class I antibody–mediated murine (SCID mice, without LPS priming) TRALI induction was completely abrogated upon monocyte depletion (and restored upon repletion with purified monocytes)⁶⁸ Suggested mechanism: Anti-MHC class I antibody binding to monocytes induces the secretion of the PMN-chemoattractant MIP-2 (murine homolog of IL-8), resulting in pulmonary PMN recruitment and TRALI⁶⁸ • Depletion or inactivation of monocytes/macrophages in vivo fully suppressed TRALI in murine model of anti-MHC class I antibody–mediated TRALI (without LPS priming)⁶⁷ Suggested mechanism: Anti-MHC class I antibody binding to endothelial cells activates complement with production of C5a, which then binds to the C5aR on monocytes/macrophages, attracting these cells to the lungs and inducing them to produce ROS, damaging the endothelium and inducing TRALI⁶⁷ • Anti-HLA class II antibodies induce monocyte activation in an ex vivo rodent model of TRALI, which subsequently results in activation of PMNs, which then damage the pulmonary endothelium⁷² • TRALI monocytes were activated in vitro by sera implicated in TRALI, resulting in increased production of TNF-α, IL-1β, and Tissue Factor over a 4-h period compared with control sera¹⁰⁷		Pathogenic
Platelets	• Occurrence of thrombocytopenia in TRALI patients^37-40 • Reported thrombocytopenia in murine anti-MHC class I antibody–mediated TRALI model based on CRP infusion⁵⁶ • Platelet depletion (platelet depleting antibody injected 4 h prior to TRALI induction) protected mice from TRALI in a murine anti-MHC class I–mediated TRALI model (with LPS priming)¹⁰⁰ Suggested mechanism: Platelets induce NET formation (which induce lung injury via direct toxicity to pulmonary endothelial cells) and targeting platelet activation with aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and TRALI⁶³ • Stored platelet-derived vascular endothelial growth factor potentially mediates increased lung vascular permeability in isolated-perfused rat lungs⁷⁹ • Plasma and lipids from stored platelets enable TRALI in an LPS-primed rat model⁷⁸ • Lyso-PC from stored platelets causes pulmonary and systemic coagulopathy in an LPS-primed rat model, via PMN-priming in vitro⁸¹ • Platelet-derived microparticles enable PMN-mediated pulmonary endothelial cell damage in vitro⁸² • Aged platelets induce lung injury via acid sphingomyelinase in an LPS-primed murine TRALI model⁸⁰	• No thrombocytopenia detected in murine model of anti-MHC class I antibody–mediated TRALI (without LPS priming)⁶⁶ • No effect of inducing thrombocytopenia or of pharmacological and genetic targeting of platelet functions, on the development of TRALI in a murine anti-MHC class I antibody–mediated TRALI model (with LPS priming)¹⁰⁸ • Platelet depletion (with platelet depleting antibody injected 24 and 48 h prior to TRALI induction or by injection of neuraminidase) did not suppress TRALI development in a murine model of anti-MHC class I–mediated TRALI (without LPS priming)⁶⁷	Pathogenic? Dispensable?
Red blood cells	• Plasma and lipids from red blood cells and leukoreduced red blood cells primed PMNs and induced ALI in rat model with LPS priming⁸⁴ • Red blood cell–derived microparticles may prime PMNs and enable TRALI in LPS-primed mice⁸³ • Lipids and supernatants from stored red blood cells activate pulmonary endothelium through the BLT2 receptor and protein kinase C activation, and predispose to ALI⁷⁷ • Transfusion of supernatant of aged red blood cells induced lung inflammation and coagulopathy in LPS-primed rats¹⁰⁹ • Injection of anti–red blood cell antibody 1 d before induction of anti-MHC class I antibody–mediated murine TRALI resulted in total suppression of TRALI development in BALB/c mice⁶⁷	• Transfusion of 35-d stored autologous red blood cells in LPS-primed human volunteers (with confirmed sepsis/endotoxemia) did not result in lung injury⁸⁹	Pathogenic
CD4⁺CD25⁺FoxP3 Tregs and dendritic cells	• Depletion of CD4⁺CD25⁺FoxP3⁺ Tregs or of CD11c⁺ dendritic cells resulted in low IL-10 levels, which enabled anti-MHC class I antibody–mediated murine TRALI (protection against anti-MHC class I antibody–mediated TRALI was associated with increased IL-10 levels)⁵² Suggested mechanism: Depletion of CD4⁺CD25⁺FoxP3⁺ Tregs or of CD11c⁺ dendritic cells in mice results in low IL-10 levels, which enables increased anti-MHC class I antibody–mediated plasma MIP-2 levels (murine homolog of IL-8), pulmonary PMN infiltration, ROS production, and TRALI development with impaired lung function⁵²		Protective
CD8⁺ T cells		Depletion of CD8⁺ T cells did not significantly result in the onset of anti-MHC class I antibody–mediated murine TRALI⁵²	No significant involvement
B cells		Depletion of B cells did not significantly result in the onset of anti-MHC class I antibody–mediated murine TRALI⁵²	No significant involvement