Novel Therapies in Allergic Disease
Cytokine-directed therapies for asthma,☆☆

https://doi.org/10.1067/mai.2001.116435Get rights and content

Abstract

Increasing knowledge of the pathophysiologic roles of various cytokines in atopic diseases has provided the basis for the development of novel therapies. Strategic approaches for cytokine inhibition include the blocking of transcription factors that lead to their expression, blockade after their release, cytokine receptor antagonism, and the inhibition of signaling pathways that are activated after cytokine-receptor binding. The proinflammatory cytokines IL-5, IL-4, IL-13, and TNF-α are among the therapeutic targets. Results with a humanized anti-IL-5 have been disappointing. Although successful in markedly reducing circulating eosinophils and in preventing eosinophil accumulation in airways, the humanized anti-IL-5 was unable to affect early or late responses to allergen or to reduce airway reactivity to methacholine challenge in patients with asthma. On the other hand, a soluble IL-4 receptor antagonist has shown clinical benefits for patients with moderate asthma who require daily inhaled corticosteroids. Agents that target IL-13 and TNF-α remain to be evaluated in asthmatic inflammation. The use of cytokines with anti-inflammatory effects may also have therapeutic value. The evaluation of such agents in human beings, including IL-10, IL-12, and IFN-γ, is at a preliminary stage, but so far results have not been encouraging. (J Allergy Clin Immunol 2001;108:S72-6.)

Section snippets

Strategic approaches

Several strategies for inhibiting proinflammatory cytokines have been considered. At the most basic level, cytokine synthesis can be inhibited by blocking the transcription factors that lead to the expression of those cytokines. In this context, the potential of nuclear factor-κB as a target has received considerable attention because it regulates the expression of multiple cytokines involved in asthma. Alternatively, an antisense oligonucleotide can be used to “mop up” the messenger RNA, thus

Interleukin-5

IL-5 plays a key role in the airway inflammation of asthma. It is essential for the production, maturation, activation, and survival of eosinophils and is also important in eosinophil chemoattraction.3 The central role of IL-5 among cytokines in the development of eosinophilia has been demonstrated in many in vivo models. Pretreatment with anti–IL-5 monoclonal antibodies has been shown to suppress allergen-induced airway eosinophilia in guinea pigs and monkeys.4, 5 In a cynomolgus monkey model

Interleukin-10

IL-10 has unique functional effects, a number of which are relevant to asthma. It inhibits the production of several proinflammatory cytokines such as IL-1β, TNF-α, and GM-CSF, as well as chemokines, particularly eotaxin and RANTES, that could be important for eosinophil recruitment.17 It also inhibits the inflammatory enzymes, such as insoluble nitric oxide synthase (iNOS) and insoluble cyclooxygenase (COX-2), potently blocks IL-5, inhibits TH2 cytokines, and reduces allergen responses by

Conclusions

Anti–IL-5 antibodies are highly effective in the long-term reduction of eosinophils. The fact that no effect on airway reactivity has been observed with anti–IL-5 treatment is disappointing, but this approach nonetheless merits further study in patients with symptomatic asthma. Evidence that IL-4 receptor antagonists have some clinical benefit in asthma when administered by inhalation is encouraging and also merits further investigation, especially since administration as a single weekly dose

References (26)

  • RW Egan et al.

    Biology of interleukin-5 and its relevance to allergic disease

    Allergy

    (1996)
  • PJ Mauser et al.

    Effects of an antibody to interleukin-5 in a monkey model of asthma

    Am J Respir Crit Care Med

    (1995)
  • HZ Shi et al.

    Infiltration of eosinophils into the asthmatic airways caused by interleukin-5

    Am J Respir Cell Mol Biol

    (1997)
  • Cited by (72)

    • Abietic acid attenuates allergic airway inflammation in a mouse allergic asthma model

      2016, International Immunopharmacology
      Citation Excerpt :

      IL-13 has the ability to induce airway inflammation and AHR [21]. Recent studies suggested that inhibition of these Th2 cytokines might be a potential therapeutic strategy for the treatment of allergic asthma [22]. In this study, we found that treatment of AA significantly inhibited OVA-induced IL-4, IL-5, and IL-13 production in a dose-dependent manner.

    • The IL6R gene polymorphisms are associated with sIL-6R, IgE and lung function in Chinese patients with asthma

      2016, Gene
      Citation Excerpt :

      IgE is a mediator of airway inflammation response and is considered an important biomarker for asthma (Bachert & Zhang, 2012; Beeh et al., 2000). IL-4 promotes the production of IgE (Berton et al., 1989), and had been considered to be a target for blocking IgE production in allergic asthma(Barnes, 2001). IL-6 promotes endogenous IL-4 production in CD4 T cells (Diehl et al., 2002; Neveu et al., 2009).

    • Immunologic Therapeutic Interventions in Asthma. Impact on Natural History

      2012, Clinics in Chest Medicine
      Citation Excerpt :

      Accordingly, blocking one cytokine will be sufficient to avoid the risk of redundancy and potentially a subsequent clinical failure.42,43 IL-4 and IL-13 are thought to play distinct important roles in B-cell commutation to IgE production, mast cell expression of the IgE receptor (fragment crystallizable [Fc] epsilon R [FcεRI]), and eosinophil recruitment.44–46 Clinical trials using monoclonal antibodies (mAbs) directed toward IL-4 and IL-4R failed to demonstrate a clinical impact on asthma outcomes.47–49

    • Amphetamine modulates cellular recruitment and airway reactivity in a rat model of allergic lung inflammation

      2011, Toxicology Letters
      Citation Excerpt :

      It is important to note that amphetamine treatment reduced the Mac-1 expression in both macrophages and granulocytes. Cytokines, especially IL-4, IL-5, IL-10, and IL-13, are expressed during asthma (Barnes, 2001). Cytokines and their activation of adhesion molecules can then contribute to cell infiltration and activation during allergic lung inflammation, which might explain the elevated levels of IL-10 and IL-4 found in samples of lung explants from allergic rats.

    View all citing articles on Scopus

    Dr Barnes has consultant arrangements with GlaxoSmithKline and receives research support from GlaxoSmithKline, Boehringer Ingelheim, Novartis, and Bayer. He is also an employee of Imperial College, London.

    ☆☆

    Reprint requests: Peter J. Barnes, MD, DM, DSc, National Heart and Lung Institute, Division of Thoracic Medicine, Dovehouse Street, London, SW3 6LY, UK.

    View full text