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Arthropod-Derived Histamine-Binding Protein Prevents Murine Allergic Asthma

Isabelle Couillin^*,, Isabelle Maillet^*,, B. Boris Vargaftig^¶, Muazzam Jacobs^||, Guido C. Paesen, Patricia A. Nuttall, Jean Lefort^¶, René Moser^||, Wynne Weston-Davies and Bernhard Ryffel^1,*

^* Centre National de la Recherche Scientifique, Institute Transgenose, Orleans, France; Key-Obs S. A., Orleans, France; Evolutec, Ltd., Oxford, United Kingdom; Centre for Ecology and Hydrology, Oxford, United Kingdom; ^¶ Deptartment of Pharmacology, Instituto de Ciências Biomédicas, University of S. Paulo, Brazil; and ^|| Institute for Biopharmaceutical Research, Matzingen, Switzerland

	Abstract

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Because histamine receptor type I blockade attenuates allergic asthma, we asked whether complete neutralization of histamine by an arthropod-derived, high affinity histamine-binding protein (EV131) would prevent allergic asthma. Intranasal administration of EV131 given before Ag challenge in immunized mice prevented airway hyperreactivity by 70%, and abrogated peribronchial inflammation, pulmonary eosinophilia, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The inhibitory effect of EV131 on bronchial hyperreactivity was comparable to that of glucocorticosteroids. These results demonstrate that histamine is a critical mediator of allergic asthma. Therefore, complete neutralization of histamine, rather than specific histamine receptor blockade, may have a profound effect on allergic asthma.

	Introduction

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Allergic asthma is a chronic disease characterized by reversible obstruction of the airways, bronchial hyperresponsiveness (BHR),² edema, infiltration of lungs by inflammatory cells, and mucus overproduction (1, 2, 3). Allergen-specific Th2 lymphocytes producing IL-4, IL-5, IL-13, IgE, and mucus overproduction are the hallmarks of asthma. In asthmatic individuals, a second contact with the sensitizing allergen results in early and late inflammatory responses. The early reaction is due to IgE-mediated mast cell degranulation, with the release of preformed bioactive molecules such as histamine and 5-hydroxytryptamine, which induce mucus hypersecretion, bronchoconstriction, and increased protein exudation. Although the initial phase may resolve, it is followed by a late-phase response characterized by infiltration of eosinophils and lymphocytes, accompanied by BHR. The repeated exposure to allergens promotes chronic inflammation, leading to the long-term sequellae of asthma.

Histamine, first identified as a potent vasoactive amine, is now recognized for its multiple regulatory activities in the respiratory, digestive, and immune systems, and CNS. Mast cells and basophils are the major producers of preformed histamine that they release from intracellular granules in response to Ag-mediated cross-linking of IgE receptors. Nevertheless, other cells release neo-formed histamine immediately after its synthesis, such as neutrophil, platelets (4), dendritic cells (DCs) (5), and T cells (6), pointing to the important role of this molecule. In lungs, mast cells are present in bronchial walls near vessels, in muscles, and in the bronchial lumen (7). Histamine was one of the first inflammatory mediators of allergic asthma recognized in human and guinea pig models (8). Interestingly, histamine has been shown to modulate cytokine production in different cell types (9), Ab and T cell responses (10) maintaining a predominant Th2 response in allergic disorders (11). Histamine exerts its effects through four receptor subtypes: histamine receptor 1 (HR1) and HR2, both expressed on lymphoid and nonlymphoid cells; HR3, mainly expressed in the brain (12); and HR4, which has been described recently in leukocytes (13), but is also present in airways (14). However, the role of histamine as a critical effector molecule in a murine model of allergen-induced bronchoconstriction has been questioned, because histamine itself fails to induce direct bronchoconstriction under conditions in which 5-hydroxytryptamine and acetylcholine are effective (15). Furthermore, HR1 antagonists are not recognized as clinically effective therapy against asthma (16)

Although blood-feeding ectoparasites can cause histamine-mediated inflammation in the host, ticks have evolved to suppress inflammation and facilitate feeding by secreting histamine-binding proteins at the site of feeding (17, 18, 19). The tick Rhipicephalus appendiculatus secretes three histamine-binding proteins, which have been purified, cloned, expressed, and characterized (20). Their crystallographic structure and biological activity indicate that they sequester histamine, competing with HRs for histamine binding. Both histamine-binding proteins rEV131 and rEV504 bind histamine with high affinity. However, rEV131 has a distinctive feature because it presents a second specific binding site for histamine with lower affinity than the high affinity binding site (20, 21).

In this study, using rEV131, we demonstrate that neutralization of histamine inhibits experimental allergic asthma, suggesting that histamine is a critical mediator in its pathogenesis, and opening new perspectives for asthma therapy.

	Materials and Methods

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Animals and immunization

The BP2 strain of mice was obtained from Janvier, France (15, 22). The local ethics committee approved all protocols used in this study. The mice, aged 6–8 wk, were immunized s.c. twice at weekly intervals with a 0.4 ml saline containing 100 µg of OVA and 1.6 mg of alum for the initial experiments, and for subsequent experiments the Ag dose was reduced to 1 µg of OVA per injection. One week after the second immunization, at day 14, intranasal challenge was performed under light i.v. ketamine anesthesia by applying 50 µl of OVA in alum-free saline solution (10 µg) or saline alone as a control.

The rEV131 protein (340 µg, m.w. 20,406; Evolutec) or budesonide (375 µg, m.w. 430.5; AstraZeneca, Uppsala, Sweden), a potent corticosteroid (positive control), was administered intratracheally (50 µl in saline buffer) under ketamine anesthesia, 1 h before the Ag challenge and/or immediately before the OVA challenge. However, a single administration of EV131, 1 h prior to challenge, proved to be equally effective. We chose the intratracheal route for the administration of the protein and budesonide to assure optimal airways deposition, although the intranasal administration was active. To ascertain that the effect is due to histamine scavenging, histamine-saturated EV131 (incubation at molar ratios 1 and 2 for 30 min of histamine and EV131) was compared with native EV131 for inhibition of BHR (histamine dihydrochloride, m.w. 184; Sigma-Aldrich, St. Louis, MO). The HR antagonists, mepyramine (340 µg, m.w. 402; Sigma-Aldrich), cimetidine (340 µg, m.w. 409; Sigma-Aldrich), and thioperamide (340 µg, m.w. 409; Sigma-Aldrich) were administered intranasally in 50 µl with saline buffer 1 h before the Ag challenge.

Airways resistance

The airways resistance was evaluated by whole-body plethysmography (2). BHR to aerosolized methacholine was investigated at several time points after OVA challenge. Unrestrained conscious mice were placed in whole-body plethysmography chambers (Buxco Electronics, Sharon, CO). Mice were ventilated on high oxygen conditions to avoid hypoxemia induced by methacholine administration. Methacholine at 50 mM was aerosolized for 1 min, and mean airway bronchoconstriction readings, as assessed by enhanced respiratory pause (Penh), were obtained over 15-min periods. Penh can be conceptualized as the phase shift of the thoracic flow and the nasal flow curves; increased phase shift correlates with increased respiratory system resistance.

Penh is calculated by the formula Penh = (Te/RT – 1) x PEF/PIF, where Te is expiratory time, RT is relaxation time, PEF is peak expiratory flow, and PIF is peak inspiratory flow.

The mouse is placed in barometric plethysmography with two chambers linked to suction pump, which ensure constant airflow, as described before. The animal is introduced in the first chamber separated from the second in which pressure corresponds to atmospheric pressure. Every compartment is linked to two parts of a differential pressure captor, connected to an electronic amplifier, and signals are analyzed by software. This system allows quantification of many parameters during several respiratory cycles. Penh values correspond to means of 11 events (cycles) every 5 s in raw data. Penh values are indicated for three points before (–3 to –1 min) and 14 points after (+1 to +14 min) methacholine nebulization. In this case, indicated Penh value is the mean of Penh values between 1 min before and 1 min after the point (e.g., Penh values at +5 min correspond to the mean of all values between point +4 min and point +6 min).

Bronchoalveolar lavage (BAL)

BAL was performed 3 days after intranasal challenge by canulating the trachea under ketamine anesthesia and washing four times with 0.5 ml each of ice-cold PBS. The lavage fluid was centrifuged, and the supernatant was frozen for cytokine determinations. The cell pellet was resuspended in PBS and counted by a hemocytometer chamber, and cytospin preparations were made using a Shandon cytocentrifuge. The cells were analyzed after differential staining with May-Grüenwald-Giemsa.

Lung histology

After BAL, the mice were killed (3 days after OVA challenge). The whole lung was removed and fixed in 4% buffered formaldehyde for standard microscopic analysis H&E and periodic acid Schiff reagent staining. The peribronchial infiltrate and the smooth muscle hyperplasia were assessed by a semiquantitative score (0–3) by two independent observers.

Dosage of IL-4 and IL-5

IL-4 and IL-5 in the BAL fluid were evaluated by ELISA. Briefly, 96-well microtiter plates were coated with monoclonal rat anti-mouse IL-4 (BVD4-1D11; BioSource International, Camarillo, CA) or monoclonal rat anti-mouse IL-5 (R&D Systems, Lille, France) in 0.1 M carbonate buffer, pH 8.2, and incubated overnight at 4°C. Plates were washed and blocked with PBS containing 1% of BSA for 2 h. After washing, dilutions of recombinant murine IL-4 or IL-5 or samples were applied overnight at 4°C. Then biotinylated rat anti-IL-4 Ab (BVD6-24G2; BioSource International) or biotinylated rat anti-IL-5 Ab (R&D Systems) was added for 2 h at 4°C. Plates were washed and incubated with ExtrAvidin peroxidase conjugate (at 0.05 µg/ml to each well; Sigma-Aldrich) for 45 min at room temperature. Plates were developed with tetramethylbenzidine substrate (Dynex, Cergy-Pontoise, France). The reaction was stopped with sulfuric acid 2 N, and the plates were read at 450 nm with an automatic microplate reader. The lower limits of detection of these assays are 10 pg of IL-4/ml sample and 5 pg of IL-5/ml.

Statistical analysis

Data are presented as means and SEM indicated by error bars. Statistical significance was determined by Student’s t test. Values of p < 0.05 were considered statistically significant.

	Results

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The histamine-binding protein EV131 prevents BHR in Ag-sensitized mice

Because histamine is produced during allergic asthma, we tested the potential interference of the arthropod-derived histamine-binding protein EV131 on BHR. Upon Ag challenge, the mice developed a robust BHR in response to aerosolized methacholine at 24 h (Fig. 1A). Administration of EV131 by the intratracheal route, 1 h and just before OVA challenge, inhibited methacholine-induced bronchoconstriction (70% of controls; p < 0.01). The vehicle alone, saline, had no effect on BHR. The effect of EV131 on BHR was matched by the inhibition induced by glucocorticosteroid budesonide, used as a control inhibitor (70%; p < 0.01). To test whether the inhibitory effect is related to histamine scavenging, we compared histamine-presaturated EV131 and native EV131 on BHR. As expected, the inhibitory effect of presaturated EV131 with a 2-molar excess of histamine was abrogated (Fig. 1B). EV131 presaturated at equimolar histamine showed loss of activity as compared with native EV131 on BHR of OVA-challenged mice, suggesting that the two histamine pockets are implicated in histamine scavenging.

View larger version (28K): [in this window] [in a new window]   FIGURE 1. EV131 inhibits OVA-induced BHR in mice sensitized with Ag (A), while histamine-saturated EV131 loses its activity (B). A, BP2 mice were immunized on days 0 and 7 with OVA. The mice were given 50 µl of NaCl (saline) or EV131 (340 µg in NaCl) intratracheally and challenged with 50 µl of NaCl or OVA 1 h later. BHR to methacholine was measured 24 h after challenge by the noninvasive enhanced pause (Penh) and expressed as a function of time. The results represent the mean for two independent experiments (n = 8 mice per group). Inhibition by EV131 and by budesonide is significant at p < 0.01 (**). B, Histamine-saturated EV131 (molar ratio 1 and 2) and native EV131 were given to immunized mice in the identical protocol as described before. Histamine-saturated EV131 (molar ratio 2) lost its inhibitory effect and was significantly different from native EV131 (p < 0.01), while EV131 with histamine at equimolar amounts had partial activity (p < 0.05). Representative results from two independent experiments (n = 4 mice per group).

Reduction of pulmonary inflammation and of the recruitment of eosinophils by EV131

Ag challenge caused a substantial recruitment of inflammatory cells into the BAL fluid at 72 h. Administration of EV131 before OVA challenge reduced significantly the numbers of mononuclear cells in the BAL fluid (p < 0.05; Fig. 2A). Budesonide had a slightly more pronounced effect (p < 0.01; Fig. 2A). Only few eosinophils and neutrophils were found in the BAL fluid of saline-challenged mice. By contrast, the Ag challenge resulted in a significant increase of eosinophil counts in the BAL fluid (p < 0.01; Fig. 2B). EV131 administration before the Ag challenge prevented largely the recruitment of eosinophils (p < 0.01; Fig. 2B). Furthermore, we demonstrated that the prevention of eosinophil recruitment was due to histamine scavenging, as histamine-presaturated EV131 was ineffective (data not shown). Finally, budesonide had an inhibitory effect on the recruitment of all cell types (p < 0.01; Fig. 2B). Representative cytospin preparations of BAL obtained from saline control or OVA-challenged mice in the presence or absence of inhibitors are shown in Fig. 3.

View larger version (25K): [in this window] [in a new window]   FIGURE 2. EV131 inhibits OVA-induced eosinophil recruitment in BAL fluid. BAL fluid was collected at 72 h after OVA challenge, and cytospin preparations were prepared: Total cell counts (A) and differential cell counts in BAL (B). The results are pooled from two independent experiments; mean values and SEM are given (n = 8 mice per group). Differences are significant, p < 0.05 (*) and p < 0.01 (**), respectively.

View larger version (132K): [in this window] [in a new window]   FIGURE 3. Cytospin preparation of BAL with reduced eosinophil recruitment by EV131. Micrographs of cytospin preparations of BAL at 72 h after NaCl (A) or OVA (B) challenge compared with OVA-challenged mice administered EV131 (C) or budesonide (D). May Grüenwald Giemsa staining and magnification x100. Arrows mark eosinophils in cytospin preparations. The micrographs are representatives for three independent experiments (four mice per group per experiment).

View larger version (132K): [in this window] [in a new window]   FIGURE 4. EV131 inhibits inflammation and mucus hypersecretion in OVA-challenged mice. Inflammatory changes of lungs of saline (A)- and OVA (B)-challenged mice: significant peribronchial and perivascular eosinophil infiltration in mice challenged with OVA (arrows mark peribronchial infiltration by eosinophils). EV131 inhibits peribronchial and perivascular eosinophil infiltration (C). H&E staining. EV131 inhibits mucus secretion of lungs in OVA-challenged mice. Mucus secretion changes in lungs of saline (D)- and OVA (E)-challenged mice: significant mucus secretion in mice challenged with OVA (arrows mark mucus secreted by epithelial cells). EV131 inhibits mucus secretion in mice challenged with OVA (F). Periodic acid Schiff mucus staining. Intermediate power micrographs are shown on A, C, D, E, and F (magnification x200), and a higher magnification shows eosinophil infiltration on B (magnification x400). These micrographs are representatives of three independent experiments, with four mice per group each.

Allergic asthma involves the recruitment of Th2-biased T cells, resulting in increased production of Th2 cytokines. Ag challenge of immunized mice resulted in increased levels of IL-4 and levels of IL-5 (Fig. 5; p < 0.01) in the BAL fluid. EV131 given before Ag challenge inhibited significantly IL-4 and IL-5 (Fig. 5; p < 0.05) levels. The steroid control budesonide was slightly more effective than EV131 in inhibiting the production of IL-4 and of IL-5 (p < 0.01). Therefore, neutralization of histamine with EV131 appears to inhibit the allergen-induced Th2 cytokine response.

View larger version (17K): [in this window] [in a new window]   FIGURE 5. Reduced IL-4 and IL-5 in BAL fluid by EV131 administration. IL-4 (A) and IL-5 (B) levels were measured in the BAL fluid by ELISA 24 h after NaCl or OVA challenge. Significant increased IL-4 and IL-5 levels were found in mice challenged with OVA vs NaCl. EV131 inhibits IL-4 and IL-5 secretions in mice challenged with OVA. Mean values and SEM are given from two independent experiments (eight mice per group), p < 0.05 (*) and p < 0.01 (**).

We further investigated the duration of the effect of EV131 on BHR. The inhibitory effect of EV131 was maintained for 48 h after OVA challenge in all mice (Fig. 6A) and, although reduced, was still present at 72 h, when animals received two intratracheal administrations of EV131 (Fig. 6B). Thus, EV131 administered before Ag challenge has a persistent effect.

View larger version (26K): [in this window] [in a new window]   FIGURE 6. The inhibitory effect of EV131 on BHR is effective for 48 and 72 h after OVA challenge. OVA-compared with NaCl-challenged mice still exhibit BHR to methacholine at 48 h (A) and 72 h (B) postchallenge. EV131 (340 µg) administration still inhibits this BHR at 48 h (A) and at 72 h (B). Mean values with SEM are given, and the results are representative of two independent experiments (n = 4 mice per group). *, p < 0.05. Inhibition by EV131 at 48 h: p < 0.01 (**) for time 2 min, and thereafter p < 0.05 (*) (A). Inhibition by EV131 at 72 h: p < 0.05 (*) from 5 min onward (B).

View larger version (22K): [in this window] [in a new window]   FIGURE 7. Inhibition of OVA-induced BHR by HR blockade. Inhibition of OVA-induced bronchial hypersensitivity by HR1 antagonist mepyramine and by HR2 antagonist thioperamide. Mice were treated with NaCl, mepyramine, cimetidine, or thioperamide in 50 µl of NaCl buffer 1 h before challenged with OVA. Penh values were measured 24 h after OVA challenge (n = 8 mice per group). Inhibition by mepyramine: p < 0.01 between 3 and 6 min, and thereafter p < 0.05 (*). Inhibition by thioperamide: p < 0.01 between 2 and 6 min, and thereafter p < 0.05 (*).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Histamine plays a critical role in allergic asthma because it induces contraction and hyperplasia of airway smooth muscles, mucus secretion, plasma exudation, and vasodilatation, essentially via HR1 and HR4 (12, 23). Modulation of BHR by HR antagonists in mice has already been reported (24). In agreement with previous observations, we confirm in our system that a high dose of HR1 antagonist mepyramine blocks BHR, whereas HR2 antagonist cimetidine does not share this property. High dose of thioperamide, which has HR3 and HR4 antagonistic properties, also inhibited BHR in the murine model. Despite sequence homology and structural similarities, HR3 and HR4 have distinct pattern of expression. Indeed, HR4 subtype is essentially expressed on eosinophils, DCs, basophils, Th cells, mast and B cells, and in human lung cells, including fibroblasts, smooth muscle, epithelial, and endothelial cells (13, 25, 26, 27), whereas HR3 subtype is mainly located in the brain (28). Prevention of BHR by thioperamide and the specific expression pattern of HR4 subtype suggest that stimulation of this receptor is involved in allergic disorders. It can be postulated that the profound effects induced by the histamine-binding protein EV131 are in part due to the fact that HR4 is not activated, in addition to suppression of the other HR. The presently available HR antagonists are of limited clinical use, because the high doses required to inhibit allergic asthma lead to unacceptable adverse effects (29).

EV131 has a high affinity binding for histamine, as no competition was observed with other related compounds such as the HR1 antagonist mepyramine and the HR2 antagonist cimetidine in vitro assays (20). EV131 binds histamine in a competitive manner toward the HR1 on the smooth muscle cells of guinea pig ileum (20). Furthermore, EV131 inhibits histamine, but not serotonin- or bradykinin-induced contraction of guinea pig ileum. The effect of EV131 is dose dependent, and saturating concentrations of histamine or preincubation of EV131 with histamine abrogate the inhibitory effect of EV131 (G. Paesen, unpublished observations). To ascertain that the effect on the allergic lung model is due to histamine scavenging, we tested presaturated EV131. We showed that the histamine-saturated EV131 lost its inhibitory activity on BHR and eosinophil recruitment.

These findings account for the ability of EV131 to sequester histamine. Indeed, the crystal structure of EV131 reveals two high affinity sites for histamine binding (20). Allergen challenge enhances histamine release upon OVA-specific IgE cross-linking on mast cell and subsequent degranulation with release of histamine in sensitized mice, leading to bronchoconstriction, eosinophilia, and mucus hypersecretion (30). Histamine may also induce maturation of DCs, which polarize naive CD4⁺ T cells toward a Th2 phenotype, altering the repertoire of cytokines and chemokines secreted by mature DCs, as compared with DCs that have matured in the absence of histamine (11, 31, 32). Immature DCs express two active HRs, HR1 and HR2 (31). Histamine signaling through HR1 and HR2 increases IL-10 production and reduces IL-12 secretion (11, 33, 34). Therefore, local histamine neutralization by EV131 might abrogate in part DC differentiation and thereby contribute T cell polarization in the lung. EV131 reduced the allergen-induced recruitment of eosinophils as well as mucus hyperproduction, which may be due to the direct neutralizing effects of histamine or the modulation of the cytokine profile. Indeed, IL-4 and IL-5 levels in the BAL fluid of OVA-challenged mice were down-regulated by EV131. Moreover, as eosinophils are an important source of IL-4 in tissues, the reduced eosinophil recruitment observed following EV131 treatment may contribute to the diminution of IL-4 observed in the BAL fluid (35, 36). Conversely, IL-4 and IL-5 affect eosinophil recruitment and mucus production (37, 38, 39), and thereby may reduce the allergic response. IL-13 is also involved in the development of BHR and accumulation of eosinophils in the lungs, but we were unable to measure this Th-2 cytokine in the BAL fluid of OVA-challenged mice with our detection system (data not shown). Finally, we tested the effect of EV131 on exogenous histamine-induced BHR, and find that EV131 prevents BHR induced by intratracheally administered histamine (data not shown).

Antihistamines, essentially HR1 antagonists, have been used for decades against asthma, but with very limited efficacy, particularly as a monotherapy. Because the effects of histamine are mediated by at least four receptor subtypes, located in different cells and tissues, the neutralization by histamine-binding protein may be more efficient than an antagonism at the level of a specific receptor subtype. Furthermore, avoiding the blockade of receptors, such a therapeutic approach could trigger less adverse effects than antagonists and steroids. We show in this study that neutralizing histamine at the early phase may prevent the development of the late phase, and thereby control the asthmatic response.

In conclusion, topical neutralization of histamine in vivo with a high affinity arthropod-derived histamine-binding protein inhibits murine allergic asthma, suggesting a novel therapeutic approach that may be superior to the blockade of single HRs.

	Acknowledgments

 
We gratefully acknowledge Drs. Valerie Quesniaux and Marie-Noëlle Soler for corrections and suggestions, and Thomas Robert for excellent technical assistance.

	Footnotes

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Bernhard Ryffel, Institute Transgenose, Centre National de la Recherche Scientifique, 41500 Orleans, France. E-mail address: bryffel{at}cnrs-orleans.fr

² Abbreviations used in this paper: BHR, bronchial hyperresponsiveness; BAL, bronchoalveolar lavage; DC, dendritic cell; HR, histamine receptor; Penh, enhanced respiratory pause.

Received for publication April 17, 2003. Accepted for publication June 10, 2004.

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