Associate editor: M.G. Belvisi
Strategies for targeting T-cells in allergic diseases and asthma

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Abstract

T helper (Th) 2 lymphocytes play a crucial role in the initiation, progression and persistence of allergic diseases, including asthma. Drugs that interfere with the activation of T-cells or more selectively Th2-specific signaling molecules and drugs that prevent the selective migration into lung tissue are promising novel strategies for the treatment of allergic asthma. Although the mainstay asthma therapy of inhaled glucocorticoids is rather effective, targeting Th2 cells may be an important alternative in childhood. Regulatory T-cells (Treg cells) have a physiological role in protection of unwanted immune responses to auto-antigens and allergens. Literature data indicate that an imbalance between Th2 and Treg cells may underlie development and disease expression of allergic asthma. Drugs or immunotherapies that stimulate these counter-Treg cells may limit aberrant Th2 responses leading to suppression of symptoms. Furthermore, these types of treatments may offer the perspective of disease modification and long-term relief of symptoms.

Introduction

High serum levels of immunoglobulin E (IgE) antibodies to common environmental allergens like house-dust or pollen is a key determinant of allergic diseases like allergic asthma, allergic rhinitis and atopic dermatitis. IgE mediates the type-I immediate hypersensitivity reaction that is characterized by crosslinking of receptor-bound IgE on mast cells with allergen, inducing the release of preformed and newly generated mediators that elicit the symptoms of allergic disease. The prevalence of allergic diseases is very high and has shown a considerable increase during the last decades, especially in children, although this increase appears to level off (van Schayck & Smit, 2005). Allergic rhinitis alone affects more than 155 million people worldwide and over 80 million people in Europe have some form of allergic disease. Asthma is one of the most common chronic diseases with over 300 million people worldwide (GINA report 2004). While approximately 90% of children with asthma are allergic, only 50–60% of adult asthmatics display elevated serum levels of allergen-specific IgE. Asthma is further characterized by reversible airway obstruction, chronic eosinophilic airway inflammation, airway remodelling, mucus hypersecretion, and airway hyperresponsiveness (AHR) to bronchospasmogenic stimuli. T-helper (Th) 2 lymphocytes play a critical role in the initiation, progression and persistence of allergic diseases, asthma included. Initially, a disturbed balance between Th1- and Th2-mediated immune responses has been postulated to underlie aberrant Th2 reactions to harmless inhaled allergens. Indeed, allergen-specific T-cell clones isolated from the blood of allergic individuals express a typical Th2 cytokine profile secreting interleukin (IL)-4, IL-5 and minimal IFN-γ and IL-2, whereas those clones from non-atopic individuals displayed a Th1 profile (Kapsenberg et al., 1992). Furthermore, allergic asthma is associated with expression of IL-3, IL-4, IL-5 and GM-CSF in bronchoalveolar cells, strongly supporting Th2 activation (Robinson et al., 1992). Nowadays, Th2-type cytokines Il-4, IL-5, IL-13 are known to be critical for IgE production, airway eosinophilia, mucus hypersecretion and non-specific airway hyperreactivity (AHR). However, it appears that susceptibility to allergic diseases cannot solely be explained by an imbalance between Th1 and Th2 responses (Wills-Karp et al., 2001, Herrick and Bottomly, 2003). Recently, an important immunoregulatory role for regulatory T-cells (Treg cells) has been put forward, capable of suppressing both Th1- and Th2-mediated adaptive immune responses (van Oosterhout & Bloksma, 2005). Targeting these different T-cell subsets for the treatment of allergic asthma is an interesting strategy that has not yet been widely explored. Interestingly, some T-cell-directed therapies harbour the potential to induce long-lasting suppression or even complete remission of disease.

Section snippets

Modulation of T-cell receptor-induced signal transduction during T-cell activation

Activation of T-cells is initiated by processed antigen-derived peptides presented by antigen-presenting cells (APC) to the T-cell receptor (TCR)/CD3 complex. An accessory signal provided by co-stimulatory molecules on APC leads to full T-cell activation and this prevents the induction of T-cell tolerance (T-cell unresponsiveness, also called anergy), which normally occurs when T-cells are stimulated by antigen-derived peptide in absence of an appropriate accessory signal. The most potent

Modulation of T-cell differentiation into functional subsets and expression of Th2 specific transcription factors

While NF-AT and AP-1 are involved in the expression of both Th1 and Th2 cytokines, the production of a restricted Th1 or Th2 cytokine pattern requires expression of specific transcription factors. Differentiation of uncommitted Th cells into Th1 or Th2 cells is induced when T-cells undergo cell cycle progression a specific cytokine environment. The best characterized cytokine to induce Th2 differentiation is IL-4, while IL-12 is well known to induce differentiation towards a Th1 phenotype.

Targeting regulatory T-cells

With the initial discovery of Th1 and Th2 cells in the mouse that exert mutual inhibitory effects (Mosmann & Coffman, 1989), an imbalance between these 2 arms of the immune response has been postulated to underlie both Th1-mediated autoimmune diseases as well as Th2-mediated allergic diseases and asthma (Kapsenberg et al., 1992, Romagnani, 1992). The balance between Th1 and Th2 cells as an immunoregulatory system to control immune responses to self or foreign antigens, however, appears

Targeting T-cell costimulation

As described above, CD4+ T-cells require 2 independent signals for optimal activation, one through the TCR provided by engagement of the peptide-MHC class II complex on APC and a second costimulatory signal. Although various receptor-ligand pairs for T-cell costimulation have been identified, the CD28 pathway is crucial for primary activation of naive T-cells (Riley & June, 2005). CD28 is constitutively present on the cell-surface of T-cells. The 2 ligands of CD28, CD80 and CD86, are expressed

Modulation of T-cell trafficking

Chemokines orchestrate immune responses by the attraction of inflammatory cells to target organ. Chemokines are small chemotactic cytokines that induce adhesion and transmigration of leukocytes through the endothelium Arrest on the endothelium is a prerequisite for the transmigration of leukocytes. A process of rolling precedes this and specialized integrins are involved in the adhesion of T-cells to the endothelium (Luster et al., 2005). These include very late antigen (VLA)-4 and leukocyte

Indirect modulation of T-cells by targeting dendritic cells

Dendritic cells (DC) are considered to be essential for the priming of naïve CD4+ T lymphocytes by delivering signal 1 (T-cell receptor) and 2 (costimulatory). Moreover, they also provide T-cell polarizing signal 3, of which IL-12 family members (IL-12, IL-23 and IL-27) for Th1 generation and IL-10 and TGF-β for respectively Tr1 and Th3 generation, are well-known examples (Kapsenberg, 2003). Herewith, DCs play a crucial role in generation of different effector T-cell subsets, Th1 and Th2, and

Concluding remarks

Considering the central role of T lymphocytes in the regulation of disease manifestation in allergic asthma, drugs targeting disease-inducing Th2 cells or Treg cells are promising therapeutic strategies (see Fig. 1). Th2 cells can be targeted by inhibition of their activation through inhibition of TCR-induced signalling or inhibition of specific transcription factors as well as by prevention of their migration into the lung tissue. Although these interventions may not lead to long-term

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