Treatment of allergic asthma: modulation of Th2 cells and their responses

Abstract

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.

Figure 1

Helper Th2 cells play a central role in allergic asthma and could be targeted through individual allergic immune processes. (1) Allergen handling and presentation by activated APC to naïve CD4+ T cells induces their activation. (2) Activated naïve CD4+ T cells differentiate to Th2 cells, or (3) possibly to other types of helper T cells e.g. Th1, Th17 or Treg cells. (4) Secondary exposure to allergen leads to Th2 cell activation, (5) as well as their migration into the lungs. (6) Activated Th2 cell-mediated asthma is caused in part by the secretion of interleukins e.g. IL-4, IL-5 and IL-13. These cytokines stimulate B cell activation and IgE secretion. Th2 cell cytokines and IgE activate cells of the innate immune system e.g. eosinophils, mast cells, etc. causing the release of vasoactive, pro-inflammatory mediators, smooth muscle contraction, mucus hypersecretion, oedema and, eventually, airway remodelling. (7) Homeostasis and survival of memory T cells in the lymph nodes and lungs perpetuates disease. Interruption of these molecular and cellular targets may reduce symptoms and pathological consequences of allergic asthma.

Figure 2

Promising cellular and molecular target candidates for inhibiting memory Th2 cells in allergic asthma are grouped according to the subchapters of the text. Targets in the inner circle (dash line) were tested in clinical trials, whereas other targets are still in pre-clinical stages. Treatment targets are divided into the following categories: Red colour indicates target inhibition; Blue colour indicates target activation; and Green colour indicates targets that can be inhibited or activated to inhibit Th2 cells. For details, please refer to the text. Abbreviations: DC - dendritic cell; FasL - Fas ligand; IL - interleukin; IL-25R - interleukin 25 receptor; IL-33R - interleukin 33 receptor; miRNA - microRNA; Mφ - macrophage; PDE - phosphodiesterase; STAT - Signal transducer and activator of transcription; Th1 - helper T cell type 1; Th2 - helper T cell type 2; TLR - Toll like receptor; Treg - regulatory T cell; TSLP - thymic stromal lymphopoietin.