Th2 cells and/or their secreted effector molecules mediate the immune response to allergens and are triggered by exposure to specific allergens leading to allergic asthma. Thus, inhibiting or eliminating Th2 cells is a beneficial strategy for treating asthma as long as generalised immunosuppression is avoided. Additionally, it is especially important to consider targeting Th2 cells early in disease because when disease is chronic additional factors may cause perpetuation. Although there are a myriad of potential Th2 targets (Figure ), the optimal, most effective anti-Th2 cell target for the clinic remains elusive.
Figure 2 Promising cellular and molecular target candidates for inhibiting memory Th2 cells in allergic asthma are grouped according to the subchapters of the text. Targets in the inner circle (dash line) were tested in clinical trials, whereas other targets are (more ...)
Aside from anti-IgE therapy for severe asthma, there are no major new drugs for the treatment of asthma in the last 20 years. The latest research in allergic asthma that has elucidated key factors governing Th2 immunity and identified potential targets is predominantly from animal models. Now, the challenge is to discover candidates, which best translate from animal models to patients. However, choosing the most effective new drug target candidate is especially difficult because human data is often lacking or incomplete. Additionally, the use of accurate, predictive biomarkers to evaluate Th2-modulating drugs such as FEV1, Quality of Life, reduction in steroid use, decrease allergen-induced late phase response and others are important to ensure that the efficacy/adverse effect profiles are standardised and enable easier decision-making for the best candidates. We would argue that the most promising new compounds for the clinic are those in which proof of concept in patients is established e.g. anti-IL-13 antibodies and CRTH2 antagonists. Other candidates currently tested in the clinic are anti-IL-5, anti-IL-4 and anti-IL-9 compounds and CCR4 antagonists. However, based on available human data, we suggest that the epithelial cell-derived cytokines TSLP, IL-25 and IL-33, which drive Th2 responses are the most promising candidates, with TLSP the clear frontrunner.
Steroids are efficient for treating asthma because they inhibit numerous pro-inflammatory responses and induce numerous anti-inflammatory pathways. Thus, targeting a single mediator may not suffice for the treatment of allergic asthma because of the redundant immune and inflammatory pathways involved upon allergen challenge. Thus, we suggest that targeting more than one molecule simultaneously using dual specific antibody/protein platforms to engineer new drugs will be the next major approach in drug discovery. However, while this approach creates a scenario in which numerous targets can be combined, the caveat is that optimal candidates must be carefully chosen. Another important consideration for the therapeutic strategy for allergic asthma is that drugs may need to be developed for specific subtypes of disease in which particular cellular and molecular pathways drive the disease. One example is the anti-IL-5 mAb, which is only effective in asthmatics with very high sputum and lung eosinophil numbers. This example suggests that it is beneficial to better categorise patients and consider personalised medicine based on a clear classification of disease.
These are exciting times for Th2 cell immunology as the results of basic research are defining key molecular and cellular components in the response to allergens. This information is already being converted to targets that are being tested in the clinic. Currently, irrespective of approach, we consider that a successful strategy for the treatment of allergic asthma will include a selective inhibition of Th2 cells with the ultimate aim of eliminating allergen-specific Th2 immune responses. We anticipate that new candidates will be approved in the near future and offer treatment options for patients suffering with asthma and other allergic diseases.