A new class of human mast cell and peripheral blood basophil stabilizers that differentially control allergic mediator release.
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 C(70)-tetraglycolic acid significantly inhibited degranulation and cytokine production from mast cells and basophils, while C(70)-tetrainositol blocked only cytokine production in mast cells and degranulation and cytokine production in basophils. The early phase of FcepsilonRI 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. C(70)-tetraglycolic acid was able to block mast cell-driven anaphylaxis in vivo, while C(70)-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 FcepsilonRI-specific molecules in mast cells and basophils. These next generation fullerene derivatives represent a new class of compounds that interfere with FcepsilonRI signaling pathways to stabilize mast cells and basophils. Thus, fullerene-based therapies may be a new approach for treating allergic diseases.
Norton
Sarah K
SK
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, USA.
Dellinger
Anthony
A
Zhou
Zhiguo
Z
Lenk
Robert
R
Macfarland
Darren
D
Vonakis
Becky
B
Conrad
Daniel
D
Kepley
Christopher L
CL
D000707:Anaphylaxis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000818:Animals; D015549:Basophil Degranulation Test; D001491:Basophils / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D037741:Fullerenes / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D056747:Immunomodulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D050997:Nanomedicine / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
C034102:FcRI protein, human; D037741:Fullerenes; D047908:Intracellular Signaling Peptides and Proteins; C069836:fullerene C70