title: Peripheral blood monocyte-derived chemokine blockade prevents murine transfusion-related acute lung injury (TRALI).
abstract: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality and can occur with any type of transfusion. TRALI is thought to be primarily mediated by donor antibodies activating recipient neutrophils resulting in pulmonary endothelial damage. Nonetheless, details regarding the interactions between donor antibodies and recipient factors are unknown. A murine antibody-mediated TRALI model was used to elucidate the roles of the F(ab')2 and Fc regions of a TRALI-inducing immunoglobulin G anti-major histocompatibility complex (MHC) class I antibody (34.1.2s). Compared with intact antibody, F(ab')2 fragments significantly increased serum levels of the neutrophil chemoattractant macrophage inflammatory protein 2 (MIP-2); however, pulmonary neutrophil levels were only moderately increased, and no pulmonary edema or mortality occurred. Fc fragments did not modulate any of these parameters. TRALI induction by intact antibody was completely abrogated by in vivo peripheral blood monocyte depletion by gadolinium chloride (GdCl3) or chemokine blockade with a MIP-2 receptor antagonist but was restored upon repletion with purified monocytes. The results suggest a two-step process for antibody-mediated TRALI induction: the first step involves antibody binding its cognate antigen on blood monocytes, which generates MIP-2 chemokine production that is correlated with pulmonary neutrophil recruitment; the second step occurs when antibody-coated monocytes increase Fc-dependent lung damage.
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Keenan Center for Biomedical Research, St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada; and.
authors.forename: Christopher G J
authors.initials: CG
authors.lastname: McKenzie
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Keenan Center for Biomedical Research, St. Michael's Hospital, Toronto, ON, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Kim
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada;
authors.forename: Tarandeep K
authors.initials: TK
authors.lastname: Singh
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada;
authors.forename: Youli
authors.initials: Y
authors.lastname: Milev
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Departments of Medicine.
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.affiliation: Toronto Platelet Immunobiology Group, Toronto, ON, Canada; Keenan Center for Biomedical Research, St. Michael's Hospital, Toronto, ON, Canada; Canadian Blood Services, Toronto, ON, Canada; and Departments of Medicine, Pharmacology, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Semple
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000401:mortality / Q000517:prevention & control*; D000818:Animals; D054426:Chemokine CXCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018925:Chemokines / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D005682:Gadolinium / Q000494:pharmacology; D007035:Hypothermia / Q000209:etiology; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D065227:Transfusion Reaction
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D005682:Gadolinium; C038958:gadolinium chloride