Mouse model of hemolytic-uremic syndrome caused by endotoxin-free Shiga toxin 2 (Stx2) and protection from lethal outcome by anti-Stx2 antibody.
Hemolytic-uremic syndrome (HUS) results from infection by Shiga toxin (Stx)-producing Escherichia coli and is the most common cause of acute renal failure in children. We have developed a mouse model of HUS by administering endotoxin-free Stx2 in multiple doses over 7 to 8 days. At sacrifice, moribund animals demonstrated signs of HUS: increased blood urea nitrogen and serum creatinine levels, proteinuria, deposition of fibrin(ogen), glomerular endothelial damage, hemolysis, leukocytopenia, and neutrophilia. Increased expression of proinflammatory chemokines and cytokines in the sera of Stx2-treated mice indicated a systemic inflammatory response. Currently, specific therapeutics for HUS are lacking, and therapy for patients is primarily supportive. Mice that received 11E10, a monoclonal anti-Stx2 antibody, 4 days after starting injections of Stx2 recovered fully, displaying normal renal function and normal levels of neutrophils and lymphocytes. In addition, these mice showed decreased fibrin(ogen) deposition and expression of proinflammatory mediators compared to those of Stx2-treated mice in the absence of antibody. These results indicate that, when performed during progression of HUS, passive immunization of mice with anti-Stx2 antibody prevented the lethal effects of Stx2.
Sauter
Kristin A D
KA
Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, USA.
Melton-Celsa
Angela R
AR
Larkin
Kay
K
Troxell
Megan L
ML
O'Brien
Alison D
AD
Magun
Bruce E
BE
D000818:Animals; D000907:Antibodies, Bacterial / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000992:Antitoxins / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D002648:Child; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000097:blood; D005340:Fibrinogen / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology / Q000648:ultrastructure; D007970:Leukopenia / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D011507:Proteinuria / Q000139:chemically induced; D022641:Shiga Toxin 2 / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000992:Antitoxins; D016207:Cytokines; D022641:Shiga Toxin 2; D005340:Fibrinogen; D003404:Creatinine