Preclinical evaluation of the ribosome-inactivating proteins PAP-1, PAP-S and RTA in mice

Fabio Benigni, Silvana Canevari, Massimo Gadina, Elena Adobati, Andrés JoséMaria Ferreri, Elena Ferraris Di Celle, Roberto Comolli, Maria Ines Colnaghi

Research output: Contribution to journalArticle

Abstract

In a preclinical mouse model the plant ribosome-inactivating proteins (RIPs) pokeweed antiviral proteins PAP-1, and PAP-S and ricin A-chain (RTA) induced a pathological elevation of serum concentrations of glutamate pyruvate transaminase (GPT) and blood urea nitrogen (BUN) and had a significant immunosuppressive effect on B- and T-lymphocytes. The present analysis and comparison of the biodistribution and systemic/organ toxicity associated with RIP injection suggest a possible in vivo mechanism of action of PAP-1 and PAP-S and identify several limitations in the clinical use of these two toxins and RTA. When administered intravenously, PAP-1 and PAP-S consistently accumulated in kidneys and induced histologically documented damage to kidney and liver, with a ld50 of 3.3 mg/kg and 1.6 mg/kg for PAP-1 and PAP-S, respectively. In mice injected with PAP-S after chlorpromazine (CPZ) administration, GPT levels returned to normal between 24 and 72 h after toxin injection, while the BUN levels remained elevated. Mortality of the animals was delayed but all mice eventually succumbed. All the three toxins inhibited the expansion of anti-sheep red blood cells (SRBC) antibody-forming cells and the production of anti-SRBC antibody levels, although PAP-S showed the most potent activity. Despite the immunosuppressive activity, all toxins were highly immunogenic.

Original languageEnglish
Pages (from-to)829-839
Number of pages11
JournalInternational Journal of Immunopharmacology
Volume17
Issue number10
DOIs
Publication statusPublished - 1995

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Keywords

  • blood urea nitrogen
  • chlorpromazine
  • glutamate pyruvate transaminase
  • immunosuppression
  • immunotoxin
  • ribosome-inactivating protein

ASJC Scopus subject areas

  • Immunology
  • Pharmacology

Cite this

Benigni, F., Canevari, S., Gadina, M., Adobati, E., Ferreri, A. J., Ferraris Di Celle, E., Comolli, R., & Colnaghi, M. I. (1995). Preclinical evaluation of the ribosome-inactivating proteins PAP-1, PAP-S and RTA in mice. International Journal of Immunopharmacology, 17(10), 829-839. https://doi.org/10.1016/0192-0561(95)00068-D