Allergen-specific Th2 cells as targets for immune intervention in allergic disease

Allergen-specific Th2 cells from atopic individuals generally belong to the T helper 2 (Th2) subset producing, among other cytokines, high levels of IL-4, IL-5 and IL-13, but low levels of IL-2 and IFN-γ following activation. Both IL-4 and IL-13 induce IgE synthesis, which is inhibited by IFN-γ. IL-4, but not IL-13, also directs differentiation of naive CD4+ T cells into Th2 cells. Furthermore, IL-5 induces the differentiation of eosinophils and eosinophilia, whereas IL-3, IL-4 and IL-10 produced by Th2 cells, synergize with c-kit ligand in promoting mast cell growth. These observations indicate that allergy is a Th2 cell disease, and that targeting of allergen-specific Th2 cells may provide an efficient way to intervene in allergic inflammation. Three different approaches aimed at inhibiting the function or differentiation of allergen-specific Th2 cells are discussed. It is shown that an IL-4R and IL-13R antagonist inhibits IL-4-driven Th2 cell differentiation and human IgE production both in vitro and in SCID-hu mice. In addition, it is discussed that allergen-specific Th2 cells can be rendered anergic following stimulation with allergen-derived peptides, representing T cell activation inducing epitopes. These anergic Th2 cells fail to produce IL-4, IL-5 and IL-13, to proliferate, and to provide help to B cells for IgE synthesis after rechallenge with allergen- and antigen-presenting cells. Finally, it is shown that IL-4-driven allergen-specific Th2 cell differentiation can be redirected into a Th0 and Thl cell differentiation pathway by stimulating these IL-4-driven allergen-specific Th cell populations in the presence of IL-12, or by co-stimulating these cells via a novel T cell receptor, designated signalling lymphocyte activation molecule (SLAM). The clinical implications of these approaches are discussed.