Environmental Control and Immune Modulation in Asthma Treatment

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American Lung Association/American Thoracic Society International Conference
Day 3 - April 27, 1999

Environmental Control and Immune Modulation in Asthma Treatment

Erwin W. Gelfand, MD

It is well known that allergen exposure correlates with asthma severity and asthma exacerbations. This has been especially well documented for such allergens as house dust mites, cockroaches, and animal dander, particularly from cats.

Reducing allergen exposure, although intuitively obvious as a management approach, has had a less than stellar track record when applied to asthma control in clinical practice. That is not to say that it cannot be effective when carried out to the extreme. The oft-quoted Dutch study of children removed from a dust mite-ridden environment to the mountains of Davos, which were dust mite-free, showed a remarkable clinical improvement in asthma control.

In general, however, repeated washing of pets, persistent vacuuming with highly efficient filters, and air cleaners with high efficient particle removers, have all had limited success. Even though allergen levels can be significantly reduced through use of such methods, clinical disease changes very little in response.

Similarly, conventional immunotherapy has had limited success in allergic asthma when compared with such interventions as desensitization to bee stings. It is in the light of these realities that researchers are exploring many new approaches for immunotherapy in asthma. These include development of recombinant, engineered or modified peptides and proteins. Investigators discussed several of these approaches Tuesday.

DNA Vaccination Explored

Taking advantage of molecular biology techniques, Dr. Eyal Raz of La Jolla, Ca, discussed recent findings using immunotherapeutic DNA, suggesting that DNA vaccination may turn out to be an effective alternative to conventional immunotherapy in allergic asthma ^[1].

One such approach utilizes plasmid DNA encoding the genes for specific proteins. When studied in animals, injections of plasmid DNA resulted in persistent expression of protein and were associated with polarization of the immune response to a Th1 phenotype, ie, increased interferon-g (IFNg) and lower levels of interleukin 4.

In studies using plasmids encoding ovalbumin (OVA), allergic (eosinophilic) inflammation in the lung was virtually prevented. Thus, tiny amounts of persistently liberated antigen had significant benefits in curtailing allergic inflammation.

In contrast to this antigen-specific approach with plasmid DNA, other researchers are using certain bacterial DNA sequences. These so-called immunostimulatory DNA oligonucleotides (ISS-ODN), used in a murine module of allergic airway inflammation, markedly reduced airway hyperresponsiveness, airway eosinophilia, and IL-5 levels while increasing the levels of IFNg.

These ISS-ODNs were equally potent when administered intraperitoneally, intratracheally, or intranasally. They appeared to be more effective than corticosteroids at reducing allergic inflammation. Their site of action is unclear, however, and may be working at several levels in the innate immune system on natural killer (NK) cells or in the acquired immune system, on antigen-presenting cells. This novel approach has shown that allergen specificity is irrelevant. A major unanswered question is the consequence of converting all Th2 responses to a Th1 phenotype.

Th1/Th2 Balance?

Thomas Platts-Mills from Charlottesville, VA, questioned the paradigm of Th1 and Th2, suggesting that the non-allergic state is not simply one of Th1 cells versus Th2 cells in an allergic individual ^[2]. He discussed a series of studies carried out in Northern Sweden where certain markers, eg, antigen-specific IgG4 antibodies (traditionally thought to be a Th2 marker), were equally demonstrated in both allergic and non-allergic individuals.

Platts-Mills also emphasized that high exposure to certain allergens, cat, for example, does not necessarily equate with allergic sensitization. In addition, he emphasized the importance of allergen exposure in schools, suggesting that attempting to avoid allergens only in the home are not likely to be sufficient to control asthma symptoms.

A final issue discussed, one likely of major importance in considering immunotherapy in patients with asthma, was the experience of beekeepers who, after suffering several stings, develop tolerance to subsequent stings. However, this "state of tolerance" was short-lived and did not prevent susceptibility when encountered several months later.

Indoor Allergens in the Inner City

Dr. Meyer Kattan of New York City discussed the important role of indoor allergens ^[3], reviewing the results of a significant inner-city asthma study.

In this study of approximately 1500 children, sensitivity to cockroaches far exceeded that to house dust mites or cats. Exposure levels and sensitization were highly correlated with prick skin tests, as were numbers of hospitalizations, symptom scores and numbers of physician visits. The results clearly identified the major consequences of the combination of sensitization and exposure versus either alone.

References

Raz E: DNA vaccines for asthma and allergic diseases, in, Plaut M, Smartt E (chairs): Environmental control and immune modulation in the treatment of asthma [Session L9]. ALA/ATS International Conference, San Diego, Ca, 1999.
Platts-Mills TA: Allergen avoidance and immunization with modified allergen, in, Plaut M, Smartt E (chairs): Environmental control and immune modulation in the treatment of asthma [Session L9]. ALA/ATS International Conference, San Diego, Ca, 1999.
Kattan M: Allergen elimination in asthmatic children in the inner city, in, Plaut M, Smartt E (chairs): Environmental control and immune modulation in the treatment of asthma [Session L9]. ALA/ATS International Conference, San Diego, Ca, 1999.

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