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Rebuttal from Drs. Wenzel and Holgate

University of Pittsburgh, Pittsburgh, Pennsylvania

Stephen T. Holgate, B.Sc., M.B.B.S., M.D., D.Sc.

School of Medicine, University of Southampton, Southampton, United Kingdom

Dr. Shapiro raises excellent points in his argument for the use of mouse models in asthma research. We, like Dr. Shapiro, are not arguing for their complete abandonment, rather a measured approach to their use which fully appreciates "how far to take the analogy." To paraphrase Clint Eastwood/Dirty Harry, "A mouse has got to know its limitations"!

That said, we would like to challenge a few of the points raised by Dr Shapiro:

1. The specific molecular pathways are similar in both species. Although this may be true in some cases, numerous examples exist for species differences in molecular pathways. Of specific relevance to asthma are the profound differences in responses to interleukin (IL)-4/IL-13 activation of airway cells. In murine models, it has been reported that Th2 cytokines markedly inhibit expression of inducible nitric oxide synthase (iNOS), the enzyme responsible for the majority of exhaled nitric oxide (FE_NO). Despite this inhibition, FE_NO is known to be markedly increased in human asthma. To explain this apparent paradox, several studies have reported using various combinations of stimuli in hopes of understanding why FE_NO is increased in human asthma. However, in studies presented at the 2006 American Thoracic Society meeting, IL-13 stimulation of primary human epithelial cells in air–liquid interface culture caused a dramatic up-regulation of iNOS, in contrast to the opposite effect in previously reported murine studies (1). Taking a further example of major difference between humans and mice, studies using human macrophages failed to reproduce the up-regulation of arginase with IL-13 noted in murine cells (2). Hence, when evaluating Th2 cytokine effects on pathways demonstrated to be important to human asthma, the mouse and the human would appear to behave in an opposite manner.

2. Mouse models are representative of the known etiology or insult that causes human disease/asthma. Although we would even argue that there are serious questions to be answered about the primary role of environmental allergens in human asthma development, we are convinced that ovalbumin, the most commonly used murine "allergen," has almost never caused human asthma. In addition, we are surprised by Dr. Shapiro's statement that human researchers claim the Th2 hypothesis as their own. Clearly, the early studies of Th1 and Th2 used murine cells and cell lines (3). In fact, there is a long history of skepticism for the dichotomy of Th1 and Th2 as applied to human models.

3. Strain differences are a great strength of mouse models. We are in complete agreement on this point. However, few studies have exploited this obvious strength. Rather, the majority of studies still report largely positive results in a single strain, rather than attempting to understand why their positive response may occur profoundly in one strain and not in another. Indeed, one gains the impression that researchers deliberately select strains to reveal a specific response.

4. Animal models can prove causality. Animal studies only prove causality in the model system used, not in human disease. We would strongly argue against "going back to the animal model to confirm the mechanism." This is especially unnecessary when the pathway is already known to be active in human disease, targeted approaches in mice are supportive, and the mechanistic pathways can be further identified in primary human cells or tissues.

As introduced, mouse models can and should be used to better understand diseases like asthma through their unique ability to dissect selective pathways in a complex animal system. However, we reiterate our view that journals that publish papers using mouse or any other animal in relation to asthma should always refer to the animal species in the publication's title. Finally, we will continue to argue that the human should be at the center of research into unique human diseases such as asthma, with murine studies undertaken for preliminary and supporting purposes.

REFERENCES

1. Trudeau JB, Chu HW, Hu HZ, Bleecker ER, Meyers DA, Wenzel SE. 2006. Interleukin-13 increases iNOS expression in human air-liquid interface (ALI) epithelial cells [abstract]. Proc Am Thorac Soc 2006;2:A66.[CrossRef]
2. Scotton CJ, Martinez FO, Smelt MJ, Sironi M, Locati M, Mantovani A, Sozzani S. Transcriptional profiling reveals complex regulation of the monocyte IL-1 beta system by IL-13. J Immunol 2005;174:834–845.[Abstract/Free Full Text]
3. Cherwinski HM, Schumacher JH, Brown KD, Mosmann TR. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med 1987;166:1229–1244.[Abstract/Free Full Text]

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