L E T T E R Interleukin 5 as a drug target in allergy and asthma The role of interleukin 5 in the perpetuation of airway inflammatory, responses In a recent TiPS article, Anderson and Coyle postulated that interleukin 4 (IL4), rather than interleukin 5 (IL-5), is emerging as a critical drug target in allergy and asthma 1.This postulation is based on the essential role of IL-4 as a switch factor for B-cell IgE anti- body production and in the develop- ment of TH2 cells (both CD4 + and CD8÷). Apart from the redundancy between IL-4 and interleukin 13 (IL- 13) with respect to B-cell switching to the IgE-isotype, this approach may be not as successful as suggested. The major problem is that in an already established disease IL-4 does not appear to be crucial for its perpetuation. Anderson and Coyle briefly touch upon this subject when they discuss the longevity of the TH2 response. At present there is strong evidence that IL-4 is not necessary for an ongoing allergic response. First, Iwamoto and co-workers have demonstrated that in animal models of antigen-induced eosinophil recruit- ment antibodies to IL-4 are not effective when administered after sensitization 2. The recruitment of eosinophils appears to be mediated by TH2 cells since antibodies to CD4÷ T-cells or antibodies to IL-5 inhibit these migratory responses 3,4. These data imply that activation of memory cells with TH2 characteristics is not strictly dependent on IL-4. Second, TH2 cells can be maintained and expanded in vitro for a relatively long period of time in the absence of IL-4, suggesting that once polarization to 'TH2-1ike' cells has occurred this phenotype is retained indefinitely and may be modulated only tem- porarily5. Third, few data are avail- able that indicate IgE production by memory B cells is affected by anti- bodies to IL-4. In contrast, there are strong indications that antigen- specific IgE antibody production by memory B cells is only partially dependent on IL-4 (Ref. 6). Since the clinician is confronted with patients who have already developed allergic responses, IL-4 may not be the ideal primary drug target to focus on. However, preven- tive treatment of individuals who are predisposed to become allergic remains a possible area in which IL-4 may be an important drug target. However, these individuals would probably have to continue this treat- ment for their entire lives. Further- more, it should be considered that approaches designed to inhibit IL-4 activity (for example, soluble IL-4 5 receptors or neutralizing antibodies) have been shown, in practice, to maintain IL-4 activity7. Ultimately, complete IL-4 blockade may lead to ablation of IgE responses, as has been observed in mice where the IL-4 gene was inactivateds. However, in these mice germinal centre formation was disrupted although T- and B-cell development remained normal. This illustrates that, due to the pleiotropic activities of IL-4 and its various regulatory influences, it is not advisable to neutralize IL-4 activity completely and risk introducing unwanted side effects9. A. J. M. Van Oosterhout and H. F. J. Savelkoul* Department of Pharmacology, University of Utrecht, PO Box 80.082, 3508 TB Utrecht, The Netherlands, and *Department of Immunology, Erasmus University, Rotterdam, The Netherlands. References 1 Anderson,G. P. and Covle, A. J. (19q4) Trends Pharmacol.Sci. 15,324-332 2 Iwamoto, I., Tomoe, S., Tomioka, H., Takatsu,K.and Yoshida, S. (1992) J. Leuko~ cyte Biol. 52, 572-578 3 Nakajima, H. et al. (1992) Am. Rev. Respir. Dis. 146, 374-377 4 Van Oosterhout,A. J. M. et al. (1993) Am. Rev. Respir. Dis. 147, 548-552 5 Swain, S. L. (1993)Res.Immunol. 144, 616~20 6 Van Ommen,R., Vredendaal,A. E. C. M. and Savelkoul, H. F. J. (1994) Scand. I. lrnmunol. 40,491-501 7 Debets, R. and Savelkoul,H. F. J. (1994) Imrnunol. Today 15,455-458 8 Kuhn, R., Rajewsky, K. and Muller, W. (1991) Science 254,707-710 9 Savelkoul, H. F.J. andVanOmmen, R. Eur. Respir. 1. (in press) Anderson and Coyle reply Targeting TH2 cells in allergy and asthma We would like to thank Van Oosterhout and Savelkoul for their astute comments and interest in our ideas. Several issues where we differ in opinion have been raised, and these warrant further comment. As Van Oosterhout and Savelkoul indi- cate, we specifically address the problem of the use of drugs directed against IL-4 and conclude that such agents may emerge as the first true preventative therapies for allergy and asthma. Indeed, our own work suggests that antibodies to IL-4 are only effective in suppressing eosinophilic inflammation when administered early in the induction of TH2 responses 1.The nature of both T-cell and B-cell memory continues to be an intensely researched and debated field of science. If we accept that there are at least experimental models where T-cell phenotype is maintained and ongoing B-cell IgE production occurs in the absence of IL-4, which question the value of such drugs in established disease, several points must be remembered. First, in progressive disease, patients will accumulate an increas- ing number of specific IgE or Tn2-cell reactivities to antigenic epitopes of one or more antigen(s) (to which they were not initially sensitive) presum- ably in an IL-4-dependent manner. Second, we suggested the importance of targeting new drugs towards the © 1995, Elsevier Science Ltd TiPS - February 1995 (Vo]. 16) 3 7