The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H 3 /H 4 receptor antagonist thioperamide, but not by H 1 or H 2 receptor antagonists. This chemotactic response is mediated by the H 4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H 4 receptor-deficient mice but was detected in H 3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H 4 but not H 3 receptors on mast cells. Activation of H 4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both G␣i/o proteins and phospholipase C (PLC) are involved in histamineinduced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1- [6-[[17␤-3-methoxyestra-1,3,5 (10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H 4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.

Histamine is a multifunctional hormone that regulates smooth muscle contraction in the airways, acid secretion in the gut, and neurotransmitter release in the central nervous system through three well characterized receptor subtypes, H(1), H(2), H(3), respectively. As part of a directed effort to discover novel G-protein-coupled receptors through homology searching of genomic databases, we identified a partial clone (GPCR105) that had significant homology to the recently identified histamine H(3) receptor cDNA. Expression of the full-length human GPCR105 in cells confers the ability to bind [(3)H]histamine with high affinity (K(D) = 5 nM). GPCR105 is pharmacologically similar to the histamine H(3) receptor in that it binds many of the known H(3) agonists and antagonists, albeit with a different rank order of affinity/potency. GPCR105 does not bind (i.e., K(D) > 10 microM) all tested H(1) and H(2) receptor antagonists such as diphenhydramine, loratadine, ranitidine, and cimetidine, but has modest affinity for the H(2) receptor agonist, dimaprit (377 nM). Whereas the H(3) receptor is expressed almost exclusively in nervous tissues, GPRC105 is expressed primarily in bone marrow and eosinophils. Together, these data demonstrate that GPCR105 is a novel histamine receptor structurally and pharmacologically related to the H(3) receptor. However, its unique expression profile and physiological role suggest that GPCR105 is a fourth histamine receptor subtype (H(4)) and may be a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.

Histamine mediates its physiological function through binding to four known histamine receptors. Here, we describe the first selective antagonist of the histamine H 4 receptor, the newest member of the histamine receptor family, and provide evidence that such antagonists have anti-inflammatory activity in vivo.

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Antigen-specific T-cell activation requires the engagement of the T-cell receptor (TCR) with antigen as well as the engagement of appropriate costimulatory molecules. One of the most important pathways of costimulation is the interaction of CD28 on the T cell with B7-1/B7-2 on antigen-presenting cells. In the present study, we have examined the in vivo effects of blocking the CD28:B7 T-cell costimulatory pathway by administration of mCTLA4-IgG in a murine model of allergic asthma. Mice were sensitized with ovalbumin and exposed to repeated ovalbumin inhalation challenges. In mice treated with a control antibody at the time of ovalbumin challenge a significant increase in the number of eosinophils (12.8 +/- 4.3 x 10(3) cells, P < 0.05) in the bronchoalveolar lavage (BAL) fluid and airway hyperresponsiveness to methacholine (49 +/- 15%, P < 0.05) was observed. In addition, serum levels of ovalbumin-specific IgE were significantly (P < 0.01) increased after ovalbumin challenge compared with saline challenge (1,133 +/- 261 experimental units [EU]/ml and 220 +/- 63 EU/ml, respectively). In mice treated with mCTLA4-IgG at the time of ovalbumin challenge, the infiltration of eosinophils into BAL fluid and the development of airway hyperresponsiveness to methacholine were completely inhibited. The upregulation of ovalbumin-specific IgE levels in serum was attenuated by mCTLA4-IgG treatment. Furthermore, addition of mCTLA4-IgG to cultures of parabronchial lymph node cells from sensitized mice inhibited the ovalbumin-induced interleukin-4 production. These data indicate the therapeutic potential of blocking T-lymphocyte costimulation by CTLA4-IgG as a possible immunosuppressive treatment for patients with allergic asthma.