Therapeutic options in allergic disease: Antihistamines as systemic antiallergic agents

Therapeutic options in allergic disease: Antihistamines as systemic antiallergic agents Gailen D. Marshall, Jr, MD, PhD Houston, Tex As has been reported throughout this supplement, the pathophysiologic factors of allergic diseases involve many elements of systemic disease–effector-cell recruitment from circulation, stimulation of bone marrow progenitors, systemic effector-cell priming, anaphylactic reactions, and others. With this understanding, allergic inflammation can be thought of as a reflection of systemic immunologic responses with compartmentalized manifestations in various organ systems, including the upper respiratory tract, lungs, gastrointestinal tract, and skin. Thus, any therapeutic approach to the treatment of allergic disease should address, in addition to the localized disease manifestations, the systemic immunologic dysregulation. Second-generation antihistamines (cetirizine, fexofenadine, loratadine) have been used since the 1980s to treat localized allergy symptoms in upper airways, skin, and, in some cases, the lungs; however, the efficacy of these agents in controlling systemic immune dysregulation and chronic allergic inflammation (eg, nasal congestion) has not been proved. The potential role of newer antihistamines in the amelioration of both localized and systemic aspects of allergic disease represents an active area of interest. Desloratadine, a new selective histamine H1-receptor antagonist with potent antihistaminic and antiinflammatory activity, is introduced and its potential for treating the systemic aspects of allergic disease is discussed. (J Allergy Clin Immunol 2000;106:S303-9.) Key words: Allergic inflammation, antihistamine, anti-inflammatory, desloratadine, systemic

It is now commonly understood that an allergic reaction involves the production of allergen-specific IgE, which binds to mast cells and, on subsequent cross-linking by allergen reexposure, causes mast-cell degranulation with the release of preformed mediators such as histamine. Depending on the target organs affected, signs and symptoms of the specific allergic condition ensue. Yet, it is less well appreciated that the immunologic basis for local syndromes (such as allergic rhinitis, asthma, and atopic dermatitis) is actually a systemic dysregulation of immunity. This review examines the components of the

From the Division of Allergy and Clinical Immunology, The University of Texas-Houston Medical School. Dr. Marshall receives research support and is a member of Schering-Plough advisory council and speakers bureau. Reprint requests: Gailen D. Marshall, Jr, MD, PhD, Division of Allergy and Clinical Immunology, The University of Texas-Houston Medical School, 6431 Fannin 4.044MSB, Houston, TX 77030. Copyright © 2000 by Mosby, Inc. 0091-6749/2000 $12.00 + 0 1/0/110165 doi:10.1067/mai.2000.110165

Abbreviations used ICAM: Intercellular adhesion molecule

IgE-mast cell–eosinophil system in normal host defense and hypersensitivity syndromes and compares the advantages and limitations of systemic versus local therapeutic approaches.

THE IMMUNE RESPONSE AND HUMORAL MEDIATORS In the normal host, an antigen for a specific protective immune response elicits a complex series of events that results in a mixed cellular and humoral protective response, the intensity and nature of which depend on the specific inciting antigen.1,2 Generally speaking, extracellular parasites (eg, bacteria, protozoa) incite a humoral response, whereas intracellular parasites (eg, virus, fungi, mycobacteria) elicit a cell-mediated response. The host immune response has a variety of mechanisms (the nature of antigen-presenting cells,3 the major histocompatibility complex restriction,4 and the availability of specific T- and B-cell components5) to direct the immune response in the humoral or cellular direction. Dendritic cells, especially the Langerhans’ cells, are specialized to play a central role in the initiation and coordination of primary immune responses. They shuttle antigen from interfaces with the external environment to lymph nodes, where they present the antigen to naive T cells with the use of major histocompatibility complex class II. However, the central control of the cellular versus humoral response to an antigenic challenge appears to be through the production of a specific cytokine milieu.6 A central source of these cytokines is the CD4+ TH cell, which consists of TH1 and TH2 cell subpopulations.7 Human TH1 cells secrete a specific cytokine profile that includes IFN-γ and TNF-α. These cytokines are important helper factors in cellular immune responses, including the generation of antigen-specific cytotoxic T lymphocytes and natural killer cells.8 Additionally, IFN-γ in particular is important because of its antagonistic activity against TH2 cytokines.9 IL-12, produced by several cell types (particularly activated macrophages), plays a central role in inducing IFN-γ production by TH1 cells.10 In contrast, TH2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13, cytokines that are involved in immunoglobulin isotype switching and the proliferation and differentiation of B cells into antibodyS303

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secreting plasma cells.11 In particular, IL-4 and IL-13 are involved in the isotype switch of B cells from IgM to IgE, the antibody responsible for classic allergic disease. IL-4 and IL-10 are also regulatory cytokines, which antagonize the activities of TH1 cytokines.12 Thus, it can be said that the nature, intensity, and duration of a specific immune response depends on the delicate balance between TH1 and TH2 numbers and/or activities.13 Because it is now appreciated that many cells other than TH cells produce IFN-γ, IL-4, IL-5, IL-9, and IL-10, many scientists refer to these as type-1 and type-2 cytokines, which represent cellular and humoral immune responses, respectively. The production of type-1 and type-2 cytokines by naive T cells therefore depends on a combination of the type of antigen encountered (eg, by dendritic cells) and the specific local cytokine environment. IgE is 1 of the 5 major isotypes of immunoglobulin molecules produced by humans; it is produced naturally in response to several antigenic stimuli, including helminths.14 The switch from IgM to IgE occurs under the influence of 2 primary cytokines, IL-4 and IL-13,15,16 and involves mast cells and eosinophils in a normal host defense mechanism. In contrast, an allergic reaction occurs when the same IgE-mast cell–eosinophil mechanism is directed against an otherwise harmless antigenic stimulus (such as pollen, mold, and insect and animal proteins, collectively referred to as allergens). In the genetically susceptible host, allergen-specific IgE is formed after initial exposure of naive T and B cells. The allergenspecific IgE binds to mast cells that are located typically at mucosal surfaces and around blood vessels (perivascular). Subsequent exposure of the host to the specific allergen allows for a crosslinking of the mast cell-bound IgE, which results in mast-cell activation and degranulation.17 Depending on a variety of factors that include allergen load, distribution, immune activation state of the host, and target organs involved, the allergic individual experiences an immediate (5 to 60 minutes) local reaction, such as allergic rhinitis (nose, eyes), asthma (lungs), eczema (skin), or gastroenteritis (gut).18 Because these acutephase responses are mediated primarily by histamine, they may respond to therapeutic intervention with classic antihistamines. Multiple organs can simultaneously be affected to produce clinical anaphylaxis, a surprisingly rare event considering the number of allergic individuals.19 In more than one-half of allergic individuals, a second round of symptoms occurs approximately 6 to 24 hours after the initial allergen exposure because of the influx of inflammatory cells and production/release of newly formed mediators at the target organ site. This late-phase reaction is less responsive to therapies more classically aimed at immediate mast-cell activity. It is as yet unclear why certain allergic reactions are local, whereas others are systemic. This is particularly perplexing in light of evidence that demonstrates systemic arming of mast cells in patients with single-organ allergic diseases. IgE-armed mast cells can be found in the lungs of patients with allergic rhinitis,20 in the noses of patients with allergic asthma,21 and on the skin of both, as evidenced by positive

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immediate hypersensitivity skin testing.22 Patients with local organ manifestations of allergic disease can, under certain circumstances, be pushed to a systemic reaction, as evidenced by the rare but alarming systemic manifestations that can occur after allergen immunotherapy injection23 and even after skin testing.24 These reactions can be of such a nature in time of onset and intensity as to be life threatening. This has prompted a general recommendation for waiting at least 20 to 30 minutes after an injection in a clinical setting where emergency treatment is promptly available.25

THERAPEUTIC APPROACHES IN ALLERGIC DISEASES Interestingly, virtually all of the earliest treatments for allergic diseases were systemic (ie, therapy with broad distribution in the body after administration). Soon after von Pirquet recognized the immediate hypersensitivity nature of an allergic reaction, Noon26 reported on methods to desensitize allergic patients by injecting the offending agent into the sensitive individual. Symptomatic relief was provided by a variety of potions, pills, and remedies, most of which were taken orally. As medical research became more sophisticated, it was soon discovered that histamine was responsible for some of the clinical manifestations of allergy (Table I). Shortly thereafter, during the 1940s, the first-generation antihistamines were developed.27 These initial molecules included diphenhydramine, phenoxybenzamine, pyrilamine, and tripelennamine, several of which are still in use today. In addition to demonstrating potent H1-receptor antagonism, these molecules were shown to inhibit mast-cell degranulation and allergic inflammation.28 However, they have major soporific and anticholinergic effects that limit their clinical use.29 It soon became clear that, although antihistamines could positively affect the symptoms of sneezing, itching, and drainage that are associated with allergic rhinitis, they did little or nothing for nasal congestion/obstruction. Blockage of the nasal mucosa occurs initially as a vascular phenomenon caused by acute engorgement of the nasal venous plexi. It is against this early-phase phenomenon that α-adrenergic agonists are efficacious.30 However, although this class was useful for symptom relief, adverse effects such as rebound nasal congestion, cardiovascular (tachycardia), and central nervous system (stimulant) effects limit their use. In contrast to acute nasal congestion, chronic nasal obstruction in allergic rhinitis is caused by the release of inflammatory proteins from the infiltration of eosinophils and basophils that accompany the late-phase allergic response. The next major therapeutic development was the discovery of the salutary effects of corticosteroids as anti-inflammatory agents in a variety of clinical conditions, including allergic reactions. Corticosteroids act as important inhibitors of inflammatory responses and may also affect subsequent chronic inflammatory changes. The initial enthusiasm was somewhat dampened by the development of Cushingoid symptoms with prolonged systemic use. The desire to maintain or increase the effectiveness of

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these pharmacologic agents while reducing their systemic adverse effects was approached with the development of topically applied medications. Indeed, nasal decongestants, corticosteroids, and even antihistamines were developed for intranasal (sprayed) delivery, with little or no resulting adverse effects. However, it soon became clear that prolonged use of topical decongestants led to rebound nasal congestion, otherwise known as rhinitis medicamentosum.31 Nevertheless, to date, studies have demonstrated the long-term safety of intranasal corticosteroids in most patients with allergic rhinitis.32-34 With effective topical medications readily available, it may seem enigmatic that a return to systemic therapy with fewer or (ideally) no side effects is being emphasized. This is based on the increasing understanding that allergic diseases are systemic immune dysfunctions with localized or compartmentalized manifestations; these systemic immune dysfunctions may actually be harbingers for future multisystem involvement. For instance, allergic rhinitis and/or atopic skin conditions precede asthma in up to 50% of patients.35 As old drug categories are revisited and new ones are discovered, their impact on the systemic allergic phenotype is being examined not only at the clinical level but also at the cellular and molecular levels. With the appreciation of the immunoregulatory network imbalances that result in TH1/TH2 cytokine ratios favoring IgE production and mast-cell activity and eosinophil growth, development, and migration, there is an ongoing reevaluation of the ideal combination of preferably anti-inflammatory agents for the treatment of allergic diseases. Pharmaceutical classes currently under investigation include leukotriene modifiers,36 methylxanthines/phosphodiesterase inhibitors,37 and antihistamines.38

Antihistamines as systemic antiallergic drugs Although the relative potencies of antihistamines were initially based on their ability to competitively inhibit the H1-receptor binding of histamine,39 it has been well known for some time that many of the older antihistamines were also capable, in appropriate doses, of inhibiting histamine release from mast cells40 and perhaps mast-cell activation itself.41 More recently, it has been reported that some antihistamines can also regulate the expression and/or release of cytokines,42 chemokines,43 adhesion molecules,44 and/or inflammatory mediators (Fig 1).45 Such properties, combined with improved adverse event profiles, make these agents important potential tools for continuous, long-term regulation of both early- and late-phase allergic reactions. The antiallergic properties of antihistamines generally refer to their ability to inhibit mast-cell and basophil activity (eg, degranulation). Such activity includes inhibiting the release of preformed mediators including histamine, tryptase, leukotrienes, and others. Lichtenstein and Gillespie46 demonstrated inhibition of allergeninduced histamine release from human basophils with first-generation antihistamines. This effect was shown to be independent of the H1-receptor antagonism of these

TABLE I. Histamine H1-receptor–mediated responses Target cell

Smooth muscle Endothelium Sensory nerves Cutaneous Peripheral Lung Goblet cell

Pharmacologic effect

Bronchoconstriction, vasodilation Increased permeability Pruritus, burning, stimulation Prostanoid secretion Decreased mucus viscosity

compounds. Other investigators have shown similar antiallergic properties of some second-generation antihistamines that include cetirizine,47 azelastine,48 terfenadine/fexofenadine,49 and loratadine.50 Chronic allergic inflammation, a product of the latephase reaction, has components similar to other forms of inflammation that include chemotaxis of inflammatory cells followed by activation and differentiation, with subsequent production and release of various mediators. The cells involved in allergic inflammation include antigenpresenting cells (eg, macrophages), mast cells, basophils, T cells, and the major effector inflammatory cells, eosinophils (Fig 1). Additionally, recent studies have demonstrated that the epithelial/endothelial cells of the target organs are active participants in the recruitment and activation of inflammatory cascades. This occurs with the production of selected cytokines, chemokines, adhesion molecules, and inflammatory mediators, all of which contribute to the milieu that ultimately leads to end-organ dysfunction. It has been demonstrated that several second-generation antihistamines, most particularly cetirizine, can inhibit the influx of eosinophils to the site of allergen challenge in sensitized individuals.51,52 This could occur by any of several mechanisms: inhibition of chemokine formation, altering/inhibiting adhesion molecule expression on the target endothelium/ epithelium, or a direct effect on the eosinophil itself by inhibiting adhesion molecule expression, activation, or survival. Studies have demonstrated that some antihistamines can alter adhesion molecule expression on epithelium53 and eosinophils,44 decrease in vitro cytokineenhanced eosinophil survival,54 and alter eosinophil activation/granule release.55 It is also important to note that some antihistamines have demonstrated abilities to alter the production of certain cytokines both in vitro and in vivo. These include inflammatory cytokines (such as TNF-α, IL-1β, and IL-6)56 and immunoregulatory TH1/TH2 cytokines (such as IL-4 and IL-13).57 This can occur in both basophils and T cells. 58 Further, second-generation antihistamines have been shown to be active in the down-regulation of inflammatory mediators such as superoxides, prostaglandins, platelet-activating factors, and others.59,60 These regulatory activities position the second-generation antihistamines as potential fundamental therapeutic agents in more allergic/immunologic conditions than just for symptom relief in patients with allergic rhinitis.

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FIG 1. Pathophysiologic factors of allergic inflammation. Key participants in the pathophysiologic factors of type 1 hypersensitivity include antigen-presenting cells (which present allergens to T lymphocytes), T lymphocytes (which produce cytokines that are important for eosinophil activation and chemotaxis, and B lymphocyte production of allergen-specific IgE), and IgE (which binds to mast cells and basophils, eliciting degranulation and release of proinflammatory mediators). Also shown are potential target sites for antiallergic therapy (circled X). Therapies can be targeted to stabilize mast cells and basophils, to modulate cytokine release by T lymphocytes and other cell types, to alter cell adhesion and chemoattraction, and to inhibit H1-receptor binding in target tissues.

TABLE II. In vitro anti-inflammatory properties of desloratadine* Target

Challenge

Nasal epithelium

Histamine

Umbilical vein (endothelium)

Histamine

Mast cell line Basophil line Nasal polyp epithelium

Ca ionophore PMA TNF-α

Effect of desloratadine

Reference

↓ICAM-1 ↓HLA-DR ↓P-selectin ↓IL-6, IL-8 ↓IL-6, IL-8 ↓IL-6, IL-8 ↓RANTES

Vignola et al67 Molet et al69 Lippert et al66 Lippert et al66 Lebel et al68

HLA-DR, Human leukocyte antigen-DR; Ca, calcium; PMA, phorbolmyristate acetate; RANTES, regulated on activation, normal T cell expressed and secreted. *Unrelated to H -receptor inhibition. 1

Systemic immune effects of desloratadine Although the potential for the use of second-generation antihistamines in the chronic management of allergic conditions has been high, concern remains related to necessary doses to maximally affect mast-cell and inflammatory-cell activity. This is clinically relevant because current dosages are based primarily on H1receptor blockade potency. Several of the second-generation antihistamines have definable dose-related adverse events at higher doses, particularly soporific and anticholinergic effects.61 Such therapeutic index issues may well be addressed by turning to newer antiallergy agents, some of which are active metabolites of second-generation compounds. One such agent that has been carefully studied is descarboethoxyloratadine, also known as

desloratadine. Desloratadine is a potent H1-receptor antagonist, having relative potency up to 4 times that of its parent compound, loratadine.62 In laboratory studies it has also been reported to possess antiallergic, antiinflammatory, and immunomodulatory activities.62-69 The anti-inflammatory properties reported for desloratadine are varied but still somewhat limited because of the relatively recent development of the drug. Desloratadine has been shown to inhibit intercellular adhesion molecule-1 (ICAM-1) expression by nasal epithelial cells67 and P-selectin expression in umbilical vein epithelium,69 the latter with relatively low concentrations (nanomolar range) of desloratadine (Table II).66-69 This inhibitory activity could result in decreased inflammatory cell trafficking in target tissues, a distinct anti-inflammatory

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TABLE III. Mediator release responses inhibited by desloratadine in vitro Target cell

Lung mast cells Tissue mast cells Basophils Basophils Basophils Basophilic leukemia (rat)

Challenge

Anti-FcεRI Anti-FcεRI Anti-FcεRI, mite Antigen, Con A, aIgE Ca ionophore Antigen

Mediator

Histamine, LTC4, PGD2 Histamine, LTC4, PGD2, tryptase Histamine, LTC4 Histamine Histamine Histamine

Reference

Genovese et al64 Genovese et al64 Genovese et al64 Kleine-Tebbe et al65 Berthon et al71 Berthon et al71

FcεRI, High-affinity IgE receptors; LTC4, leukotriene C4; PGD2, prostaglandin D2; Con A, concanavalin A; aIgE, anti-IgE antibody; Ca, calcium.

event. Desloratadine also inhibits the release of IL-8, RANTES, and soluble ICAM-1 from human bronchial epithelial cells,70 which suggests that this agent may have a direct effect on epithelial cells (Table III).64,65,71 Secretion of various mediators from other cell types is also affected by the presence of desloratadine, including the inflammatory cytokines TNF-α, IL-3, IL-6, IL-8, and GM-CSF by human leukemic mast-cell and basophil lines.66 In particular, the inhibition of IL-6 and IL-8 was achieved by relatively low (range, 1 × 10–6 to 1 × 10–11 molar) concentrations of desloratadine.66 An immunoregulatory potential for desloratadine may be reflected by its ability to alter IL-4/IL-13 production by basophils in mixed leukocyte cultures. The effects of desloratadine on IL-4 and IL-13 are preferential to those that regulate histamine and leukotriene C4 release by basophils and occur at relatively low concentrations. Such regulation could be important because IL-4 and IL13 control IgE production; mast-cell growth and development; expression of adhesion molecules such as ICAM-1, vascular cell adhesion molecule-1 and very late antigen-4; and B-cell growth and development.72 Further, histamine and leukotriene C4 indirectly influence eosinophil activity by regulating IFN-γ production. IFN-γ in turn inhibits TH2 cells, a major source of IL-5 (growth factor for eosinophils). Because there is clear evidence that the local cytokine milieu influences the relative TH1/TH2 balance, inhibiting basophilic IL-4/IL-13 may have antiallergic/anti-inflammatory effects through the inhibition of the TH2 phenotype.

Systemic therapy for a systemic illness: potential role of antihistamines Increasing evidence supports the hypothesis that the risk of atopy is a systemic risk; the atopic phenotype is a composite of genetic and environmental influences.17 Several studies suggest that the first year of life is a critical time for the development of immunoregulatory imbalances that may not manifest in allergic/asthmatic phenotypes until some years later.73 Environmental influences such as “hygienic” reduction in endotoxin levels,74 early vaccination with agents that contain adjuvants (eg, alum) known to preferentially stimulate TH2 responses,75 alteration of diet,76 liberal use of antibiotics that result in altered normal body flora,77 an increasingly stressful lifestyle,78 and increasingly polluted atmospheres (particularly in urban areas)79 may all contribute to the

alarmingly steady increase in the prevalence of allergy and asthma. Early systemic intervention may prevent the spread of mast cell-mediated conditions to multiorgan systems. Allergic rhinitis precedes asthma formation in up to 50% of affected children.80 Agents with systemic activity, such as allergen immunotherapy and antihistamines, may be capable of altering the natural history of allergy and asthma development by changing the immunoregulatory milieu, particularly IL-4 and IL-13.81 Further, the high therapeutic index for antiallergic and anti-inflammatory effects of newer agents, such as desloratadine, offers promise for improved therapeutic and perhaps even prophylactic options. REFERENCES 1. Roth JA. Characterization of protective antigens and the protective immune response. Vet Microbiol 1993;37:193-9. 2. Zinkernagel RM. Some general aspects of immunity to viruses. Vaccine 1994;12:1493-4. 3. Meyaard L, Schuitemaker H, Miedema F. T-cell dysfunction in HIV infection: Anergy due to defective antigen-presenting cell function? Immunol Today 1993;14:161-4. 4. Dieli F, Asherson GL, Bonanno CT, Sireci G, Salerno A. Major histocompatibility complex control of the class of the immune response to the hapten trinitrophenyl. Immunology 1995;84:355-9. 5. Shearer GM, Clerici M. In vitro analysis of cell-mediated immunity: clinical relevance. Clin Chem 1994;40:2162-5. 6. Maher JJ. Cytokines: overview. Semin Liver Dis 1999;19:109-15. 7. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145-73. 8. Rogers LA, Zlotnik A, Lee F, Shortman K. Lymphokine requirements for the development of specific cytotoxic T cells from single precursors. Eur J Immunol 1991;21:1069-72. 9. Parronchi P, De Carli M, Manetti R, Simonelli C, Sampognaro S, Piccinni MP, et al. IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol 1992;149:2977-83. 10. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 1994;84:4008-27. 11. Yssel H, Groux H. Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases. Int Arch Allergy Immunol 2000;121:10-8. 12. Lester MR, Hofer MF, Gately M, Trumble A, Leung DY. Down-regulating effects of IL-4 and IL-10 on the IFN-gamma response in atopic dermatitis. J Immunol 1995;154:6174-81. 13. Romagnani S. Th1 and Th2 in human diseases. Clin Immunol Immunopathol 1996;80:225-35. 14. Pritchard DI, Hewitt C, Moqbel R. The relationship between immunological responsiveness controlled by T-helper 2 lymphocytes and infections with parasitic helminths. Parasitology 1997;115(suppl):S33-44.

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