Redirecting Th2 responses in allergy

Abstract

In the last few years, evidence has been accumulated to suggest that allergen-reactive Th2 cells play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, the cellular triad involved in allergic inflammation. Th2 cells do represent a polarized arm of the effector specific response that plays some role in the protection against gastrointestinal nematodes. They also act as regulatory cells for chronic and/or excessive Th1-mediated responses. Th2 cells are generated from precursor naive Th cells when the specific antigen is encountered in an IL-4-containing microenvironment. However, the source of IL-4 required at the initiation of the response for the development of naive Th cells into Th2 effectors is still unknown. Both FcεR1 non-T cells and a specialized subset of CD1-restricted NK1.11 CD41 T cells have been suggested to quickly provide IL-4 to the naive Th cell; however, a more likely possibility is that the maturation into the Th2 pathway mainly depends upon the levels and the kinetics of autocrine IL-4 production by naive Th cells themselves at priming. The question of how these Th2 responses are enhanced in atopic patients is also unclear. Both the nature of the TCR signaling provided by the allergen peptide ligand and a dysregulation of IL- 4 production likely concur to determine the Th2 profile of allergen-specific Th cells, the genetic dysregulation of IL-4 production probably being overwhelming. Some gene products selectively expressed in Th2 cells, such as c-Maf, or selectively controlling the expression of IL-4, such as STAT6, have recently been described. Moreover, CD81 T cell subsets and cytokines, such as IL-12, IFNα, and IFN-γ, that dampen the production of IL-4 as well as the development and/or the function of Th2 cells have been identified. These findings suggest that an inherited dysregulation of gene(s) controlling IL-4 expression and/or alterations of mechanisms that regulate Th2 development and function may favor Th2 responses against common environmental allergens, particularly in patients who develop severe atopic disorders. However, the role of environmental factors influencing the balance between Th1 and Th2 responses in the development of mild or common atopy should also be considered. For example, the significant reduction in childhood infections (particularly tubercular infection) that induce the production of cytokines antagonistic to Th2 development may be partly responsible for the rising prevalence of allergy observed in the last few decades in developed countries. The new insights into the pathophysiology of T cell responses in atopic diseases provide exciting opportunities for the development of novel immunotherapeutic strategies. These include the induction of nonresponsiveness in allergen-specific Th2 cells by allergen peptides or redirection of allergen-specific Th2 responses by Th1-inducing cytokines, altered peptide ligands, allergens incorporated into recombinant microorganisms or bound to appropriate adjuvants, and plasmid DNA vaccination. In patients with severe atopic disorders, the possibility of nonallergen-specific immunotherapeutic regimens designed to target Th2 cells or Th2-dependent effector molecules, such as specific IL-4 transcription factors, IL-4, IL-5, and IgE, may also be considered.