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Interleukin-5 and eosinophils as therapeutic targets for asthma Paul S. Foster, Simon P. Hogan, Ming Yang, Joerg Mattes, Ian G. Young, Klaus I. Matthaei, Rakesh K. Kumar, Surendran Mahalingam and Dianne C. Webb Extensive clinical investigations have implicated eosinophils in the pathogenesis of asthma. In a recent clinical trial, humanized monoclonal antibody to interleukin (IL)-5 significantly limited eosinophil migration to the lung. However, treatment did not affect the development of the late-phase response or airways hyperresponsiveness in experimental asthma. Although IL-5 is a key regulator of eosinophilia and attenuation of its actions without signs of clinical improvement raises questions about the contribution of these cells to disease, further studies are warranted to define the effects of anti-IL-5 in the processes that lead to chronic asthma. Furthermore, eosinophil accumulation into allergic tissues should not be viewed as a process that is exclusively regulated by IL-5 but one in which IL-5 greatly contributes. Indeed, data on anti-IL-5 treatments (human and animal models) are confounded by the failure of this approach to completely resolve tissue eosinophilia and the belief that IL-5 alone is the critical molecular switch for eosinophil development and migration. The contribution of these IL-5-independent pathways should be considered when assessing the role of eosinophils in disease processes. Published online: 5 March 2002

Paul S. Foster*, Simon P. Hogan, Ming Yang, Joerg Mattes, Ian G. Young, Klaus I. Matthaei, R.K. Kumar, Surendran Mahalingam Dianne C. Webb Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia. *e-mail address: [email protected] Rakesh K. Kumar School of Medical Sciences, The University of New South Wales, Sydney 2052, Australia.

Allergic asthma is recognized as a chronic inflammatory disease of the airways that is characterized by reversible airways obstruction in association with aberrant CD4+ T helper 2 (Th2) lymphocyte responses to common environmental stimuli [1,2]. Indeed, the hallmark features of allergic asthma – elevated serum immunoglobulin E (IgE), mucus hypersecretion, eosinophilia and enhanced bronchial reactivity (airways hyperresponsiveness [AHR]) to nonspecific spasmogenic stimuli – have all been linked to the effector functions of Th2 cytokines [e.g. interleukin (IL)-4, 5, 9, 10 and 13] [2]. Collectively, it is these mediators that are thought to promote airways obstruction in asthma, which predisposes to wheezing, shortness of breath and life-threatening limitations in airflow. Although the etiology and pathophysiology of asthma are complex [3,4], a model based on eosinophil-driven disease has emerged as a central paradigm. In this model, Th2 cells, through the secretion of IL-5, regulate http://tmm.trends.com

pathogenic processes that predispose to the development of airways obstruction and AHR. In this article, we focus on the current debate as to the role of IL-5 and eosinophils in the pathogenesis of allergic asthma. Furthermore, we propose that although IL-5 plays a central role in eosinophil function, it is not essential for development or migration of this granulocyte to sites of allergic disease. Thus, pathways independent of IL-5 but not of eosinophils might still contribute to pathogenesis. IL-5-regulated eosinophilia as key pathogenic mechanism in asthma The paradigm of IL-5, eosinophils and asthma

The notion that IL-5-regulated eosinophilia plays a central role in the pathogenesis of asthma is based on extensive circumstantial evidence from clinical investigations that show a strong correlation between eosinophils, their secreted products and IL-5, with severity and exacerbation of disease (see Fig. 1) [5–20]. Once recruited to sites of allergic inflammation, eosinophils become activated and are thought to induce disease through the release of proinflammatory molecules and granular proteins [21,22]. In particular, there is evidence that eosinophilic products damage the respiratory epithelium and induce AHR [5,19,23,24]. Increased numbers of eosinophil and basophil colony forming units (progenitor cells) are also found in the blood of allergic individuals, and elevated numbers correlate with exacerbation of disease [25–32]. Thus, severity and exacerbations of asthma are directly linked to eosinophil regulatory pathways, although no clear pathogenic mechanism has yet been identified. The eosinophil paradigm identifies IL-5-regulated eosinophilia as a central pathogenic pathway, because of the proposed central role of this cytokine in eosinophil development and movement, and circumstantial evidence from clinical studies. For example, levels of IL-5 and cells expressing mRNA for this cytokine are elevated in blood and lung secretions of asthmatics [6–13,15–17,33,34]. Furthermore, after allergen-induced late-phase asthmatic responses, levels of IL-5 increase in the lung and correlate with the degree of eosinophilic inflammation [5–13,16,17]. Inhibition of IL-5 function in animal models of asthma also results (although not always) in attenuation of hallmark features of disease, in particular eosinophilia and AHR [14,15,35–38]. The state of IL-5 and asthma therapy

The specificity of IL-5 for eosinophil-regulated processes in conjunction with data from animal models of asthma has led to the development of a humanized (IgG-k) monoclonal antibody to IL-5 (hmAb-IL-5) and a recent clinical trial to determine the therapeutic value of targeting this molecule in asthmatics [39]. Importantly, this trial through the provision of a blocking agent, which specifically

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Fig. 1. Model for interleukin (IL)-5-dependent and IL-5-independent lung eosinophilia. (a) Eosinopoiesis is induced in the bone marrow in response to stimulatory molecules that include IL-5 and eotaxin, which are expressed in response to antigen provocation to the lung. Both mature eosinophils and their progenitors migrate from the bone marrow via the blood to the lung compartment where the localized expression of IL-5 and eotaxin promote further maturation and activation of these cells. In particular, IL-5 plays a crucial role in promoting the development of eosinophilia in the bone marrow and blood compartments. (b) In contrast, an eotaxin-dependent mechanism that drives eosinophil accumulation (albeit in reduced numbers) in the allergic lung persists in the absence of IL-5. This pulmonary eosinophilia that is independent of IL-5 occurs in the absence of allergy-induced eosinophilia in the bone marrow or blood compartments suggesting that extramedullary sites may be the source. This eosinophil might be regulated through IL-13, which induces eotaxin production. Notably, this IL-5-independent pool of eosinophils in the lung is sufficient to generate airways hyperreactivity toward spasmogenic provocation.

targets IL-5 in humans, has allowed the testing of the causal role of this cytokine, and indirectly, of eosinophils in human disease. This trial was an extension of successful investigations in primates where hmAb-IL-5 was shown to be active on circulating and airway eosinophilia as well as blocking AHR, and was an important step in determining tolerability of such a targeted treatment in asthmatics. http://tmm.trends.com

Notably, administration of hmAb-IL-5 limited eosinophil migration into the lung but failed to inhibit the development of the late-phase asthmatic response and AHR after allergen provocation [39]. Although this study was primarily designed to test efficacy and tolerability of the treatment and not its effect on asthma (acute exacerbation, chronic disease processes or frequency of utilization of medication) it has been used by some commentators to inappropriately exclude eosinophils from the mechanism of asthma pathogenesis. The result of this trial is also confounded by the dogma that IL-5 is the critical regulator of eosinophil development and migration. A closer examination of the paper by Leckie et al. [39] has also raised questions about whether this study had the methodological power to either support or refute the concept that eosinophils play an important role in the mechanisms predisposing to allergen-induced changes in airways function [40]. Although hmAb-IL-5 treatment reduced eosinophil numbers in the blood and sputum (the primary aim and result of this study), the lack of effect of treatment

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on allergen-induced changes in lung function are ambiguous [40]. For example, the investigators failed to demonstrate significant changes in allergen-induced AHR to histamine (the spasmogen employed in this study) during the baseline period or after placebo treatment. Furthermore, the sample size and the methodological approach to assessing changes in AHR might have been inadequate to draw valid statistical conclusions [40]. It should also be noted that although the studies evaluating anti-IL-5 were performed in asthmatics, the investigators only evaluated AHR and the late asthmatic response. Although these two phenomena are clearly related to asthma, they are not asthma, but a wellestablished model of studying asthma in humans. Analysis of eosinophil numbers in allergen-challenged patients that received either the low or high dose of hmAb-IL-5 showed that, although significantly reduced this cell persists in the lung (sputum). Furthermore, although measurement of eosinophil numbers in the blood might be indicative of the efficacy of hmAb-IL-5, it does not provide information on whether or not these cells are accumulating in the lung. It should be remembered that blood eosinophilia is not a feature of all disorders characterized by the accumulation of eosinophils in tissues, and only a subset of patients with asthma have both peripheral blood and tissue eosinophilia [22]. Furthermore, a fall in blood eosinophil numbers below baseline could reflect inhibition of efflux from the bone marrow as well as sequestration into tissues. Measurement of eosinophil levels in respiratory secretions under conditions where eosinophil regulatory pathways have been impaired (in animal studies) is not always indicative of the numbers of this cell in lung tissues [41]. Mechanisms that regulate the spatial and temporal aspects of eosinophil migration from blood to tissue compartments and then into the airways lumen could be differentially controlled [41]. Thus, equilibrium does not exist between blood, tissue and airways (lumen) eosinophils and the numbers of eosinophils in one compartment should not be used to reflect those in another. It should also be highlighted that eosinophils have resided in the allergic lungs of these asthmatic individuals at some time before the initiation of the investigations with hmAb-IL-5 [39]. Collective analysis of the paper by Leckie indicates that it should not be used by commentators to exclude IL-5 and/or eosinophils in the pathophysiology of asthma. This study provides an important proof of principle – that attenuation of IL-5 function in asthmatics decreases circulating numbers of eosinophils and their subsequent recruitment to the airways. In the following section we highlight the important role that IL-5 plays in eosinophil biology and also indicate that other pathways regulate eosinophil development and migration independently of this cytokine. http://tmm.trends.com

Regulation of eosinophil recruitment to the allergic lung Role of IL-5 in eosinophil development, mobilization and homing

There is a sustainable body of literature that has demonstrated the central importance of IL-5 in the development, differentiation, activation, survival and trafficking of eosinophils [33]. Collectively, and in part, because of the cellular specificity of the actions of IL-5, these investigations have led to the concept/paradigm that eosinophils cannot develop or adequately function in the absence of IL-5. However, these conclusions have been drawn primarily from in vitro experimental systems where the delivery of factors to culture media is strictly controlled [33,42–45]. Thus, the concept of IL-5 being essential rather than an important cofactor for eosinophil function might not be warranted. Work from our laboratory extensively characterized IL-5−/− mice at baseline and under allergic inflammatory conditions [15,46–49]. Under baseline conditions mature eosinophils are found in bone marrow and in blood and tissues (albeit significantly reduced in the circulation), indicating that IL-5 is not essential for eosinophil differentiation, maturation, survival or subsequent migration from the bone marrow [50]. IL-3 and granulocyte–macrophage colony stimulating factor (GM-CSF) are known to prime progenitor cells for IL-5 responsiveness, and all three cytokines employ the β-common chain to transduce signals [33]. However, although IL-5, IL-3 and GM-CSF all contribute to eosinopoiesis, mature eosinophils are also found in the bone marrow of mice deficient in these factors or in common components of their receptor signaling systems (the β-common chain) [15,51]. This demonstrates the presence of alternative, as yet unidentified pathways that regulate eosinophil differentiation and maturation. Furthermore, rapid blood eosinophilia can also be induced in naive IL-5−/− mice by the intravenous instillation of the eosinophil-specific chemokine eotaxin, indicating that these cells are functional and can migrate in response to specific chemotactic stimuli [49]. Unlike wild-type littermates, allergic IL-5−/− mice [systemically sensitized to allergen and subsequently aeroallergen challenged (mouse asthma models)] do not generate eosinophilia in blood or bone marrow compartments in response to allergen provocation of the lung, and this greatly reduces the level of eosinophils recruited to the airways [15,47,48]. However, since basal levels of eosinophils are still produced in IL-5−/− mice, residual tissue eosinophilia persists (albeit significantly reduced) in the allergic airways of these mice. The adoptive transfer of wild-type or IL-5−/− eosinophils to the blood of allergic IL-5−/− mice during aeroallergen challenge also increases the number of eosinophils recruited to the airways, indicating that IL-5 does not play an obligatory role in the homing of this leukocyte to the allergic lung [50]. The transfer of wild-type Th2 cells

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to allergic IL-5−/− mice fully restores blood and airways eosinophilia, indicating that Th2 cells (with IL-5) provide the signal(s) that underpin eosinopoiesis and blood eosinophilia. Our results suggest that the critical roles for IL-5 are in the expansion of the eosinophil pool in the bone marrow and in the induction of blood eosinophilia in response to allergic stimulation. IL-5 also amplifies tissue recruitment of this leukocyte in response to locally derived chemotactic signals by increasing the circulating pool of eosinophils. This cytokine also participates in the maintenance of baseline levels of eosinophils in the blood and tissues. However, additional factors that are under the control of Th2 cells regulate eosinophil homing to sites of allergic disease and amplify eosinopoiesis. IL-5, tissue eosinophilia and the regulation of AHR in experimental models

Careful dissection of all anti-IL-5 studies in animal models of allergic disease shows that eosinophils have resided in the allergic lung at some time before the measurement of lung function (assessed by AHR) or are still present (albeit in reduced numbers) at the time of analysis [14,15,37,38,48,52–57]. For example, although we and others have observed that eosinophil trafficking to the allergic lung is markedly attenuated in IL-5−/− mice or those treated with anti-IL-5 antibodies in comparison with wild-type responses, a marked residual tissue eosinophilia can persist in these mice after allergen inhalation [14,15,37,48,52,53]. Importantly, this residual tissue eosinophilia in allergic mice is significantly greater than that observed in naive non-allergic controls [50]. Indeed, blood eosinophil levels in allergen-challenged allergic IL-5−/− mice are lower than those observed in naive wild-type mice (as is seen in clinical trials with anti-IL-5 compared with controls), yet appreciable numbers of eosinophils accumulate independently of this cytokine in the allergic lung (and in models of gastrointestinal allergy) [48,50,58,59]. Thus, measurement of blood levels of eosinophils in clinical trials might not be indicative of whether this cell is still accumulating during allergen provocation of the lung. We have also observed that the degree of residual tissue eosinophilia correlates with the induction of AHR. Tissue eosinophil levels are 10–100-fold greater in the BALB/c IL-5−/− mice where AHR persists in comparison with the C57BL/6 strain where airways reactivity was abolished in the absence of IL-5 [15,48]. Thus, anti-IL-5 treatment does not completely inhibit the accumulation of eosinophils in the allergic lung and this cell might therefore still contribute to pathogenesis. Recently, we have shown that local chemokine networks in the allergic lung regulate eosinophil accumulation independently of IL-5, and that this mechanism plays an important role in disease processes [50]. In the absence of IL-5 and eotaxin, http://tmm.trends.com

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tissue eosinophilia is abolished in BALB/c mice and so is AHR. (It is important to note that inhibition of eotaxin alone does not abolish eosinophilia and AHR; targeting both pathways is required). These studies indicate that pathways operated by local chemokine systems (in particular those which involve CCR3, the eotaxin receptor) play an important role in regulating the recruitment of eosinophils into tissues independently of IL-5, and that this mechanism is linked to the induction of disease. Importantly, this mechanism also operates in the absence of a blood eosinophilia. We have also investigated the role of IL-5 in chronic models of disease (6 weeks of antigen exposure) in mouse systems [60–62]. In our chronic model, inflammation and eosinophilia are confined to the epithelium and lamina propria of the airways. The airways also exhibit many morphological features of chronic asthma (subepithelial fibrosis, epithelial hypertrophy, mucus cell metaplasia and hyperplasia). In this model, AHR and tissue accumulation of eosinophils are abolished in IL-5−/− mice. However, when antigen is delivered at a greater dose to IL-5−/− mice, over a longer period (6 months, different chronic model), eosinophils accumulate in the subepithelia regions and AHR develops (Foster et al., unpublished). We are yet to determine responses in mice deficient in both eotaxin and IL-5 in such longitudinal studies. Interestingly, tissue eosinophilia (albeit reduced) is also a predominant feature of IL-5−/− mice with allergic inflammation of the gastrointestinal tract [59] and the lung infected with Toxocara canis [58]. Eosinophils also fluctuate normally (albeit at reduced levels) in the uterus of IL-5−/− mice during the oestrus cycle [63]. Notably, a blood eosinophilia is not always a feature of disorders characterized by the accumulation of this cell in diseased tissues [22]. For example, patients with gastroesophageal reflux have eosinophilia in the oesophagus but rarely have elevated blood levels of this cell type, and only a subset of patients with asthma has both peripheral blood and tissue eosinophilia [22]. Thus, the contribution of IL-5 to pathogenesis could be more important where a substantial blood eosinophilia is required to maintain tissue levels of this cell type for disease progression. Conclusions

It should be remembered that asthma is a complex chronic disorder in which many cellular pathways might contribute. Furthermore, animal models are only representative of certain aspects of disease processes. However, they serve as the cornerstone to test clinical paradigms that are largely based on circumstantial observations that are often (by nature) made under conditions that are difficult to control. Although the role of the eosinophil in asthma remains to be determined we have been able to show, by using

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the mouse as a model of Th2-mediated eosinophilia and allergic disease, that the regulation of eosinophil accumulation in tissues is complex and can occur in the absence of observable accumulation in the blood or airways spaces (lavage fluid). We have also shown that very low levels of eosinophils in tissues can be sufficient to promote features of allergic disease (AHR). These pathways might or might not be relevant to human disease, but should be considered when analyzing studies that address eosinophil migration and the role of this cell in pathogenesis. Indeed, analysis of tissue levels of cellular infiltrates (spatial and temporal) should be central to determining the efficacy of any new anti-asthma therapies. References 1 Bochner, B.S. et al. (1994) Immunological aspects of allergic asthma. Annu. Rev. Immunol. 12, 295–335 2 Wills-Karp, M. (1999) Immunological basis of antigen-induced airways hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 3 Galli, S.J. (1997) Complexity and redundancy in the pathogenesis of asthma: reassessing the roles of mast cells and T cells. J. Exp. Med. 186, 343–347 4 Drazen, J.M. et al. (1996) Sorting out the cytokines of asthma. J. Exp. Med. 183, 1–5 5 Gleich, G.J. and Adolphson, C. (1993) Bronchial hyperreactivity and eosinophil granule proteins. Agents Actions (Suppl. 43), 223–230 6 Azzawi, M. et al. (1990) Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am. Rev. Respir. Dis. 142, 1407–1413 7 Azzawi, M. et al. (1992) T lymphocytes and activated eosinophils in airway mucosa in fatal asthma and cystic fibrosis. Am. Rev. Respir. Dis. 145, 1477–1482 8 Bentley, A.M. et al. (1992) Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am. Rev. Respir. Dis. 146, 500–506 9 Bentley, A.M. et al. (1993) Increases in activated T lymphocytes, eosinophils, and cytokine mRNA expression for interleukin-5 and granulocyte/macrophage colony- stimulating factor in bronchial biopsies after allergen inhalation challenge in atopic asthmatics. Am. J. Respir. Cell Mol. Biol. 8, 35–42 10 Sur, S. et al. (1995) Eosinophilic inflammation is associated with elevation of interleukin-5 in the airways of patients with spontaneous symptomatic asthma. J. Allergy Clin. Immunol. 96, 661–668 11 Sur, S. et al. (1995) Allergen challenge in asthma: association of eosinophils and lymphocytes with interleukin-5. Allergy 50, 891–898 12 Jarjour, N.N. et al. (1997) The immediate and late allergic response to segmental bronchopulmonary provocation in asthma. Am. J. Respir. Crit. Care Med. 155, 1515–1521 13 Hamid, Q. et al. (1991) Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J. Clin. Invest. 87, 1541–1546 14 Hamelmann, E. et al. (1997) Antiinterleukin-5 antibody prevents airway hyperresponsiveness in a murine model of airway sensitization. Am. J. Respir. Crit. Care Med. 155, 819–825 http://tmm.trends.com

Eosinophil trafficking is a complex process [64], and although IL-5 is a key regulator of eosinophil function, alternative pathways operate in conjunction with this cytokine to promote the accumulation of eosinophils in allergic tissues. Importantly, local chemokine systems play a central role independently of IL-5 in the recruitment of eosinophils into inflamed tissues. The contribution of IL-5-dependent and -independent mechanisms for the recruitment of eosinophils into tissues in various allergic inflammatory disorders must be considered in therapeutic strategies designed to identify the role of this granulocyte in the induction, progression or exacerbation of disease.

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42 Clutterbuck, E.J. et al. (1989) Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood 73, 1504–1512 43 Campbell, H.D. et al. (1987) Molecular cloning, nucleotide sequence, and expression of the gene encoding human eosinophil differentiation factor (interleukin 5). Proc. Natl. Acad. Sci. U. S. A. 84, 6629–6633 44 Lopez, A.F. et al. (1988) Recombinant human interleukin 5 is a selective activator of human eosinophil function. J. Exp. Med. 167, 219–224 45 Yamaguchi, Y. et al. (1988) Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival. IL-5 as an eosinophil chemotactic factor. J. Exp. Med. 167, 1737–1742 46 Kopf, M. et al. (1996) IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity 4, 15–24 47 Hogan, S.P. et al. (1998) Interleukin-5-producing CD4+ T cells play a pivotal role in aeroallergeninduced eosinophilia, bronchial hyperreactivity, and lung damage in mice. Am. J. Respir. Crit. Care Med. 157, 210–218 48 Hogan, S.P. et al. (1998) A novel T cell-regulated mechanism modulating allergen-induced airways hyperreactivity in BALB/c mice independently of IL-4 and IL-5. J. Immunol. 161, 1501–1509

49 Mould, A.W. et al. (1997) Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J. Clin. Invest. 99, 1064–1071 50 Foster, P.S. et al. (2001) Elemental signals regulating eosinophil accumulation in the lung. Immunol. Rev. 179, 173–181 51 Nishinakamura, R. et al. (1996) Hematopoiesis in mice lacking the entire granulocyte-macrophage colony- stimulating factor/interleukin-3/ interleukin-5 functions. Blood 88, 2458–2464 52 Corry, D.B. et al. (1996) Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 53 Nagai, H. et al. (1993) Effect of anti-IL-5 monoclonal antibody on allergic bronchial eosinophilia and airway hyperresponsiveness in mice. Life Sci. 53, L243–L247 54 Tournoy, K.G. et al. (2000) Airway eosinophilia is not a requirement for allergen-induced airway hyperresponsiveness. Clin. Exp. Allergy 30, 79–85 55 Tournoy, K.G. et al. (2001) The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent. J. Immunol. 166, 6982–6991 56 Karras, J.G. et al. (2000) Inhibition of antigeninduced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma. J. Immunol. 164, 5409–5415

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57 Shardonofsky, F.R. et al. (1999) Therapeutic efficacy of an anti-IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma. J. Allergy Clin. Immunol. 104, 215–221 58 Takamoto, M. et al. (1997) Eosinophilia, parasite burden and lung damage in Toxocara canis infection in C57Bl/6 mice genetically deficient in IL-5. Immunology 90, 511–517 59 Hogan, S.P. et al. (2001) A pathological function for eotaxin and eosinophils in eosinophilic gastrointestinal inflammation. Nat. Immun. 2, 353–360 60 Kumar, R.K. and Foster, P.S. (2001) Murine model of chronic human asthma. Immunol. Cell Biol. 79, 141–144 61 Foster, P.S. et al. (2000) Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma. Lab. Invest. 80, 655–662 62 Temelkovski, J. et al. (1998) An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. Thorax 53, 849–856 63 Robertson, S.A. et al. (2000) Uterine eosinophils and reproductive performance in interleukin 5-deficient mice. J. Reprod. Fertil. 120, 423–432 64 Hogan, S.P. et al. (1998) Cellular and molecular regulation of eosinophil trafficking to the lung. Immunol. Cell Biol. 76, 454–460

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A TRENDS guide to Cancer Therapeutics Translating basic cancer research into new cancer therapeutics Paul Workman and Stanley B. Kaye STI571 (Gleevec) as a paradigm for cancer therapy Brian J. Druker The ErbB receptor family: a therapeutic target for cancer Johann S. de Bono and Eric K. Rowinsky Unraveling the complexities of the Raf/MAP kinase pathway for pharmacological intervention Roman Herrera and Judith S. Sebolt-Leopold Complexities in the development of cyclin–dependent kinase inhibitor drugs Edward A. Sausville Therapeutic exploitation of the p53 pathway David P. Lane and Sonia Lain

Epigenomics and epigenetic therapy of cancer Robert Brown and Gordon Strathdee Proteasome inhibition: a novel approach to cancer therapy Julian Adams Hsp90 inhibitors as novel cancer chemotherapeutic agents Len Neckers HIF-1 and tumor progression: pathophysiology and therapeutics Gregg L. Semenza The emerging fields of suicide gene therapy and virotherapy David Kirn, Ion Niculescu-Duvaz, Gunnel Hallden and Caroline J. Springer

FREE online throughout April – cancer-related news, features and reviews from TRENDS and Current Opinion journals. See supplement for details http://bmn.com/cancerbiology

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