The development of allergy or other types of immune hypersensitivity is an important undesirable effect of acquired immunity in mammals, particularly humans. There are several types of allergy. The present invention is concerned with atopic allergy. Atopic allergy is characterized by an excess production of IgE antibody, which attaches to mast cells and basophils. A single mast cell or basophil may bind as many as a half a million molecules of IgE. When an antigen binds to at least two IgE molecules bound on the surface of a mast cell or a basophil, the cell ruptures or otherwise is caused to release several substances including histamine, leukotrienes (previously referred to as “slow reacting substance of anaphylaxis”), eosinophilic chemotactic factor, proteases, neutrophil chemotactic substance, heparin, platelet activating factors and bradykinin. Release of these substances results in dilation of local blood vessels, attraction of eosinophils and neutrophils to the reactive site, damage to local tissues by proteases, increased permeability of the capillaries and loss of fluid into the tissues, and contraction of smooth muscle cells. A number of different abnormal tissue responses ensue including anaphylaxis, urticaria, hay fever and asthma.
In anaphylaxis, a widespread allergic reaction occurs throughout the vascular system and in closely associated tissues. Body-wide vasodilation as well as increased permeability of the capillaries with resultant marked loss of plasma from the circulation occurs. Death may result from circulatory shock within minutes. In addition, leukotrienes are released which may elicit a massive asthma attack and death by suffocation.
Urticaria results when an antigen enters specific skin areas and causes local anaphylactoid reactions and skin swelling commonly known as “hives.”
In hay fever, the allergic reaction occurs in the nose. Histamine released in response to the reaction causes local vascular dilation, with resultant increased capillary pressure as well as increased capillary permeability. Both of these effects cause rapid fluid leakage into the tissues of the nose and the nasal linings become swollen and secretory.
Asthma is characterized by spastic contraction of the smooth muscle in the bronchioles, which causes extreme difficulty in breathing. Asthma occurs in 3 to 5 percent of all people at some time in their life. The usual cause of asthma is hypersensitivity of the bronchioles to foreign substances in the air. About 70 percent of the asthma which occurs in younger patients, i.e., those under 30 years of age, is caused by allergic hypersensitivity, in particular, by sensitivity to plant pollens. In older persons, the cause of asthma is almost always hypersensitivity to non-allergic type irritants such as air pollution and the like.
The three hallmark features of allergic disease are the presence of excessive mast cells and eosinophils, and the production of IgE. The cytokines responsible for this activity are interleukin 4 (IL-4A) for IgE production (Finkelman et al., 1986, Proc. Natl. Acad. Sci. USA 83:9675-9678; Coffman et al., 1986, J. Immunol. 136:949-954), IL-5 in the case of eosinophilia (Sanderson et al., 1986, Proc. Natl. Acad. Sci. USA 83:437-440), and the combination of IL-3, IL-4, and IL-10 in the case of mast cell production (Thompson-Snipes et al., 1991, J. Exp. Med. 173:507-510).
The initiation of the immune response to a pathogen requires a complex series of interactions among certain cell populations generally involving cytokine production as reviewed by Gause and Lu (1996, In: Cytokine Regulation of Humoral Immunity, Snapper, ed., John Wiley and Sons, New York). Within hours after immunization with a pathogen, a highly pronounced and restricted cytokine pattern is detectable in lymphoid organs. Generally, the immune response may be classified according to the CD4+ T-helper (Th) cells associated therewith as either a type I response, mediated by T-helper type 1 cells (Th1), or type 2 response, mediated by T-helper type 2 cells. More recently, it has been demonstrated that the type 1 and type 2 responses may each be mediated by cells other than Th1 or Th2.
The type 1 response involves Th1-type cytokines including IFN-γ and IL-2 and, since IFN-γ is a mediator for activation of macrophages and monocytes, the type 1 response is associated with cellular immunity and inflammation. In contrast, Th2 cells are mediators of Ig production (humoral immunity) and produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 (Tanaka et al., 1996, In: Cytokine Regulation of Humoral Immunity, pp. 251-272, Snapper, ed., John Wiley and Sons, New York). However, the cellular and humoral immunity compartments are intertwined as exemplified by the role of IL-6 in both responses which is mediated by complex interactions between various cells and the cytokines produced thereby. It has been demonstrated that interaction of Th2 cells with B cells induces a humoral response (characterized by Ig production) in that IL-4 signaling through CD40 induces IL-6 production which enhances Ig synthesis. In contrast, interaction of Th1 cells with macrophages or monocytes causes production of, inter alia, IL-6 which, in turn, causes an inflammatory response. Therefore, certain cytokines may play a role in both humoral and cellular immune responses and the production of cytokines orchestrates a highly complex series of responses.
Of the humoral responses, the immune response mediated by IgE has been the most studied perhaps due to the fact that IgE mediates a unique and potent set of effector functions that are central features of allergy and asthma. The principal cellular pathway leading to IgE production involves B-cell activation via CD40-IL-4 signaling causing B cells to class switch to IgE. In mice, there is compelling evidence that IL-4 is required for virtually all primary IgE responses. More specifically, treatment of mice with an excess of anti-IL-4 neutralizing antibody inhibits 95-99% of primary IgE response to various stimuli (Finkelman et al., 1986, Proc. Natl. Acad. Sci. U.S.A. 83:9675-9678; Finkelman et al., 1988, J. Immunol. 141:2335-2341; Finkelman et al., 1988, J. Immunol. 140:1022-1027). Additionally, IFN-γ and antibodies to IL-5 and IL-4 inhibit pulmonary eosinophilia in allergic mice sensitized by ovalbumin challenge (Kung et al., 1995, Inflamm. Res. 44:S185-S186). Further, homozygous deletion transgenic mice lacking the IL-4 gene have only trace amounts of IgE after infection with various pathogens known to stimulate IgE production (Kuhn et al., 1991, Science 254:707-710; von der Weid et al., 1994, Eur. J. Immunol. 24:2285-2293). Also, Lee et al. (1997, J. Exp. Med. 185:2143-2156) demonstrated that transgenic mice which constitutively express IL-5 develop many of the pathologies associated with asthmatic patients including eosinophil invasion of peribronchial spaces, epithelial hypertrophy, goblet cell hyperplasia, increased mucus production, and exhibit eosinophil recruitment to the airway lumen at levels comparable to asthmatic patients. Thus, these studies confirm the crucial role of IL-4 and other type 2 cytokines in IgE switching in mice and, more importantly, in the etiology of allergic disease.
Although the role of IL-4 in IgE switching and/or the development of allergic disease in humans is not as clear as it is in mice, the data suggest that IL-4 and/or IL-13 are the major inducers of IgE switching in humans; further, Th2-like type 2 responses have been demonstrated in a variety of allergic and parasitic diseases (Sher and Coffman, 1992, Annu. Rev. Immunol. 10:385-409; Yssel et al., 1992, J. Immunol. 148:738-745; Romagnani, 1994, Annu. Rev. Immunol. 12:227-257; Wierenga et al., 1990, J. Immunol. 144:4651-4656; Coffman, 1996, In: Cytokine Regulation of Humoral Immunity, pp. 379-389, Snapper, ed., John Wiley and Sons, New York). In addition, the prior art suggests that various disease conditions are associated with type 2 cytokine abnormalities as summarized by Hagiwara and Klinman (1996, In: Cytokine Regulation of Humoral Immunity, pp. 409-430, Snapper, ed., John Wiley and Sons, New York). For instance, Kay et al. (1997, Int. Arch. Allergy Immunol. 113:196-199), demonstrated that IL-4 and IL-5 production by eosinophils may amplify local allergic inflammatory responses in humans. Therefore, within the complex and interactive cytokine network which regulates the magnitude, nature and duration of immune responses against self and foreign antigens, there is mounting evidence of the role of the Th2-type cytokines, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13, in various disease states in humans including asthma.
The allergic reaction that occurs in the allergic type of asthma is believed to occur in the following manner. The typically allergic person has a tendency to synthesize large amounts of IgE antibodies. In asthma, these antibodies are mainly attached to mast cells in the lung interstitium in close association with the bronchioles and small bronchi. When pollen is inhaled by a person hypersensitive to the pollen, (i.e., to which the person has already developed IgE antibodies), the pollen reacts with the mast cell-attached antibodies and causes the cells to release several substances including histamine, leukotrines, eosinophilic chemotactic factor, and bradykinin. The combined results of the release of these factors is the production of localized edema in the walls of the bronchioles as well as secretion of thick mucus into bronchiolar lumens, and spasm of the bronchiolar smooth muscle causing the airway resistance to increase markedly.
The majority of treatments for allergies in humans involves the administration of compounds which are directed to neutralizing the effects of the substances released from mast cells or basophils. Thus, a plethora of antihistamines and other compounds are available which neutralize the effects of histamines and the like following their release from mast cells or basophils. The drawbacks of such treatments is the necessity that they are used essentially subsequent to the allergic event and do not prevent future allergic events in the patient.
Current treatment for asthma includes the administration of compounds that control the airway inflammatory component of the disease, e.g., primarily corticosteroids, sodium cromolyn, methylxanthines and leukotriene pathway modifiers (see, e.g., Drazen et al., 1999, New Eng. J. Med. 340:197-206). In addition, there are available rapid relief compositions that counteract bronchospasm, e.g., primarily beta-adrenergic agents. These compounds have several disadvantages in that there is a risk that they will not be effective and despite their administration, the asthma attack will continue. In addition, several side effects are associated with prolonged use of these type of compounds, particularly in the case of corticosteroids and beta-adrenergic agents; further, there is a progressive loss of sensitivity to these treatments after prolonged use. In severe asthma, these compounds are only of limited efficacy. Further, these compounds are non-selective, i.e., they do not specifically target the lung, therefore, side-effects affecting other organs are a potential risk. In addition, there is an increasing body of evidence which indicates there may be an increased risk of dying from bronchial asthma following prolonged treatment of asthma using long-acting beta-adrenergic agents such as fenoterol (Pearce et al., 1990, Thorax 45:170-175; Spitzer et al., 1992, New Engl. J. Med. 326:560-561).
Approximately fifteen million individuals in the U.S. suffer from asthma, and the disease is the cause of more than five thousand deaths annually in the U.S. In children, asthma represents the most prevalent chronic disease, requiring the most frequent use of emergency room visits and hospitalizations. The overall annual cost for asthma care in the U.S. is estimated to be about nine billion dollars. Asthma is the most common cause of school and work absenteeism in the U.S.
To date, there are no long-term preventative treatments available for allergies in humans. Given the fact that allergic responses, and particularly asthma, are on the rise in the human population, there is a long felt need for the development of therapies which are designed to prevent as well as treat an allergic response in a human patient. The present invention satisfies this need.