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Therapeutic attempts to reduce the action of cytokines and chemokines offer promise. The chemokine receptor CCR3 is expressed on mast cells, eosinophils, basophils and IL-2-activated T lymphocytes. It appears that activation of these receptor sites can influence the migration of these cells into mucosa (Murdoch and Finn, 2000). Chemokine receptor antagonists have the potential to inhibit eosinophilia in particular. Other chemokine receptor antagonists that offer promise are CXCR1 and 2.

The implementation of monoclonal antibodies in humans has been slow because, when they are created from rat B cells, they are recognized as being foreign. However, hybrid antibodies are now being engineered to block a variety of molecules such as IgE (Adelroth et al., 2000), IL-4 and IL-5, or entire cell lineages such as TH2 cells by adding exotoxins to the antibodies (Leckie et al., 2000) (Fig. 16.1).

Another strategy is to block key molecules involved in inflammation. Trials of soluble IL-4 receptors in asthma have already taken place (Borish et al., 2001).

It has been suggested that there is a balance in an individual's helper T-cell response between TH1 cells and Th2 cells (Berger, 2000). TH1 cells produce cytokines that produce the pro-inflammatory responses responsible for killing intracellular parasites and for perpetuating autoimmune responses. TH2 cells produce cytokines associated with the promotion of IgE and eosinophilic responses in atopy (Fig. 16.2). It has been suggested that in allergic rhinitis and seasonal asthma, an individual with a genetic predisposition toward a TH2-biased immune system could move away from this bias if exposed to certain environmental stimuli early in life (Openshaw and Walzl, 1999; Openshaw and Hewitt, 2000). Early exposure to microbial agents may be the appropriate stimulus causing the immune system in these individuals to move toward a TH1-depend-ent system (Strachan et al., 2000). Without this biological programming, the bias would persist and the individual would tend toward a TH2-dependent system— for example, atopy. Ways are now being sought to augment the TH1 response by methods such as recombinant IL-12 or Toll-like receptors that recognize DNA motifs in bacteria and induce IL-12 and other host defenses when activated (Hemmi et al., 2000).

Gene therapy is a broad term for many possible techniques, including neutralizing segments of genes and altering the gene sequence or messenger RNA. Antisense therapy involves using complementary coding sequences and binding these irreversibly to sense RNA, preventing protein translation, or to genomic DNA, thereby blocking transcription. While the potential for these techniques is great, their safe application in humans poses great problems at present.

Middle Turbinate
Fig. 16.1 A micrograph (x100) showing a mast cell expressing IL-4 in close proximity to a plasma cell (PC).
Mucociliary Transport Rhinitis
Fig. 16.2 Grass pollen allergen-specific IgE is stained brown and is localized to mast cells within the nasal mucosa of this atopic individual with persistant allergic rhinitis.

Phosphodiesterase inhibitors also have potential as anti-inflammatory agents in rhinitis. Cyclic AMP (cAMP) is metabolized by a superfamily of phos-phodiesterases and has broad effects in suppressing the immune and inflammatory cell activity. Phos-phodiesterase inhibitor-4 is the major cAMP-hydrolyz-ing isoenzyme in inflammatory and immune cells. Phosphodiesterase inhibitors have activity on a variety of human inflammatory cells (basophils, monoctyes) in vitro. Phosphodiesterase inhibitors can also inhibit the antigen-induced proliferation and cytokine production of peripheral mononuclear cells obtained from atopic individuals. Their development holds promise in the treatment of asthma and rhinitis.

A better understanding of the genetics of mucus production (Voynow et al., 1998) and of mucus rhe-ology (Quraishi et al., 1998) may help those in whom

Fig. 16.3 The distribution of positive skin prick tests in the general population.

Skin Prick Test

Fig. 16.3 The distribution of positive skin prick tests in the general population.

O Intermittent rhinitis O Persistent rhinitis O Skin prick test positive these appear to be abnormal and improve biorheologi-cal matching or the efficiency of mucociliary clearance.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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