New millennium: The conquest of allergy
The role of lymphocytes in allergic disease☆,☆☆,★

https://doi.org/10.1067/mai.2000.104575Get rights and content

Abstract

In the last few years strong evidence has accumulated to suggest that allergen-reactive type-2 T helper (TH2) cells play an important role in the induction and maintenance of the allergic inflammatory cascade. First, cytokines and chemokines produced by TH2 cells (GM-CSF, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, macrophage-derived chemokine) and those produced by other cell types in response to TH2 cytokines or as a reaction to TH2-related tissue damage (eotaxin, transforming growth factor-β, IL-11) account for most pathophysiologic aspects of allergic disorders (production of IgE antibodies; recruitment or activation of mast cells, basophils, and eosinophils; mucus hypersecretion; subepithelial fibrosis; and tissue remodeling). The TH2 hypothesis may also explain the complex genetic background responsible for allergic disorders. Several genes are involved in the development and regulation of TH2 cells and may provide the reason why the prevalence of atopic allergy is increasing in Western countries. Indeed, a dramatic change has occurred in the last several decades in the “microbial” environment of children, thus probably altering the balance between TH1 and TH2 responses to “innocuous” antigens (allergens) in favor of TH2 responses. Finally, the TH2 hypothesis offers exciting opportunities for the development of novel immunotherapeutic strategies targeted to address allergen-specific TH2 cells or TH2-derived effector molecules in atopic individuals. (J Allergy Clin Immunol 2000;105:399-408.)

Section snippets

DEFINITION AND PROPERTIES OF TH2 CELLS

TH2 cells represent a polarized form of the T helper cell–mediated immune response characterized by the production of IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13 but not of IFN-γ and TNF-β. By contrast, the other polarized form of the T helper cell response, which is defined as TH1, is characterized by the production of IL-2, IFN-γ, and TNF-β but not of the TH2-type cytokines.8, 9 The TH1/TH2 polarization is clear-cut in the murine models on the basis of artificial immunization or infection,

FACTORS RESPONSIBLE FOR TH2 POLARIZATION

In the last few years the factors responsible for the polarization of the specific immune response into a predominant TH1 or TH2 pathway have been extensively investigated. Current evidence suggests that TH1 and TH2 cells are not derived from distinct lineages but rather develop from the same T helper cell precursor under the influence of both environmental and genetic factors acting at the level of antigen presentation. Among the environmental factors, a role for the route of antigen entry,

TRANSCRIPTION FACTORS THAT REGULATE THE DEVELOPMENT OF TH2 CELLS

The demonstration that early IL-4 expression during an immune response is critical for determining the development of TH2 cells has raised interest in the molecular basis of its regulation. The binding of cytokines to their receptors typically results in rapid tyrosine phosphorylation of signal transducers and activators of transcription (STATs). Of these, STAT6 appears selectively activated by IL-4 and knockout of Stat6 gene results in deficient TH2 responses, inasmuch as in these animals T

MECHANISMS RESPONSIBLE FOR ALLERGEN-SPECIFIC TH2 RESPONSES IN ATOPIC INDIVIDUALS

It is well known that the expression of the allergic phenotype is dependent on 2 major factors: a genetic predisposition and the environmental interactions.

MULTIPLE ROLE OF TH2 CELLS IN THE INITIATION AND MAINTENANCE OF ALLERGIC INFLAMMATION

The role of TH2 cells in allergic inflammation is not limited to their ability to induce the production of allergen-specific IgE antibodies by B cells and to promote the eosinophilic infiltration in target tissues. Recent data suggest that at least some pathophysiologic consequences of allergic reactions may occur in the absence of the IgE response. Indeed, B-cell–,72 IgE-,73 CD40-,74 and mast cell-75 gene deficient mice can develop asthma, whereas CD4+ T-cell-21, IL-4-22, STAT6-23, and IL-5-24

POSSIBLE TH2-BASED NOVEL IMMUNOTHERAPEUTIC STRATEGIES IN ALLERGIC DISORDERS

The “TH2 hypothesis” and the new insights in the pathogenesis of allergic disorders provide exciting opportunities for the development of novel immunomodulatory regimens. These approaches may be addressed to target allergen-specific T cells (allergen-specific immunotherapy) or their effector molecules (nonallergen-specific immunotherapy)99 (Table III).

. Possible novel immunotherapeutic strategies for allergic disorders on the basis of the “TH2 hypothesis”

Targeting allergen-specific TH2 cells
 

Acknowledgements

We thank Dr Francesca Brugnolo for the excellent assistance in preparing the schemes reported in this article.

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    ☆

    Supported by grants from Consiglio Nazionale Ricerche (National Research Council) and from Instituto Superiore Sanita (Superior Institute of Health).

    ☆☆

    New Millennium series supported by a grant from Novartis Pharmaceutical Corp. East Hanover, NJ.

    ★

    Reprint requests: Sergio Romagnani, MD, Department of Internal Medicine, Section of Clinical Immunology, Allergy, and Respiratory Disorders, University of Florence, Viale Morgagni 85, Florence 50134, Italy.

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