Rescue of rhesus macaques from the lethality of aerosolized ricin toxin
Chad J. Roy, … , Larry Zeitlin, Nicholas J. Mantis
Chad J. Roy, … , Larry Zeitlin, Nicholas J. Mantis
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e124771. https://doi.org/10.1172/jci.insight.124771.
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Research Article Immunology Pulmonology

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

Abstract

Ricin toxin (RT) ranks at the top of the list of bioweapons of concern to civilian and military personnel alike, due to its high potential for morbidity and mortality after inhalation. In nonhuman primates, aerosolized ricin triggers severe acute respiratory distress characterized by perivascular and alveolar edema, neutrophilic infiltration, and severe necrotizing bronchiolitis and alveolitis. There are currently no approved countermeasures for ricin intoxication. Here, we report the therapeutic potential of a humanized mAb against an immunodominant epitope on ricin’s enzymatic A chain (RTA). Rhesus macaques that received i.v. huPB10 4 hours after a lethal dose of ricin aerosol exposure survived toxin challenge, whereas control animals succumbed to ricin intoxication within 30 hours. Antibody intervention at 12 hours resulted in the survival of 1 of 5 monkeys. Changes in proinflammatory cytokine, chemokine, and growth factor profiles in bronchial alveolar lavage fluids before and after toxin challenge successfully clustered animals by treatment group and survival, indicating a relationship between local tissue damage and experimental outcome. This study represents the first demonstration, to our knowledge, in nonhuman primates that the lethal effects of inhalational ricin exposure can be negated by a drug candidate, and it opens up a path forward for product development.

Authors

Chad J. Roy, Dylan J. Ehrbar, Natasha Bohorova, Ognian Bohorov, Do Kim, Michael Pauly, Kevin Whaley, Yinghui Rong, Fernando J. Torres-Velez, Ellen S. Vitetta, Peter J. Didier, Lara Doyle-Meyers, Larry Zeitlin, Nicholas J. Mantis

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Figure 3

Histopathology associated with RT exposure and huPB10 intervention.

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Histopathology associated with RT exposure and huPB10 intervention. H&am...
H&E-stained tissue sections of lung tissues collected from (A) healthy control animals, (B) RT-treated animals, and RT-treated animals that received huPB10 at (C) 4 hours or (D) 12 hours. Tissues in B and D were collected during necropsy from animals that succumbed to ricin intoxication, whereas the tissue in C was collected from an animal that survived RT exposure but was euthanized upon completion of the study on day 14. Tissues from (B) RT-treated and the (D) huBP10 intervention at 12 hours demonstrated severe neutrophilic infiltration of bronchioles (br), space around blood vessels (bv), and interstitium, as compared with healthy controls shown in A. Alveolar spaces (alv; arrows) of RT and 12 hour-treated animals were expanded by edema (asterisks) and hemorrhage. (C) Animals treated with huPB10 at 4 hours demonstrated multifocal areas of fibrosis and mild eosinophilic and neutrophilic infiltration (arrowheads; see Supplemental Figure 2). Original magnification 10×. Scale bar: 100 μm.