Based on the studies reported here, it is clear that targeting of a number of cell-surface molecules and soluble mediators may be beneficial in asthma. DCs activated with TSLP are involved in the generation of Tr1s in the thymus, but Th2 cells in the periphery. Improved understanding of the signals that drive this divergent pathway may identify novel molecules as targets for intervention either alone, or in combination with TSLP. Signaling of tolerogenic DCs to naive T cells can lead to the development of IL-10-secreting Tr1-like regulatory cells. TGF-P is crucial in the development of CD4 + CD25+ Treg and induces expression of the master regulatory transcription factor Fox p3. While TGF-P has profibrotic characteristics that may compromise its use as a therapeutic, a combination of TGF-P and IL-10 may enhance regulatory function while reducing associated fibrosis. IL-6 is an archetypal proinflammatory cytokine that is able to enhance allergic airway disease and suppress the generation of Treg. Blockade of the IL-6 pathway has already been achieved in other clinical disorders and may prompt studies to evaluate this form of intervention in asthma.44 TSLP induces expression of the Th2 chemokines TARC and MDC, which drive recruitment of Th2 T cells to sites of allergic inflammation. Inhibitors of CC che-mokine receptor 4, the receptor for these molecules, are already being developed for the treatment of asthma.
In conclusion, CD4+CD25+ T cells and IL-10-producing Tr1s have the capacity to suppress Th2 responses to allergen. Particular combinations of DCs and cytokines induce Treg development. Immune responses to allergens in healthy individuals include a dominant regulatory element. There is evidence that the function of Treg may be defective in those with allergic diseases including rhinitis, atopic dermatitis, and asthma. The exact mechanisms of suppression employed by some Treg remain controversial and may differ for the various regulatory populations. SIT appears to induce allergen-specific regulation that contributes to the efficacy of the treatment. Corticosteroids and other compounds such as vitamin D3 can induce regulatory characteristics in T cells through induction of IL-10. Improved understanding of regulatory mechanisms in development of allergic sensitization and their manipulation with immunotherapy and pharmacotherapy holds the promise of vaccination and treatment strategies for asthma and other allergic diseases.