Reassessing the Th2 cytokine basis of asthma

https://doi.org/10.1016/j.tips.2004.03.008Get rights and content

Abstract

T helper (Th) 2 cytokines, particularly interleukin 4 (IL-4), IL-5 and IL-13, might be important in the development of allergic asthma. Humanized monoclonal antibodies (hMAbs) against IL-5, and a recombinant soluble human IL-4 receptor have been developed as possible treatments for this disorder. However, these approaches have not yet proven to be successful in the treatment of persistent asthma, suggesting that neither IL-4 nor IL-5 is important in asthma pathogenesis. Indeed, there is insufficient information about the efficacy of soluble IL-4 receptor and the anti-IL-5 hMAbs in the treatment of asthma to draw firm conclusions about the importance of these Th2 cytokines. Nevertheless, because IL-4 is required for IgE production and IL-5 is required for eosinophilopoesis, these Th2 cytokines must remain important candidates for a role in the pathogenesis of allergic asthma.

Section snippets

T-helper cells in allergic asthma

The association of peripheral blood lymphopenia (a decrease in the number of lymphocytes) with increases in the number of eosinophils and the level of IgE in allergic asthmatics was made almost 30 years ago [6]. Several years later, Parish and Luckhurst [7] reported that T cells obtained from the airways, but not the peripheral blood, of asthmatic subjects released mediators that promoted eosinophil, but not neutrophil, chemokinesis and chemotaxis. Around this time a functional differentiation

Efficacy of anti-IL-5 antibodies and the soluble IL-4 receptor in asthma

To evaluate the role of IL-4 and IL-5 in asthma, it was necessary to develop antagonists for these cytokines. Efforts to do this resulted in the development of humanized monoclonal antibodies (hMAbs) directed against IL-5 and a recombinant human soluble IL-4 receptor as an IL-4 antagonist. These molecules were initially validated in mouse models of allergic inflammation and were then evaluated in asthmatic patients (Table 1). In one study, 24 mild allergic asthmatic subjects were treated with

The Th2 hypothesis in asthma is alive, but ailing

There is, as yet, insufficient information about the efficacy of the soluble IL-4 receptor and the anti-IL-5 MAbs in the treatment of asthma to draw firm conclusions about the importance of IL-4 and IL-5 in asthma pathogenesis, and to evaluate the credibility of the Th2 hypothesis for allergic asthma. It is clear, however, from studies evaluating the hMAb directed against the high-affinity IgE receptor (FcϵR1) (omalizumab) that the presence of high levels of IgE plays an important role in the

Concluding remarks

The Th2 cytokines, such as IL-4, IL-5 and IL-13, remain likely to be of central importance in the pathogenesis of allergic asthma. The lack of a striking benefit demonstrated with the hMAbs against IL-5 either in protecting against allergen inhalation challenge or in moderate to severe asthma does not exclude a potential role for IL-5 or eosinophils in asthma. The study designs and/or the patient populations chosen for these trials limit the possibilities for interpretation of results. Despite

References (38)

  • S. Gupta

    Lymphocyte subpopulations, serum IgE and total eosinophil counts in patients with bronchial asthma

    Clin. Exp. Immunol.

    (1975)
  • W.E. Parish et al.

    Eosinophilia VI, spontaneous synthesis of chemokinetics, chemotactic, complement receptor-inducing activities for eosinophils by bronchial T lymphocytes of asthmatic-bronchitic patients

    Clin. Allergy

    (1982)
  • T.R. Mosmann

    Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins

    J. Immunol.

    (1986)
  • A. Bossie

    Activation of murine B cells from different tissues with different mitogens. Isotype distribution of secreted immunoglobulins in the presence and absence of IL-4-containing T cell supernatants

    J. Mol. Cell. Immunol.

    (1987)
  • B. Masinovsky

    IL-4 acts synergistically with IL-1 beta to promote lymphocyte adhesion to microvascular endothelium by induction of vascular adhesion molecule-1

    J. Immunol.

    (1990)
  • A. Bentley

    Tissue eosinophilia and increased numbers of cell expressing mRNA for IL-4 and IL-5 occur in asthma but not bronchiectasis

    J. Allergy Clin. Immunol.

    (1998)
  • J.G. Zangrilli

    sVcam-1 Levels after segmental antigen challenge correlate with eosinophil influx, IL-4 and IL-5 production, and the late-phase response

    Am. J. Respir. Crit. Care Med.

    (1995)
  • C.J. Sanderson

    Interleukin-5: an eosinophil growth and activation factor

    Dev. Biol. Stand.

    (1988)
  • A.F. Lopez

    Recombinant human interleukin 5 is a selective activator of human eosinophil function

    J. Exp. Med.

    (1988)
  • Cited by (62)

    • Interleukins | IL-4

      2021, Encyclopedia of Respiratory Medicine, Second Edition
    • Combination of fish oil and ethanol extracts from Spirulina platensis inhibits the airway inflammation induced by ovalbumin in mice

      2018, Journal of Functional Foods
      Citation Excerpt :

      Cytokines acting within the inflammatory reactions are small proteins released by cells, including tumor necrosis factor (TNF), interleukin (IL), interferon (IFN), chemokine, and lymphokine. The imbalance between Th1 and Th2 cytokines and the enhancement of chemokine ligand 11 (CCL11) are major pathogenesis of asthmatic inflammation (O'Byrne, Inman, & Adelroth, 2004). To investigate the effect of CFS on cytokines in allergic airway inflammation, the levels of Th1 (IFN-γ), Th2 (IL-4, IL-5, IL-13) cytokines and chemokine (CCL 11) in the BALF of OVA-challenged mice were quantified by ELISA assays.

    • Novel treatments of asthma and allergic diseases

      2014, Paediatric Respiratory Reviews
      Citation Excerpt :

      However, several clinical trials on the use of soluble recombinant human IL-4Rα (altrakincept) and humanized anti-IL4 neutralizing antibody (pascolizumab) were not encouraging [57] (Table 1). Therefore, recent approaches are focusing on drugs whose action suppresses the activity of both IL4 and IL13, because of their redundant mechanisms in the IgE production [58]. Recently, a variant of IL-4 (pitrakinra) that blocks IL-4 receptor α, common to IL-4 and IL-13, has been developed.

    View all citing articles on Scopus
    View full text