Review article
The TH1/TH2 paradigm in allergy

https://doi.org/10.1016/S1380-2933(97)10005-7Get rights and content

Abstract

Recent evidence has been accumulated to suggest that allergen-reactive type 2 helper T cells (Th2) play a triggering role in the activation and/or recruitment of IgE antibody-producing B cells, mast cells and eosinophils, i.e. the cellular triad involved in the allergic inflammation. Interleukin (IL)-4 production by a still unknown cell type (T cell subset, mast cell/basophil?) at the time of antigen presentation to the Th cell is critical for the development of Th2 cells. Other cytokines, such as IL-1 and IL-10, and hormones, such as calcitriol and progesterone, also play a favoring role. In contrast, cytokines such as interferon (IFN-α, IFN-γ, IL-12 and transforming growth factor (TGF)-β, and hormones, play a negative regulatory role on the development of Th2 cells. However, the mechanisms underlying the preferential activation by environmental allergens of Th2 cells in atopic individuals still remain obscure. Some gene products selectively expressed in Th2 cells or selectively controlling the expression of IL-4 have recently been described. Moreover, cytokines and other gene products that dampen the production of IL-4, as well as the development and/or the function of Th2 cells, have been identified. These findings allow us to suggest that the up-regulation of genes controlling IL-4 expression and/or abnormalities of regulatory mechanisms of Th2 development and/or function may be responsible for Th2 responses against common environmental allergens in atopic people. The new insights in the pathophysiology of T cell responses in atopic diseases provide exciting opportunities for the development of novel immunotherapeutic strategies. They 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 severe atopic patients, 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 suggested.

Introduction

Atopic diseases are genetically determined disorders characterized by an increased ability of B lymphocytes to synthesize IgE antibodies towards ubiquitous antigens (allergens) able to activate the immune system after inhalation or ingestion and after penetration through the skin. IgE antibodies are able to bind to high affinity Fcε receptors (FcεRI) present on the surface of mast cells/basophils. Allergen-induced FcεRI cross-linking triggers the release of vasoactive mediators, chemotactic factors and cytokines that are responsible for the allergic events. Eosinophils are also involved in the pathogenesis of allergic reactions, as these cells usually accumulate at the site of allergic inflammation and release toxic products contributing to tissue damage.

The mechanisms linking IgE-producing B cells, mast cells/basophils and eosinophils in the pathogenesis of allergic reactions have remained unclear until distinct subsets of CD4+ helper T (Th) cells, based on their profile of cytokine secretion, were discovered. The cumulative study on the functional properties of helper Th cell subsets is known as the ‘Th2 hypothesis’ for the pathogenesis of allergic reactions [1]. This review summarizes the role of allergen-reactive Th2 cells in the pathogenesis of human allergic disorders and the possible mechanisms involved in the regulation of Th2 cell development. Finally, it will examine novel therapeutic strategies for atopic diseases, particularly those able to redirect the Th2 response.

Section snippets

The Th1/Th2 paradigm

Murine CD4+ Th1 cells secrete interferon-gamma (IFN-γ), interleukin (IL) 2 and tumor necrosis factor (TNF)-β, which promote macrophage activation, production of opsonizing and complement-fixing antibodies, antibody-dependent cell cytotoxicity, and DTH [2]. For these reasons, it is possible to refer to Th1 cells as cells responsible for phagocyte-dependent host responses [3]. On the other side, Th2 cells, which produce IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, provide optimal help for antibody

The ‘Th2 hypothesis’ in atopy

As reported above, Th2 cells produce IL-4 and IL-13 which stimulate IgE and IgG4 antibody production, IL-5 which recruits and differentiates eosinophils and IL-10, which together with IL-4 and IL-13, inhibit several macrophage functions, thus explaining why the mast cell/eosinophil/IgE-producing B cell triad is involved in the pathogenesis of allergy [1]. Strong evidence has been accumulated to support this concept that Th2 cells play a central role in atopy.

The study of cytokine profile of

Mechanisms involved in the regulation of Th2 development

The mechanisms responsible for the preferential development of allergen-reactive Th2 cells in atopic subjects have not yet been completely clarified.

Possible genetic alterations favoring allergen-specific Th2 responses in atopic subjects

The possibility that atopic subjects have a genetic dysregulation at level of IL-4 produced by Th cells is supported by several observations. First, CD4+ T cell clones from atopic individuals are able to produce noticeable amounts of IL-4 and IL-5 in response to bacterial antigens, such as PPD and streptokinase, that usually evoke responses with a restricted Th1-like cytokine profile in nonatopic individuals [82]. Second, T-cell clones generated from cord blood lymphocytes of newborns with

New immunotherapeutical approaches in atopy

Based on these new insights and the biotechnological advances, novel opportunities of treatment of allergic disorders can be hypothesized. It may be addressed to target allergen-specific T cells (allergen-specific immunotherapy-IT) or their effector molecules (non allergen-specific IT).

Concluding remarks

There is a general consensus that the Th-cell population contains functionally distinct subsets defined by the patterns of cytokines they produce in response to different types of antigenic stimulation. Although Th1 and Th2 cells were first identified by in vitro analysis of murine T-cell clones, strong evidence now exists for similar subsets in vivo, in mice, rats and humans. These two extremely polarized forms of the specific cellular immune response, evoked by intracellular parasites and

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