Mechanisms of Allergy: Important Discoveries

Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 214–226 DOI: 10.1159/000358740

Histamine Receptors and Antihistamines: From Discoveryto Clinical Applications

Mauro Cataldi a · Francesco Borriello b · Francescopaolo Granata b · Lucio Annunziato a · Gianni Marone b

a Department of Neuroscience, Reproductive and Odontostomatologic Sciences, and b Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), School of Medicine, University of Naples Federico II, Naples , Italy

H 4 R by several immune cells and its involvement in the development of allergic inflammation provide the ra-tionale for the use of anti-H 4 R antagonists in allergic and in other immune-related disorders.

© 2014 S. Karger AG, Basel

The discovery and characterization of histamine, its receptors and blocking drugs is one of the most fascinating chapters of the history of medicine. Pharmacologists, medicinal chemists, molecular bi-ologists and clinical immunologists all contributed to the synthesis and clinical application of some of the most successful and widely used drugs ever. Out-standing scientists worked in this field and two No-bel Prizes have been awarded for the discovery of histamine H 1 (Daniel Bovet in 1957) and H 2 (Sir James Black in 1988) receptor (H 1 R and H 2 R) an-tagonists. Although histamine was synthesized and characterized at the beginning of the last century, new knowledge of this mediator and its pharmaco-

Abstract

The synthesis and the identification of histamine marked a milestone in both pharmacological and im-munological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in aller-gic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine re-ceptors (H 1 R, H 2 R, H 3 R and H 4 R) have been identified. The Nobel Prize in Physiology and Medicine was award-ed to Daniel Bovet in 1957 for the discovery of antihis-tamines (anti-H 1 R) and to Sir James Black in 1988 for the identification of anti-H 2 R antagonists. Anti-H 1 R and an-ti-H 2 R histamine receptor antagonists have revolution-ized the treatment of certain allergic disorders and gas-tric acid-related conditions, respectively. More recently, anti-H 3 R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of

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Histamine Receptors and Antihistamines 215

logical properties continue to accumulate day by day. In the present chapter, we will review this ex-traordinary story with a special emphasis on its im-plications in allergy and clinical immunology.

The Discovery of Histamine

In 1907, Windaus and Vogt [1] chemically syn-thesized and, in 1910, Ackermann [2] isolated hista-mine as a metabolite of bacterial histidine fermenta-tion. Henry Dale, a young pharmacologist at Sir Wellcome’s research laboratories in London, was working on ergot fungi extracts that were used for the treatment of postpartum bleeding. Dale’s mis-sion was to identify the active ingredient(s) respon-sible for this activity [3] . Dale had the intuition that a novel substance could have a much higher contrac-tant activity on the uterus than all those identified so far. Watching a demonstration of the new in vitro assay for uterus contraction developed by Kehrer, a German obstetrician, he realized that the so-called ‘ergotinum dialysatum’ of Wernich was much more potent than ergot itself. With the help of the chemist George Barger, Dale isolated a new base from ergot-inum dialysatum that could replicate the effect of the dialysatum on a cat uterus [4, 5] .

In 1910, Dale and Laidlaw reported the first phys-iological characterization of β-imidazolyl ethyla-mine, the chemical formula of histamine [6] . This work remains a milestone in pharmacology for its exhaustive experimental approach and for the tre-mendous impact it had on future research. They demonstrated that this molecule caused vasodila-tion, the contraction of smooth muscles in the air-ways, uterus and the intestine, stimulated heart rate and contractility, and induced a shock-like syn-drome when injected into animals.

During the following decade, the effects of his-tamine administration were intensively investigat-ed. In 1920, Popielski [7] reported that histamine also affects the activity of the stomach by potently stimulating hydrochloric acid secretion in the dog. In 1924, Lewis and Grant [8] described the classic ‘triple response’ elicited by the subcutaneous injec-tion of histamine consisting of a red spot due to vasodilatation, a wheal which was the consequence

of increased permeability and flare due to an axon reflex.

During the first 20 years after the synthesis of his-tamine, it was unclear whether this mediator could have any physiological role. In 1927, C.H. Best et al. [9] isolated crystalline histamine from liver and lungs, providing formal evidence that histamine is physiologically present in the body. Later, W. Feld-berg and coworkers [10–12] provided compelling evidence that histamine is a mediator of experimen-tal anaphylaxis. In 1952, J.F. Riley and G.B. West [13, 14] demonstrated that mast cells are the predomi-nant cellular source of histamine. Subsequently, ba-sophil leukocytes were identified as the main source of histamine among blood cells [15] .

The Synthesis of the First Antihistamines

and the Identification of H 1 R

In 1937, while working in the laboratory of Ernest Fourneau at the Institut Pasteur in Paris, Daniel Bovet started a research program aiming to identify new drugs that could block the actions of histamine. Bovet tested several compounds that were part of the large collection of molecules previously synthesized by Fourneau [16] . He described two benzodioxanes, compound 883 F and compound 933 F, which were slightly effective in preventing histamine shock in guinea pig [17–19] . Based on these results, twenty con-geners of these compounds were synthesized leading, in 1937, to the identification of the first potent hista-mine antagonists, thymoxyethyldiethylamine (929 F) [20] and N,N’-diethyl-N’-phenyl-N’-ethylethylenedi-amine (1571 F) [21] . Unfortunately, these compounds proved to be too toxic for clinical development. More effective and better-tolerated compounds were soon developed by chemical modification of their structure. Bernard Halpern [22] first used N’-dimethylethylene-diamine clinically, which matched the requirements of safety and efficacy for clinical development in hu-mans. It has been marketed since 1942 by Rhone-Pou-lenc under the brand name of Antergan. This com-pound was soon replaced by its derivative, mepyra-mine, which was marketed under the brand name of Neo-Antergan and for years represented the gold stan-dard of histamine H 1 R antagonists.

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The Identification of H 2 R and the Synthesis

of the First H 2 Blockers

In the late 1940s, it became clear that some of the actions of histamine were refractory to inhibition by classical antihistamines. In particular, mepyramine did not block the effects of histamine on heart rate and on gastric hydrochloric acid secretion [23, 24] . In 1948, Folkow et al. [25] first suggested that two different classes of histamine receptors should exist because the antihistamine blocker Benadryl could block the vasodilator effect of low, but not of high concentrations of histamine. A limitation of those studies was the absence of a mathematical model to analyze the interactions between increasing concen-trations of agonists (e.g. histamine) and antagonists (e.g. antihistamines). In 1947, Hans Schild [26] de-scribed a mathematical method for the evaluation of drug antagonism (the pA2 value). In particular, he evaluated the effects of two antihistamines (Neo-Antergan and Benadryl) on histamine-induced ile-um contraction. By applying the pA2 method, Ash and Schild [27] showed that H 1 R antagonized by meperidine and diphenhydramine mediate the ef-fects of histamine on intestinal and uterine tone. Whilst not specifically stated in their 1966 paper, the results implied that other receptor(s) could be re-sponsible for the histamine effects insensitive to classical antihistamines.

The discovery of histamine H 2 R is linked to the name of the Nobel Laureate Sir James Black [28] . He hypothesized that anti-H 2 drugs should be more similar to histamine because anti-H 1 compounds were significantly different to histamine. Therefore, the idea behind the project was to modify the mol-ecule of histamine. This approach led to the identi-fication of burimamide that blocked histamine ef-fects on both the beating guinea pig atrium and the rat gastric acid secretion [29] . These findings, com-municated in a classical paper in Nature in 1972 [29] , provided the first pharmacological demonstration of H 2 R distinct from H 1 R. After burimamide, sev-eral other H 2 R antagonists were developed that rev-olutionized the treatment of peptic ulcer [28, 30, 31] .

Evidence that histamine acting through H 2 R in-duces both a G s -dependent increase in intracellular cAMP concentrations and a G q -dependent increase

in [Ca 2+ ] i was obtained in different tissue and cell preparations, including gastric mucosal cells, vascu-lar smooth muscle cells, brain slices and adipocytes [32] . In 1973, Lichtenstein and Gillespie [33] report-ed that H 2 R are functionally present on human ba-sophils. Subsequently, H 2 R were found on rodent mast cells [34] , human eosinophils [35, 36] and hu-man neutrophils [37] .

Histamine in the Brain

When Antergan entered clinical use, it was re-ported that it induced marked sedation. It soon be-came clear that this characteristic was typical of the entire class of the first generation of anti-H 1 drugs. In 1943, Kwiatkowski found small amounts of hista-mine in different brain regions. With the develop-ment of antibodies directed against histidine decar-boxylase, different groups mapped histaminergic neurons and their projections in the brain [38–41] . Histaminergic neurons are localized in the tuber-omammillary nucleus of the hypothalamus, project to all major areas of the brain, and are involved in several functions including the regulation of sleep/wakefulness, feeding and memory processes. The presence of histaminergic neurons and H 1 R in the brain underlies the sedative effects of the classical H 1 antagonists. There are also H 2 R in the brain, but their functions are more limited compared to H 1 R and H 3 R [42] .

In 1983, Jean-Charles Schwartz and colleagues [43] reported that histamine does inhibit its own re-lease in the isolated rat brain cortex. This histamine inhibitory activity was mimicked with an higher po-tency by N α - and N α ,N α -methylhistamine, two com-pounds weakly effective on H 1 R and H 2 R; in addi-tion, H 1 R or H 2 R agonists, as well as H 1 R antago-nists, were ineffective [43] . Conversely, several H 2 blockers, like burimamide, and the H 2 R partial ago-nist impromidine, antagonized histamine release autoinhibition [43] . These effects were observed at concentrations much higher than those required to block H 2 R. Importantly, Schild plot analysis demon-strated that these effects could not be explained as an action on H 2 R [43] . Based on these findings it was proposed that an H 3 R could exist in the brain. The

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Histamine Receptors and Antihistamines 217

same group reported the synthesis of selective li-gands for H 3 R, including the agonist (R)-α-methylhistamine and the antagonist thioperamide [44] . Using selective H 3 R agonists and antagonists it was shown that signal transduction by the H 3 R is mediated by pertussis toxin-sensitive G i /G o proteins leading to a decrease in intracellular cAMP concen-trations [45, 46] and to a decrease in extracellular Ca 2+ influx in neurons [47] .

The group of Manfred Göthert showed that H 3 R also inhibit the release of other neurotransmitters, including noradrenaline and serotonin [48–52] . Thus, histamine H 3 R modulate neurotransmitter re-lease acting as presynaptic autoreceptors or hetero-receptors.

There is compelling evidence that H 3 R could be involved in several neurological diseases like sleep-wake disorders, Alzheimer’s disease and cognitive disorders, as well as in obesity [53] . Several H 3 R ago-nists and inverse agonists/antagonists have been synthesized and some of these compounds are now being tested for therapeutic use in neurological dis-orders and obesity [53, 54] .

Cloning of H 1 R, H 2 R and H 3 R, and Generation

of Histamine Receptor Knockout Mice

Molecular biology entered the field of histamine pharmacology in the 1990s with the cloning of his-tamine receptors and the generation of histamine re-ceptor knockout mice. In 1991, Gantz et al. [55] cloned the canine H 2 R gene. Molecular biologists in different laboratories were rapidly successful in cloning the H 2 R gene from other species, including human [56] , rat [57] and guinea pig [58] . Once the H 2 R cDNAs were cloned, detailed studies on the tis-sue distribution of these receptors became possible, confirming and extending previous functional data showing that these receptors are highly expressed in a variety of tissues and immune cells [59–61] .

Cloned H 2 R were heterologously expressed for signal transduction and structure-activity studies. The group of Henk Timmerman [62] demonstrated that recombinant rat H 2 R heterologously expressed in CHO cells have a spontaneous activity that can be inhibited by H 2 antagonists. This observation was

made when the allosteric theory of receptor activity was rapidly becoming popular after the seminal work on mutant adrenergic receptors by Robert Lefkowitz et al. [63] . Following the publication of Timmerman’s paper, H 2 antagonists became the paradigmatic example of inverse agonists in phar-macology. It should be noted that, similar to the Schild plot analysis, another fundamental concept in pharmacology found a relevant application in hista-mine research.

In 2000, Kobayashi et al. [64] generated H 2 R knockout mice. Homozygous mutant mice were phenotypically normal and, unexpectedly, showed normal basal gastric pH. A marked hypertrophy of gastric mucosa and high circulating levels of gastrin were found in these mice, suggesting that when the histamine-dependent major regulatory system of hydrochloric acid secretion is genetically destroyed, compensatory mechanisms are activated to main-tain normal gastric secretion. Interestingly, these mice showed a dysregulated T lymphocyte activity. H 2 R knockout mice display upregulation of both Th1 and Th2 cytokines and decreased OVA-specific IgE production compared with wild-type and H 1 R knockout mice [65] .

H 2 R gene expression increased in human inter-leukin (IL)-4+ T cells upon bee venom exposure of non-allergic beekeepers [66] and in basophils during the first hours of ultra-rush venom immunotherapy [67] . H 2 R upregulation was responsible for the inhi-bition of IL-4 and the stimulation of IL-10 secretion by IL-4+ T cells [66] as well as the inhibition of his-tamine release and cytokine secretion from baso-phils [33, 67] . In addition, activation of H 2 R inhibits histamine release from rodent mast cells [34] , neu-trophil activation [37] , eosinophil chemotaxis [35] and degranulation [36] , γδ T cell-mediated cytotox-icity [68] , and reduces the inflammatory response of dendritic cells (DCs) to microbial ligands [69, 70] .

Owing to the inhibitory effect exerted on several immune cells, H 2 R may play a role in the develop-ment of allergy and possibly other immune-mediat-ed disorders. Interestingly, the use of histamine di-hydrochloride (a salt of histamine) in conjunction with low-dose IL-2 has been proposed as a relapse-preventive immunotherapy for patients with acute myeloid leukemia [71, 72] . It is thought that myeloid

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cell-derived reactive oxygen species inhibit natural killer (NK) cell-mediated killing of human acute myeloid leukemia blasts. Histamine via H 2 R protects NK cells from myeloid cell-dependent inactivation, probably through inhibition of reactive oxygen spe-cies production [73] .

In 1991, Yamashita et al. [74] cloned the H 1 R gene. Thanks to H 1 R cDNA cloning, the tissue dis-tribution of these receptors could be studied by Northern blot analysis. The expression of H 1 R was found to be high in the lung and small intestine, moderate in the adrenal medulla and uterus, and low in the cerebral cortex and spleen [74] . The H 1 R was later cloned in other species including mouse [75] , rat [76] and human [77] . Heterologously expressed H 1 R triggered the activation of phospholipase C, the accumulation of IP 3 and an increase in [Ca 2+ ] i via G q proteins [78, 79] .

Studies on recombinant H 1 R also helped to clar-ify the apparent paradox of the increase in intracel-lular cAMP concentration blocked by H 1 blockers that had been reported since the end of the 1970s in different native preparations [80, 81] . Working on heterologously expressed human H 1 R in CHO cells, Maruko et al. [82] demonstrated that adenylate cy-clase is indirectly activated upon H 1 R activation via G βγ subunits released from G q proteins.

In 1996, Inoue et al. [75] produced knockout mice for the H 1 R. The study of these animals con-firmed and extended previous knowledge on the physiological roles of H 1 -mediated histamine ef-fects. H 1 R knockout mice have an impairment in lo-comotor activity and exploratory behavior, and a de-crease in aggression and anxiety [83] . The study of the behavioral effect of H 1 R raised great interest be-cause of its possible implications in the pharmaco-logical activity of antipsychotic drugs, a class of com-pounds also acting on H 1 R [84] . In addition, studies performed on these knockout mice provided evi-dence that histamine via H 1 R could be involved in the neurotensin anorexic effect [85] . H 1 R knockout mice also showed a significant impairment in noci-ception and an enhancement in the sensitivity to the analgesic effect of morphine, confirming the role of these receptors in pain perception [83, 86, 87] .

H 1 R knockout mice showed lower percentages of IFN-γ-producing T cells and produced more OVA-

specific IgG1 and IgE compared with wild-type mice [65] . Interestingly, although allergen-stimulated T cells from H 1 R knockout mice exhibited an en-hanced production of Th2 cytokines, allergen-chal-lenged H 1 R knockout mice showed reduced lung Th2 cytokines associated with lower airway inflam-mation, goblet cell metaplasia and airway hyperre-sponsiveness. These conflicting results can be ex-plained, at least in part, considering that histamine promotes T cell chemotaxis. Thus, defective T cell trafficking could be responsible for reduced lung in-flammation in allergen-challenged H 1 R knockout mice [88] .

The effects of histamine acting via H 1 R on the im-mune system extend well beyond those described for T cells. Human lung macrophages (HLM), monocyte-derived macrophages (MDM) and monocyte-derived DCs express higher levels of H 1 R compared with pre-cursor monocytes. Histamine induces the release of pro-inflammatory mediators (β-glucuronidase, IL-8 and IL-6) by MDM and HLM through the activation of H 1 R [89–91] .

Interestingly, gene variability of the H 1 R can in-fluence the risk of developing specific disorders. Bphs , one of the first non-major histocompatibility complex-linked genes associated with the suscepti-bility of murine models to autoimmune diseases, was identified with the H 1 R [92] . In addition, poly-morphisms of the H 1 R were associated with the risk of developing Parkinson’s disease [93] .

Despite the intense efforts of several laboratories, H 3 R cloning proved a formidable task. It was not until 1999 that Lovenberg et al. [94] attained this im-portant result by a reverse approach. They were working at R.W. Johnson Pharmaceutical Research Institute on the identification of orphan GPCR. Among the almost 30 different orphan receptors they identified GPCR97, which was highly expressed in the brain and showed a significant structural ho-mology with several members of the biogenic amine receptor superfamily. When heterologously ex-pressed in different cell lines this receptor conferred a high responsiveness to the inhibitory action of his-tamine on adenylate cyclase activity, thus behaving as a new histamine receptor: it was dubbed the H 3 R [94, 95] . Recombinant H 3 R showed a pharmacolog-ical profile indistinguishable from H 3 R [94] . Impor-

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Histamine Receptors and Antihistamines 219

tantly, as observed for H 2 R, H 3 R also showed a rel-evant constitutive activity in heterologous expres-sion systems [96, 97] . Evidence that these receptors are also constitutively activated in native prepara-tions was reported, suggesting that they could also regulate neurotransmitter release in the absence of histamine [98] .

Different isoforms of the H 3 R were identified both in humans [99] and in rodents [95, 100] . Evi-dence was reported for isoform-specific differences in signal transduction as some isoforms, but not all, activated the MAPK cascade and caused arachidon-ic acid release [95, 100] . Once the H 3 gene was cloned, the tissue distribution of this receptor was explored by RT-PCR and in situ hybridization. These studies confirmed its preferential localization in the brain with minor expression in other tissues, including stomach, intestine, skin and thymus [100, 101] .

In 2002, Toyota et al. [102] reported the genera-tion of H 3 R knockout mice. Unexpectedly, these mice showed a decrease in locomotor activity, wheel-running behavior and body temperature, which was interpreted as the consequence of compensatory mechanisms, such as H 1 R downregulation, triggered by the increased availability of histamine in the syn-apse. Similarly, a mild obesity [103] and a reduction in anxiety [104] were reported in these mice.

Identification and Cloning of H 4 R

At the end of 2000, both Oda et al. [105] and Na-kamura et al. [106] reported the cloning of a new histamine receptor that they designated H 4 R. This result was attained by screening the human genome database for sequences similar to that of H 3 R. The newly cloned receptor showed a very limited ho-mology with all the known histamine receptors (ap-proximately 31% with H 3 R and only 23% and 22% with H 1 R and H 2 R, respectively). The existence of similar receptors was confirmed in other animal species, including mouse, rat, monkey, pig and guinea pig [107–109] . With the discovery of the H 4 R gene, the pharmacology of these receptors could be accurately defined in heterologous expression sys-tems. It was established that whereas the pharmaco-

logical profile of H 4 R is different from that of H 1 R and H 2 R, some overlap does exist with H 3 R. Spe-cifically, thioperamide acts as an inverse agonist both on H 3 R and on H 4 R and (R)-α-methylhista-mine, immepip and imetit activate both these class-es of receptors [110] . Conversely, clobenpropit and burimamide block H 3 R and activate H 4 R [111] . These initial pharmacological data showed that no available drug could distinguish between H 4 R and H 3 R, and prompted the development of selective H 4 R-acting drugs. To this aim, Jablonowski et al. [110] , working at the Johnson & Johnson pharma-ceutical research laboratories, started a high-throughput screening program to identify in the company compound collection new molecules act-ing on recombinant H 4 R. This effort led to the iden-tification of several indolylpiperazine whose SAR analysis provided useful information needed for the synthesis of the first selective H 4 R blocker, com-pound JNJ 7777120 [110, 112] .

H 4 R is preferentially expressed on immune cells, namely eosinophils [113, 114] , basophils [115] , mast cells [112, 116, 117] , NK cells, DCs, monocytes [118] and T cells [68, 119–122] . The activation of this re-ceptor is emerging as an important mechanism for the modulation of chemotaxis as well as several oth-er functions of these cells [59] .

Hofstra et al. [117] demonstrated that H 4 R mod-ulates mast cell chemotaxis by a G i/o -dependent PTX-sensitive mechanism. Mast cells from wild-type and H 3 R-deleted mice migrated in response to histamine, while mast cells from the H 4 R-deleted mice did not. Conversely, no role for H 4 R could be demonstrated in IgE-dependent mast cell degranu-lation [117] . Compound JNJ 7777120 prevented his-tamine-induced [Ca 2+ ] i increase as well as mast cell chemotaxis and submucosal mast cell accumulation in the trachea of mice after histamine inhalation [112] . By using siRNAs directed against H 4 R, Godot et al. [116] showed that histamine acting through H 4 R enhanced CXCL12-induced chemotaxis of mast cell precursors, but not mature mast cells. A role for H 4 R was also demonstrated in the modula-tion of eosinophil chemotaxis [113, 114] . Recently, it was shown in a mouse model of allergic rhinitis that histamine released from mast cells recruits H 4 R-expressing basophils to the nasal cavity, an event that

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was required for the development of early- or late-phase nasal responses following allergen challenge [115] .

A role in the control of lymphocyte activity was also proposed based on the evidence that H 4 R block-ers prevent histamine-induced IL-16 release by hu-man CD8 T cells [119] . This could be of particular importance because IL-16 induces the chemotaxis of several immune cells (CD4 T lymphocytes, eosino-phils and DCs) [123–125] and has been found in the bronchoalveolar fluid of allergen- or histamine-challenged asthmatics [126–128] . In addition, this

cytokine is highly expressed by eosinophils and mast cells [129] in the bronchial mucosa of atopic asth-matics [130] . H 4 R is also expressed by CD4 T cells and intratracheal administration of an H 4 R agonist-mitigated airway inflammation in a murine model of allergic asthma. This anti-inflammatory effect was associated with an increase in IL-10 and IFN-γ, and a decrease in IL-13 in the bronchoalveolar lavage flu-id as well as the recruitment of FoxP3+ T cells. In vitro data confirmed that, among T lymphocytes, a specific H 4 R agonist preferentially induces the che-motaxis of CD4+CD25+FoxP3+ cells [122] .

Fig. 1. Schematic representation of the expression of histamine receptors in inflammatory and immune cells. Histamine, contained in human mast cells ( MC; ∼ 3 pg/cell) and basophils ( Bas; ∼ 1 pg/cell), can be released by immunologic and non-immunologic stim-uli. Histamine via H 4 R induces the chemotaxis of several immune cells, namely mast cell precursors, basophils, eosinophils (Eos), monocytes (Mono), DCs, IL-2-activated NK cells, γδ T cells and reg-ulatory T cells (Treg). Moreover, H 4 R activation induces IL-16 and IL-31 secretion by CD8 T cells and Th2 lymphocytes, respectively, and enhances cytokine secretion from invariant NK T (iNKT) cells. H 2 R exerts mainly an inhibitory effect on immune cells. H 2 R activa-tion inhibits human basophil degranulation and cytokine secre-

tion, histamine release from rodent mast cells, neutrophil activa-tion, eosinophil chemotaxis and degranulation, γδ T cell-mediated cytotoxicity, and reduces the pro-inflammatory response of DCs to microbial ligands. H 2 R negatively regulates both Th1 and Th2 lym-phocytes. In addition, H 2 R gene expression increases in human IL-4+ T cells upon bee venom exposure in non-allergic beekeepers and its activation inhibits IL-4 and stimulates IL-10 secretion. Hista-mine enhances Th1 responses by triggering the H 1 R. HLM, MDM and monocyte-derived DCs express higher levels of H 1 R compared with precursor monocytes. Histamine induces the release of pro-inflammatory mediators (β-glucuronidase, IL-8 and IL-6) by HLM and MDM through the activation of H 1 R.

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Although the latter study suggests that H 4 recep-tor activation protects from allergic airway inflam-mation, it should be noted that H 4 R agonists were administered intratracheally and before antigen challenge. In addition, possible discrepancies be-tween human and mouse cells should be taken into account. For example, conversely to what has been observed in mice, H 4 R is highly expressed by Th2 cells or CD4 T cells stimulated with IL-4. Moreover, polyclonally activated peripheral blood mononucle-ar cells or Th2 cells stimulated with H 4 R agonists upregulated IL-31 mRNA, a cytokine involved in skin allergic inflammation and the induction of pru-ritus. Specific H 4 agonists have been shown to in-duce itch, whereas pretreatment with H 4 R antago-nists reduced the itch response to either H 4 agonists

or histamine. Interestingly, the effects of H 4 R antag-onists on pruritus are enhanced by the concurrent blockade of H 1 R [131–133] . Thus, H 4 R might con-tribute to skin allergic inflammation by activating Th2 cells and inducing pruritus via IL-31 [120] .

In summary, although the balance between pro-inflammatory and anti-inflammatory effects of H 4 R needs to be fully elucidated and requires further in-vestigation, these findings suggest that H 4 R could play a role in allergic inflammation and could, there-fore, be a potential target for drug intervention.

H 4 R has also been involved in the pathogenesis of non-allergic disorders. H 4 R blockade decreased neutrophil accumulation in experimental models of peritonitis [112] and pleurisy [134] . Moreover, H 4 R activation induces chemotaxis of IL-2-activated NK

1920: Popielski reports thathistamine stimulates gastricacid secretion

1942: Halpern reports thefirst clinical use of anti-H1R

1973: Lichtensteinidentifies H2R onhuman basophils

2003: Identification ofthe first H4R antagonist

1987: Schwartz reports thesynthesis of H3R ligands

1983: Schwartz identifies H3R in rat brain cortex

1955: Basophils are the main source of histamine among bloodcells

1952: Riley and West demonstrate the presence of histamine in mastcells

1910: Dale and Laidlaw describe thephysiological effects of histamine

1907: Windaus and Vogt chemically synthesizehistamine

1924: Lewis and Grant describe the classic‘triple response’ elicited by thesubcutaneous injection of histamine

1937: Bovet identifies the firstantihistamine

1988: Black is awarded the Nobel Prize inPhysiology and Medicine

1991: Cloning of H1R

1991: Cloning of H2R

1999: Cloning of H3R

2000: Cloning ofH4R

1957: Bovet is awarded the Nobel Prize inPhysiology and Medicine

1972: Black identifieshistamine H2R

1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

Fig. 2. A timeline of the major breakthroughs in histamine research.

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cells, DCs, THP-1 cells (a human acute monocytic leukemia cell line) [118] and γδ T cells [68] , and en-hances cytokine secretion from invariant NK T cells [121] ( fig. 1 ). Recently, a role for H 4 R has also been proposed in diabetes, cancer, neuropathic pain and vestibular disorders [135] .

Collectively, these results provide the rationale for the development of a new generation of selective antagonists of H 4 R [136] . A first oral H 4 R antago-nist, compound UR-63325 synthesized by Palau Pharma, has entered clinical trials [137] . In addition, dual H 1 R/H 4 R antagonists and/or the combination of H 1 R and H 4 R antagonists could pave the way for the development of new therapeutic strategies for certain inflammatory and immunological disorders.

Closing Thoughts

Since the discovery of histamine almost 100 years ago, several breakthroughs have marked this field of research ( fig. 2 ). Four histamine receptors have been characterized so far (H 1 R, H 2 R, H 3 R and H 4 R), and an important role for histamine has been identified in several physiological and pathological responses. In particular, histamine acting through H 1 R or H 2 R plays a fundamental role in the development of al-lergic disorders and in the regulation of gastric acid secretion, respectively. Although all histamine re-ceptors are expressed in the brain, the preferential expression of H 3 R in the central nervous system un-derlies its pivotal role in the regulation of basic ho-meostatic and higher functions, including cogni-

tion, arousal, circadian and feeding rhythms. Final-ly, the role of H 4 R in the modulation of several aspects of the immune response is now increasingly being appreciated.

Several histamine receptor antagonists/agonists have been synthesized over the last century, some of them already used for the treatment of allergic and gastric acid-related disorders (anti-H 1 R and anti-H 2 R, respectively), and others being tested in clinical trials for neurologic and immune-mediated disor-ders (anti-H 3 R and anti-H 4 R, respectively).

Despite these great advances, several questions remain to be answered. First of all, we cannot ex-clude the existence of histamine receptors beyond the four currently known. Moreover, the sequential activation of histamine receptors on immune cells and their roles in chronic inflammatory diseases as well as therapeutic procedures (e.g. vaccines and venom immunotherapy) remains to be fully eluci-dated. Further examination of this important immu-noregulatory network will likely lead to new advanc-es in our understanding of immune-mediated disor-ders and could pave the way for a more thoughtful clinical exploitation of histamine receptor agonists/antagonists.

Acknowledgements

This work was supported in part by grants from the Ministero dell’Istruzione, Università e Ricerca (MIUR), the Istituto Superiore di Sanità AIDS project ‘Role of Ba-sophils in HIV-1 Infection’, the Regione Campania ‘CISI-Lab Project’, CRÈME Project and TIMING Project.

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116 Godot V, Arock M, Garcia G, Capel F, Flys C, Dy M, Emilie D, Humbert M: H4 hista-mine receptor mediates optimal migra-tion of mast cell precursors to CXCL12. J Allergy Clin Immunol 2007; 120: 827–834.

117 Hofstra CL, Desai PJ, Thurmond RL, Fung-Leung WP: Histamine H4 receptor mediates chemotaxis and calcium mobili-zation of mast cells. J Pharmacol Exp Ther 2003; 305: 1212–1221.

118 Damaj BB, Becerra CB, Esber HJ, Wen Y, Maghazachi AA: Functional expression of H4 histamine receptor in human natural killer cells, monocytes, and dendritic cells. J Immunol 2007; 179: 7907–7915.

119 Gantner F, Sakai K, Tusche MW, Crui-kshank WW, Center DM, Bacon KB: His-tamine H 4 and H 2 receptors control hista-mine-induced interleukin-16 release from human CD8 + T cells. J Pharmacol Exp Ther 2002; 303: 300–307.

120 Gutzmer R, Mommert S, Gschwandtner M, Zwingmann K, Stark H, Werfel T: The histamine H4 receptor is functionally ex-pressed on TH2 cells. J Allergy Clin Im-munol 2009; 123: 619–625.

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121 Leite-de-Moraes MC, Diem S, Michel ML, Ohtsu H, Thurmond RL, Schneider E, Dy M: Cutting edge: histamine receptor H4 activation positively regulates in vivo IL-4 and IFN-γ production by invariant NKT cells. J Immunol 2009; 182: 1233–1236.

122 Morgan RK, McAllister B, Cross L, Green DS, Kornfeld H, Center DM, Cruikshank WW: Histamine 4 receptor activation in-duces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine mod-el. J Immunol 2007; 178: 8081–8089.

123 Center DM, Cruikshank W: Modulation of lymphocyte migration by human lympho-kines. 1. Identification and characteriza-tion of chemoattractant activity for lym-phocytes from mitogen-stimulated mono-nuclear cells. J Immunol 1982; 128: 2563–2568.

124 Kaser A, Dunzendorfer S, Offner FA, Ryan T, Schwabegger A, Cruikshank WW, Wie-dermann CJ, Tilg H: A role for IL-16 in the cross-talk between dendritic cells and T cells. J Immunol 1999; 163: 3232–3238.

125 Rand TH, Cruikshank WW, Center DM, Weller PF: CD4-mediated stimulation of human eosinophils: lymphocyte chemoat-tractant factor and other CD4-binding li-gands elicit eosinophil migration. J Exp Med 1991; 173: 1521–1528.

126 Lim KG, Wan HC, Resnick M, Wong DT, Cruikshank WW, Kornfeld H, Center DM, Weller PF: Human eosinophils release the lymphocyte and eosinophil active cyto-kines, RANTES and lymphocyte chemoat-tractant factor. Int Arch Allergy Immunol 1995; 107: 342.

127 Mashikian MV, Tarpy RE, Saukkonen JJ, Lim KG, Fine GD, Cruikshank WW, Cen-ter DM: Identification of IL-16 as the lym-phocyte chemotactic activity in the bron-choalveolar lavage fluid of histamine-challenged asthmatic patients. J Allergy Clin Immunol 1998; 101: 786–792.

128 Krug N, Cruikshank WW, Tschernig T, Erpenbeck VJ, Balke K, Hohlfeld JM, Cen-ter DM, Fabel H: Interleukin 16 and T-cell chemoattractant activity in bronchoalveo-lar lavage 24 h after allergen challenge in asthma. Am J Respir Crit Care Med 2000; 162: 105–111.

129 Laberge S, Pinsonneault S, Ernst P, Oli-venstein R, Ghaffar O, Center DM, Hamid Q: Phenotype of IL-16-producing cells in bronchial mucosa: evidence for the hu-man eosinophil and mast cell as cellular sources of IL-16 in asthma. Int Arch Al-lergy Immunol 1999; 119: 120–125.

130 Laberge S, Ernst P, Ghaffar O, Cruikshank WW, Kornfeld H, Center DM, Hamid Q: Increased expression of interleukin-16 in bronchial mucosa of subjects with atopic asthma. Am J Respir Cell Mol Biol 1997; 17: 193–202.

131 Dunford PJ, Williams KN, Desai PJ, Karls-son L, McQueen D, Thurmond RL: Hista-mine H4 receptor antagonists are superior to traditional antihistamines in the atten-uation of experimental pruritus. J Allergy Clin Immunol 2007; 119: 176–183.

132 Marson CM: Targeting the histamine H4 receptor. Chem Rev 2011; 111: 7121–7156.

133 Yamaura K, Oda M, Suwa E, Suzuki M, Sato H, Ueno K: Expression of histamine H4 receptor in human epidermal tissues and attenuation of experimental pruritus using H4 receptor antagonist. J Toxicol Sci 2009; 34: 427–431.

134 Takeshita K, Sakai K, Bacon KB, Gantner F: Critical role of histamine H4 receptor in leukotriene B4 production and mast cell-dependent neutrophil recruitment in-duced by zymosan in vivo. J Pharmacol Exp Ther 2003; 307: 1072–1078.

135 Kiss R, Keseru GM: Histamine H4 receptor ligands and their potential therapeutic ap-plications: an update. Expert Opin Ther Pat 2012; 22: 205–221.

136 Thurmond RL, Gelfand EW, Dunford PJ: The role of histamine H1 and H4 receptors in allergic inflammation: the search for new antihistamines. Nat Rev Drug Discov 2008; 7: 41–53.

137 Salcedo C, Pontes C, Merlos M: Is the H4 receptor a new drug target for allergies and asthma? Front Biosci (Elite Ed) 2013; 5: 178–187.

Prof. Gianni Marone Department of Translational Medical Sciences andCenter for Basic and Clinical Immunology Research (CISI)Division of Clinical Immunology and Allergy University of Naples Federico II, via S. Pansini 5 IT–80131 Naples (Italy) E-Mail marone @ unina.it

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