Novel Treatment Strategies in IgE-Mediated Allergy

Cytokines and Cytokine Receptor-Antagonists

Hans-Uwe Simon
Chairman and Professor of Pharmacology
Department of Pharmacology
University of Berne
Berne, Switzerland

Extensive characterization of the immunopathogenesis of IgE-mediated allergic disorders suggests that Th2 cytokines (IL-4, IL-5, IL-9, IL-13) play central roles in the inflammatory process by regulating the production of IgE, the effector functions of mast cells and eosinophils, and by promoting transendothelial cell migration. In contrast, IFN-, a so-called Th1 cytokine, has the capacity of suppressing IgE synthesis. Defective IFN- expression has often been associated with atopy and IgE-mediated allergies. The dysbalance in the expression of Th1 and Th2 cytokines might largely be responsible for the initiation and maintenance of the allergic inflammatory process in diseases such as bronchial asthma (1) or atopic dermatitis (2). The increasing knowledge in this area has provided the basis for a number of novel therapies.

One approach is simply adding cytokines, which are not sufficiently expressed, or neutralizing cytokines, which are largely produced. Other approaches to decrease cytokine levels include the blockade of signalling molecules, the inhibition of transcription factors, or decreasing the levels of specific mRNA. In this presentation, I concentrate on the first approach.

IL-12 is produced by antigen-presenting cells and drives Th1 differentiation. On the other hand, it blocks Th2 differentiation, mainly by increasing the production of IFN-. Although experiments in animal models of allergic inflammation were encouraging, clinical trials with IL-12 or IFN- were often disappointing. It is possible that local rather than systemic therapy is more efficient and less toxic. Some patients with severe corticosteroid-resistant asthma may benefit from systemic low-dose IFN- treatment (3).

The neutralization of proinflammatory cytokines is another simple approach for an anti-inflammatory therapy. A soluble IL-4 receptor antagonist has been developed and successfully used in moderate asthma (4). The neutralization of IL-13 in mice prevented airway hyperreactivity and mucus secretion (5). Soluble IL-13 receptor antagonists are currently under development for human trials. Neutralization of IL-5 by using a humanized monoclonal antibody to IL-5 reduced blood eosinophils and prevented eosinophil recruitment into the airways (6). Although the clinical efficacy of this drug appreared to be disappointing in mild asthma, further studies are required to evaluate its role in the treatment of eosinophilic disorders.

In conclusion, cytokines are targets of novel antiallergic drugs. The evaluation of such agents is at a preliminary stage. Some of the newly developed drugs might either be alone or in combination useful in the treatment of IgE-mediated allergies.

References

1. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298-304.

2. Akdis CA, Akdis M, Simon D, Dibbert B, Weber M, Gratzl S, Kreyden O, Disch R, Wüthrich B, Blaser K, Simon HU. T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis. J Invest Dermatol 1999;113:628-634.

3. Gratzl S, Palca A, Schmitz M, Simon HU. Treatment with IFN- in corticosteroid-unresponsive asthma. J Allergy Clin Immunol 2000;105:1035-1036.

4. Borish LC, Nelson HS, Lanz MJ, L. Claussen, J.B. Whitmore, J.M. Agosti, L. Garrison. Interleukin-4 receptor in moderate atopic asthma: A phase I/II randomised placebo-controlled trial. Am J Respir Crit Care Med 1999;160:1816-1823.

5. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TL, Karp CL, Donaldson DD. Interleukin-13: Central mediator of allergic asthma. Science 1998;282:2258-2261.

6. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O’Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2144-2148.

Slide presentation

Return to top
Return to WAF: Naples index