Molecular targets on mast cells and basophils for novel therapies.
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.
Department of Dermatology and Cancer Center of Eastern Finland, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland. Electronic address: ilkka.harvima@kuh.fi.
Ilkka T
IT
Harvima
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Francesca
F
Levi-Schaffer
Department of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Petr
P
Draber
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Sheli
S
Friedman
Department of Signal Transduction, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Iva
I
Polakovicova
Medway School of Pharmacy, University of Kent, Kent, United Kingdom.
Bernhard F
BF
Gibbs
INSERM UMRS 699, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'excellence INFLAMEX, Paris, France.
Ulrich
U
Blank
Clinical Immunology and Allergy, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Gunnar
G
Nilsson
Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Marcus
M
Maurer
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001491:Basophils / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors; D015550:Cell Degranulation / Q000187:drug effects; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy*; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008407:Mast Cells / Q000276:immunology*; D058990:Molecular Targeted Therapy; D043882:Receptors, Cannabinoid / Q000378:metabolism; D017455:Receptors, IgE / Q000037:antagonists & inhibitors
D018926:Anti-Allergic Agents; D015815:Cell Adhesion Molecules; D007473:Ion Channels; D043882:Receptors, Cannabinoid; D017455:Receptors, IgE
Mast cell; basophil; drug; mediator; receptor; signaling protein; survival protein; therapy