A new class of human mast cell and peripheral blood basophil stabilizers that differentially control allergic mediator release

Sarah K. Norton, Anthony Dellinger, Zhiguo Zhou, Robert Lenk, Darren MacFarland, Becky Vonakis, Daniel Conrad, Christopher L. Kepley

Research output: Contribution to journalArticlepeer-review

Abstract

Treatments for allergic disease block the effects of mediators released from activated mast cells and blood basophils. A panel of fullerene derivatives was synthesized and tested for their ability to preempt the release of allergic mediators in vitro and in vivo. The fullerene C70-tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C70-tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of Fce{open}RI inhibition was dependent on the blunted release of intracellular calcium stores, elevations in reactive oxygen species, and several signaling molecules. Gene microarray studies further showed the two fullerene derivatives inhibited late phase responses in very different ways. C70-tetraglycolic acid was able to block mast cell-driven anaphylaxis in vivo, while C70-tetrainositol did not. No toxicity was observed with either compound. These findings demonstrate the biological effects of fullerenes critically depends on the moieties added to the carbon cage and suggest they act on different Fce{open}RI-specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with Fce{open}RI signaling pathways to stabilize mast cells and basophils. Thus, fullerene-based therapies may be a new approach for treating allergic diseases.

Original languageEnglish (US)
Pages (from-to)158-169
Number of pages12
JournalClinical and translational science
Volume3
Issue number4
DOIs
StatePublished - Aug 2010

Keywords

  • Basophil
  • Drug action
  • Drug design
  • Inflammation
  • Mast cell
  • Nanomedicine

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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