Molecular targets on mast cells and basophils for novel therapies

Ilkka T. Harvima*, Francesca Levi-Schaffer, Petr Draber, Sheli Friedman, Iva Polakovicova, Bernhard F. Gibbs, Ulrich Blank, Gunnar Nilsson, Marcus Maurer

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

122 Scopus citations

Abstract

Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain-containing inositol 5′ phosphatase 1 activity or by blocking sphingosine-1-phosphate. Therapeutic interventions in mast cell-associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcγRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented.

Original languageAmerican English
Pages (from-to)530-544
Number of pages15
JournalJournal of Allergy and Clinical Immunology
Volume134
Issue number3
DOIs
StatePublished - Sep 2014

Bibliographical note

Funding Information:
Supported by the COST Action BM1007 “Mast cells and Basophils: targets for innovative therapies .” I.T.H. was supported, in part, by the Cancer Center of Eastern Finland and VTR funding of Kuopio University Hospital . F.L.-S.'s research is supported, in part, by grants from the Israel Science Foundation (grant 213/05 ); the MAARS (Microbes in Allergy and Autoimmunity Related to the Skin) EU 7th framework (grant no. HEALTH-F2-2011-261366 ); and the Aimwell Charitable Trust (London, United Kingdom). P.D. and I.P. were supported, in part, by project COST CZ LD12073 from Ministry of Education of the Czech Republic and grants 14-00703S , 14-09807S , and P302/12/G101 from the Czech Science foundation and by the Institute of Molecular Genetics ASCR ( RVO 68378050 ). I.P. was supported in part by the Faculty of Science, Charles University, Prague . U.B is supported by the French National Research Agency ( ANR-12-ISV3-0006-01 ), the Investissements d’Avenir programme ANR-11-IDEX-0005-02 , Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX.

Funding Information:
Disclosure of potential conflict of interest: I. T. Harvima has received travel support from the European Union COST action BM1007 and is employed by the University of Eastern Finland and Kuopio University Hospital. F. Levi-Schaffer has received research support from the Israel Science Foundation and the European Union FP7 Collaborative Project ; has received travel support from the European Union COST action BM1007; has a patent for CD48 as a novel target for antiasthmatic and antiallergic therapy and as a marker for early prediction of allergy issued; has a patent for bi-specific complexes for targeting cells involved in allergic-type reactions, compositions, and uses thereof issued; and has a patent on sialic acid–binding immunoglobulin-like lectin 7 and treatment of mast cell–related pathologies pending. P. Draber has received research support from the Ministry of Education of the Czech Republic , the Czech Science Foundation , and the Institute of Molecular Genetics ASCR and has received travel support from the European Union COST action BM1007. I. Polakovicova has received research support from the Ministry of Education of the Czech Republic , the Czech Science Foundation , and the Faculty of Science of Charles University and has received travel support from the European Union COST action BM1007. B. F. Gibbs has received travel support from the European Union COST action BM1007; is employed by the University of Kent; has received research support from Leverhulme Trust ; and has received payment for lectures from the University of Virginia, Southampton, Kings College London, and ALK-Abelló. U. Blank has received research support from the French National Research Agency and the Investissements d'Avenir programme ANR-11-IDEX-0005-02 , Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX and has received travel support from the European Union COST action BM1007. G. Nilsson has received research support from the Swedish Research Council and has received travel support from the European Union COST action BM1007. M. Maurer has received research support from Charit ; has received travel support from the European Union COST action BM1007; has consultant arrangements from Almirall, Bayer, Biofrontera, FAES, Genentech, GlaxoSmithKline, Recordati, Novartis, Sanofi Aventis, Merck Sharp Dohme, Moxie, UCB, and Uriach; is employed by Charité–Universitätsmedizin Berlin; and has received research support from FAES , Genentech , Novartis , Merck Sharp Dohme , Moxie , UCB , and Uriach . S. Friedman declares no relevant conflicts of interest.

Keywords

  • Mast cell
  • basophil
  • drug
  • mediator
  • receptor
  • signaling protein
  • survival protein
  • therapy

Fingerprint

Dive into the research topics of 'Molecular targets on mast cells and basophils for novel therapies'. Together they form a unique fingerprint.

Cite this