Therapeutic Exploitation of the Biology of the Innate Immune System

Activation of the innate immune system is an integral part of the pathology of allergic diseases such as asthma, with a dual role that has different emphases in disease initiation and disease perpetuation. Sadly underappreciated in the past, the resurgence in interest in innate immunobiology has been spearheaded by the identification of the TLR system and its huge contribution to health and disease.

The complex immunopathology of asthma and other allergic diseases remains poorly understood. Making the link between the innate immune system and allergic disease has now allowed us to consider targets that had previously been overlooked. Each component of the innate immune system may be a feasible drug target, but we need to consider carefully how such targets should be handled. For example, if the innate immune system is activated repeatedly over time, generating repeated acute waves of high levels of activation (potentially on a background of chronic activation), it may be appropriate to target these separately from the underlying chronic disease. This might be achieved, for example, by neutralizing IL-1 or other important upstream cytokines during acute exacerbations. The long-lived nature of the immune response also requires serious thought when designing interventional therapies and drug trials. This is well illustrated by a cursory consideration of the biology of the macrophage.

It is clear that monocytes and macrophages perform important functions as immune surveillance cells, with great potential to amplify inflammatory responses through cooperative signaling via tissue cells such as epithelium and smooth muscle. Macrophages are very long-lived cells, and a single inflammatory stimulus can result in the gradual repopulation of the lung by young monocytes that may have a different activation phenotype, and will persist for months or years in the lung tissue. Thus, preventing monocyte trafficking to the lung with drugs such as chemokine receptor antagonists is a potentially very useful therapy, but the effects of these drugs may take months of administration to become apparent and their efficacy may be different on background chronic disease compared with the disease of acute exacerbations.

However, targeting the processes of innate immunity is clearly effective and feasible. Considerable interest and excitement has been generated by the use of anti-tumor necrosis factor (TNF)-a strategies in the treatment of asthma. Neutralization of IL-1 may also represent a useful treatment. Importantly, not all therapeutic options will involve the neutralization of cytokines: targeting innate immune deficiencies that lead to impairment of viral responses in asthmatics by replacement of absent cytokines is also theoretically feasible.