Interleukin-12: potential role in asthma therapy.
Asthma is an inflammatory disease of the airways leading to significant morbidity and mortality. With advances in the understanding of the molecular and cellular mechanisms involved in the asthmatic response, researchers have identified specific mediators that may be targeted to control the inflammatory state of asthma. The Th2 hypothesis proposes that the inflammation in asthma arises from an imbalance between the two CD4+ T lymphocyte subsets, T helper (Th) type 1 and Th2. Th2 cells release many cytokines that have been shown to regulate the inflammatory response, while the Th1 cytokines counteract this response. The Th1 cytokine, interleukin (IL)-12, has been a target of intense study because it mediates the Th1 response and offers a means of modifying the asthmatic inflammatory response. Numerous murine studies have shown that this cytokine can potently inhibit allergic airway inflammation in asthma. Inhalation of IL-12 has been shown to increase its efficacy in inhibiting allergic inflammation in murine models while decreasing adverse effects seen with systemic administration of this cytokine. However, an initial study of inhaled IL-12 in humans with asthma was terminated because of adverse effects. The use of systemically administered IL-12 in patients with asthma has been limited due to cytokine toxicity. Another treatment option that has the potential of inducing a Th1 cytokine response is the use of IL-12 linked to polyethylene glycol (PEG) moieties. This mode of administration is likely to enhance cytokine delivery to the target organ, while decreasing its toxicity. IL-12 gene therapy has also been examined as a means of suppressing airway hyperreactivity in murine asthma, but its potential in human asthma has not been explored. Several recent studies have investigated the role of CpG DNA motifs as endogenous inducers of IL-12 with encouraging results in both mice and humans. These studies may result in novel Th1- inducing CpG-based immunotherapies for asthma.