Post-exposure targeting of specific epitopes on ricin toxin abrogates toxin-induced hypoglycemia, hepatic injury, and lethality in a mouse model.
Effects in the liver of fatal intoxication with the binary toxin ricin are unclear. We report a robust neutrophil influx into the liver of C57BL/6 mice after lethal parenteral ricin challenge, occurring in peri-portal and centro-lobular hepatic areas within 2 h, followed by the abrupt disappearance of hepatic macrophages/Kupffer cells. Chemokine profiles determined by microarray, ribonuclease protection assays, northern blotting, and enzyme-linked immunosorbent assays showed rapid (2 h) upregulation and persistence of those for neutrophils (CXCL1/KC, CXCL2/MIP-2) and monocytes (CCL2/MCP-1). Red blood cell pooling (8-12 h), loss of hepatocyte glycogen (8-48 h) associated with progressive hypoglycemia, fibrin deposition (24-48 h), and death (72-96 h) followed. Monoclonal antibody to ricin A chain, administered intravenously, blunted hypoglycemia, and abrogated death. This outcome was observed when anti-ricin antibody was given before toxin exposure as well as when administered approximately 10 h after toxin exposure. Targeting antibody to specific amino-acid sequences on the ricin A chain (HAEL and QXXWXXA) was critical to the therapeutic effect. Re-emergence of liver macrophages/Kupffer cells and replenishment of glycogen in previously depleted hepatocytes preceded full recovery of the host. These data identify critical events for liver injury and healing in ricin intoxication, as well as a new means and specific targets for post-exposure therapeutic intervention.
Roche
James K
JK
Division of Nephrology, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, VA, USA.
Stone
Matthew K
MK
Gross
Lisa K
LK
Lindner
Matthew
M
Seaner
Regina
R
Pincus
Seth H
SH
Obrig
Tom G
TG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000918:Antibody Specificity / Q000276:immunology*; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000506:poisoning*; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000139:chemically induced / Q000517:prevention & control; D007728:Kupffer Cells / Q000502:physiology; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D011041:Poisoning / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020127:Recovery of Function / Q000502:physiology; D012276:Ricin / Q000737:chemistry / Q000276:immunology* / Q000506:poisoning*
D000911:Antibodies, Monoclonal; D002619:Chemical Warfare Agents; D000939:Epitopes; D006003:Glycogen; D012276:Ricin
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