Therapeutic prospects for early asthma

There is good evidence that immune deviation towards a net TH2 cytokine pattern occurs early in asthma and contributes directly to disease (see page 471). However, in young children, mixed TH1/TH2 cytokine patterns have been found to be present concurrently. Physiologically, TH1- and TH2-biased immune responses reciprocally inhibit each other. It is a characteristic of lymphocyte immunobiology that during early immune deviation cytokine patterns remain plastic and can be realigned, but this plasticity is lost if stimulation is too intense or persists for too long.2 In the early stages of asthma we perhaps have the best opportunity to use immune modulators to realign and fine-tune mucosal immunity away from an excessive TH2 pattern and towards a neutral or balanced cytokine pattern. A fundamental ethical and medical issue is that almost all of the preventive agents currently envisaged would need to be given prophylactically to children at risk of asthma — yet our current understanding of the disease is such that we can not reliably or uniformly predict asthma risk in very young children.

In animals, a range of molecules able to trigger TH1-type immune responses have been demonstrated to suppress TH2-biased responses. As TH1 responses can be highly damaging to the lung, any such intervention would need to be aimed at realigning immunity rather than converting it to a TH1-biased pattern. It is a characteristic of these immune modulators that they invariably trigger a component of the ancient innate immune system. This system has evolved to rapidly distinguish highly conserved pathogen-associated-molecular-pattern molecules (PAMPs) (eg, gram-negative bacterial lipopolysaccharide [LPS]) to quickly prime specific immunity for the most appropriate cellular and humoral immune response. These agents (representing the IFN-γ/IL-12/IL-18 "TH1 inducer" group) include recombinant human interferon IFN-α (rhIFN-α), rhIFN-γ, rhIL-12 and rhIL-18. To date, trials with these agents in adults have revealed a very narrow therapeutic window (between effect and toxicity) and produced trivial or no benefit. For example, a recent trial3 showed that IL-12, given in staggered and incremental doses, reduced sputum eosinophils and showed a weak trend towards improving histamine PC20, but had no effect on allergen-induced late responses. These minimal effects were produced at the cost of marked toxicity (arrhythmias, abnormal liver function, myalgia, and severe "flu"-like symptoms).

The observation that innate immune-response triggers often suppress TH2-type responses has led to the development of a series of TH1-inducing adjuvant-like molecules. These include derivatives of bacterial DNA CpG motifs, synthetic polymer TH1 adjuvants, DNA vaccines, gene vectors, and several synthetic low molecular weight compounds (LMWCs). Advocates of this approach hope that insights gained from research into the "hygiene hypothesis" (which relates increased asthma risk to a decreased prevalence of infections that induce TH1-biased immunity) may support the use of such agents in children at risk of asthma. It is not widely appreciated that steroids and beta-agonists both suppress TH1 immunity, especially IL-12 production.4,5

One particularly attractive area of research is the use of modified peptides derived from allergens as inhibitors of T cell function. The concept employed here is that introducing subtle changes into these peptides so that they still bind to major histocompatibility complex molecules, but imperfectly activate T cells, will result in T cell inactivation, thereby reducing asthma symptoms. This field has advanced considerably with the demonstration of "promiscuity" — the capacity of one peptide to bind to different MHC molecules, thus largely circumventing the problem of HLA variation in the general population. A logical extension of this work is to combine the peptide with a TH1 adjuvant, as this could redirect the immune response if some residual T cell activation occurs.

A second, and conceptually less attractive, approach is to block key cytokines once disease has become established. Here, animal models predict inconsistent clinical outcomes, as several of the most promising potential blocking agents produce optimal outcomes only in very early disease and are ineffective against established disease. The agents of greatest current interest are blockers of the "TH2" cytokines IL-4, IL-5, IL-9 and IL-13.6 A number of very advanced concepts for possible blocking mechanisms are now in late-stage development, including

• humanised or chimeric neutralising antibodies;

• muteins (genetically altered versions of the cytokine able to bind to the appropriate receptor but not trigger a response);

• antisense oligonucleotides and related derivatives (which are designed to neutralise the mRNA message for cytokines);

• rh-receptors (which serve as sequestering sinks for cytokines by binding them with high affinity in solution);

• LMWC inhibitors of key transcription factors critical for primary induction of IL-4-dependent TH2 immune deviation;

• LMWC inhibitors of IL-13 effects targeted against the transcription factors STAT-6 and GATA-3.7,8

A recent trial in adults of an anti-IL-5 antibody9 that strongly suppresses airway inflammation, especially eosinophilia, produced trivial benefits. It is arguable that this type of agent would be better used in children at an early stage of disease, before any structural change or longer-term deterioration in lung function has occurred (see page 4210).

It is very doubtful whether any of the broad immunosuppressors currently being developed (eg, third-generation cyclosporin derivatives and potent new T cell suppressors) would be appropriate for treating asthma in the first years of life, as their toxicity is too high. However, research into the fine specificity of T cell activation has revealed novel costimulation molecules that might prove very useful. Costimulation serves two roles that are mediated by distinct molecules: reinforcement and fine-tuning of T cell activation, and, through separate inhibitor molecules, termination or down-regulation of T cell activation (eg, via inhibitory costimulation molecule [ICOS]). As some important costimulation molecules (eg, T1/ST2) are preferentially expressed in TH2-biased cell populations, it may be possible, by targeting these molecules, to achieve very selective immune manipulation in asthma.11

Thus, although immune modulators offer potential promise in preventing and treating asthma, there are problems associated with their use. Apart from issues of intrinsic safety, immune modulators seem to have little effect unless used in the early stages of disease, and memory/effector cells strongly resist immune deviation. Another, much more difficult, issue is that one of the most common serious problems in children with asthma is the occurrence of sudden exacerbations, which are most often triggered by infections, in which TH2 immunity plays little or no role.

Children with small lungs at birth or incompletely developed alveolar septation caused by in-utero or early post-partum steroids are at increased risk of asthma. This has sparked an interest in lung-function-normalising agents for use in children. Such agents might include safe relatives of growth factors, such as retinoids (and synthetic thiazolidinediones or PPAR activators), and growth factors implicated in lung development, such as HB-EGF, IGF, HGF/scatter factor and perhaps the PDGF family. It is not yet known whether these agents can reverse steroid-induced lung underdevelopment.

A particularly important area of recent adult asthma research is persistence of abnormal lung function and structure despite steroid therapy. This has raised the issue of whether new drugs can block tissue matrix deposition, which, in model systems, governs the persistence and severity of asthma phenotype.

Despite the concerns raised here about the short- and long-term safety of immune modulators in early asthma, this is clearly the window in disease natural history where best outcomes might be achieved. It is also essential, to achieve true disease prevention, that we find better predictive markers of who might develop asthma.