The Journal of Allergy and Clinical Immunology
Volume 121, Issue 2 , Pages 320-325 , February 2008

“Accentuate the negative, eliminate the positive”: Engineering allergy therapeutics to block allergic reactivity through negative signaling

  • Andrew Saxon, MD

      Affiliations

    • Department of Medicine, University of California, Los Angeles, Calif
    • Corresponding Author InformationReprint requests: Andrew Saxon, MD, 52-262 CHS, Department of Medicine, 10833 Le Conte Ave, University of California, Los Angeles CA, 90095-16908.
    • ,
  • Chris Kepley, PhD

      Affiliations

    • Department of Internal Medicine, Virginia Commonwealth University Health Systems, Richmond, Va
    • ,
  • Ke Zhang, MD, PhD

      Affiliations

    • Department of Medicine, University of California, Los Angeles, Calif

Received 31 August 2007 ,Revised 15 October 2007 ,Accepted 16 October 2007.

References 

  1. Arlen H, Mercer J. “Ac-Cent-Tchu-Ate the Positive.”. Capitol Records. 1944;
  2. Daëron M, Malbec O, Latour S, Arock M, Fridman WH. Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J Clin Invest. 1995;95:577–585
  3. Zhu D, Kepley CL, Zhang M, Zhang K, Saxon A. A novel human immunoglobulin Fc gamma Fc epsilon bifunctional fusion protein inhibits Fc epsilon RI-mediated degranulation. Nat Med. 2002;8:518–521
  4. Zhu D, Kepley CL, Zhang K, Terada T, Yamada T, Saxon A. A chimeric human –cat fusion protein blocks cat-induced allergy. Nat Med. 2005;11:446–449
  5. Munitz A, Levi-Schaffer F. Inhibitory receptors on eosinophils: a direct hit to a possible Achilles heel?. J Allergy Clin Immunol. 2007;119:1382–1387
  6. Ott VL, Cambier JC. Activating and inhibitory signaling in mast cells: new opportunities for therapeutic intervention?. J Allergy Clin Immunol. 2000;106:429–440
  7. Kepley CL, Cambier JC, Morel PA, Lujan D, Ortega E, Wilson BS, et al. Negative regulation of FcεRI signaling by FcγRII costimulation in human blood basophils. J Allergy Clin Immunol. 2000;106:337–348
  8. Oliver JM, Kepley CL, Ortega E, Wilson BS. Immunologically mediated signaling in basophils and mast cells: finding therapeutic targets for allergic diseases in the human FcεRI signaling pathway. Immunopharmacology. 2000;48:269–281
  9. Daeron M. Fc receptor biology. Annu Rev Immunol. 1997;15:203–234
  10. Suzuki H, Takei M, Yanagida M, Nakahata T, Kawakami T, Fukamachi H. Early and late events in Fc epsilon RI signal transduction in human cultured mast cells. J Immunol. 1997;159:5881–5888
  11. Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, et al. Fcε receptor I-associated lyn-dependent phosphorylation of Fcγ receptor IIB during negative regulation of mast cell activation. J Immunol. 1998;160:1647–1658
  12. Kepley CL, Zhang K, Zhu D, Saxon A. FcεRI-FcγRII co-aggregation inhibits IL-16 production from human Langerhans-like dendritic cells. Clin Immunol. 2003;108:89–94
  13. Kepley CL, Mackay G, Zhu D, Morel PA, Zhang K, Saxon A. SHIP-Grb2-Dok complexes prevent FcεRI-mediated human mast cell activation and regulate FcγRII-mediated inhibition. J Biol Chem. 2004;279:35139–35149
  14. Zhang K, Kepley CL, Terada T, Zhu D, Perez H, Saxon A. Inhibition of allergen specific IgE reactivity by a human Ig Fcγ-Fcε bifunctional fusion protein. J Allergy Clin Immunol. 2004;114:321–327
  15. Allen LC, Kepley CL, Saxon A, Zhang K. Modifications to an Fcgamma-Fcvarepsilon fusion protein alter its effectiveness in the inhibition of FcvarepsilonRI-mediated functions. J Allergy Clin Immunol. 2007;120:462–468
  16. Mertsching E, Bafetti L, Hess H, Perper S, Giza K, Allen LC, et al. A mouse Fcγ-Fcε protein that inhibits mast cells through activation of FcγRIIB, SHIP-1 and SHP. J Allergy Clin Immunol. 2007;[Epub ahead of print]
  17. Zhao W, Kepley CL, Morel PA, Okomoto LM, Fukuoka Y, Schwartz LB. Fc gamma RIIa, not Fc gamma RIIb, is constitutively and functionally expressed on skin derived human mast cells. J Immunol. 2006;177:694–701
  18. Yamada T, Zhu D, Zhang K, Saxon A. Inhibition of human IgE class switch recombination by a human Ig Fc gamma-Fc epsilon chimeric protein. J Biol Chem. 2003;278:32818–32824
  19. Schelegle ES, Gershwin LJ, Miller LA, Fanucchi MV, Van Winkle LS, Gerriets JP, et al. Allergic asthma induced in rhesus monkeys by house dust mite (Dermatophagoides farinae). Am J Pathol. 2001;158:333–341
  20. Van Scott MR, Hooker JL, Ehrmann D, Shibata Y, Kukoly C, Salleng K, et al. Dust mite-induced asthma in cynomolgus monkeys. J Appl Physiol. 2004;96:1433–1444
  21. Van Scott MR, Aycock D, Cozzi E, Salleng K. Stallings HW III. Separation of bronchoconstriction from increased ventilatory drive in a nonhuman primate model of chronic allergic asthma. J Appl Physiol. 2005;99:2080–2086
  22. Terada T, Zhang K, Belperio J, Saxon A. A chimeric human-cat Fcgamma-Fel d1 fusion protein inhibits systemic, pulmonary, and cutaneous allergic reactivity to intratracheal challenge in mice sensitized to Fel d1, the major cat allergen. Clin Immunol. 2006;120:45–56
  23. Tam SW, Demissie S, Thomas D. A bispecific antibody against human IgE and human FcgammaRII that inhibits antigen-induced histamine release by human mast cells and basophils. Allergy. 2004;59:772–780

 Supported by United States Public Health Service–National Institutes of Health grant AI-15251 and a gift from the Food Allergy Initiative. C.L.K. and K.Z. were supported by the Food Allergy and Anaphylaxis Network.

 Disclosure of potential conflict of interest: A. Saxon and K. Zhang have patent licensing arrangements with the University of California. C. Kepley has received grant support from the Food Allergy Anaphylaxis Network.

PII: S0091-6749(07)01959-8

doi: 10.1016/j.jaci.2007.10.017

The Journal of Allergy and Clinical Immunology
Volume 121, Issue 2 , Pages 320-325 , February 2008

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