Novel Treatment Strategies
in IgE-Mediated Allergy
New Directions in Immunotherapy
Hans-Jørgen Malling
Allergy Clinic, National University Hospital
Copenhagen, Denmark
Allergy is a systemic inflammatory disease with varying degree of disease manifestations from different shock organs. The orientation of the in utero Th2 screwed immune response into the future allergen-specific dominated Th1 or Th2 result in either non-atopic individuals or clinical allergic diseases. The early allergic response is dependent on the IgE-mediated release of mast cell-derived mediators such as histamine and leukotrienes. The late allergic response is caused by the cellular inflammatory response caused by infiltration of the airway mucosa with activated eosinophils and CD4+ T-cells of the Th2-type expressing mRNA predominantly for IL-4 and IL-5.
In most allergic patients the only treatment option is exclusively pharmacotherapy, and supplementary allergen-specific immunotherapy is only offered to a few patients. This paradox is not related to a lack of clinical efficacy (1) but rather to most physicians selecting a treatment that reduces or eliminate the symptoms (drugs) without any impact on the pathophysiologic mechanisms involved in the allergic inflammation. Only occasionally physicians prescribe treatments with the capacity to interfere with the regulatory mechanisms of mediator release and the inflammatory response (immunologic treatments). The contradiction is, however, not that simple, as the pharmacological treatment is highly effective and is applicable without important limitations to the vast majority of patients. However, a growing interest has emerged looking at the possible advantages of a treatment strategy interfering more fundamentally with the basis mechanisms of the disease, and with the prospect of changing the natural outcome of the allergic sensitization (disease-modifying treatment).
The development of novel approaches of disease modifying immunotherapy in allergic diseases is dependent on advances in our understanding of the molecular mechanisms of the allergic inflammation. While many novel forms of immunotherapy have shown significant promise in animal models their safety and efficacy in human subjects is only starting to be evaluated.
Allergen-specific immunotherapy
Conventional subcutaneous injection immunotherapy
Subcutaneous immunotherapy represents the standard immunotherapy
care of allergic patients (2). The clinical efficacy has been
documented in most controlled studies, and the magnitude of efficacy
is equivalent or even to better than pharmacologic treatment (1).
Although the level of evidence for the long-term efficacy and
the preventive capacity of subcutaneous immunotherapy is still
incomplete, it has a capacity to prevent the development of new
sensitizations in monosensitized patients (3), and to prevent
the development of asthma in rhinitic patients (4). Of major concern
is the risk of inducing systemic anaphylactic reactions. The mechanisms
of the classical subcutaneous allergen-specific immunotherapy
are complex. In inhalant allergy redirection of the allergen-specific
Th2 response towards a Th1 switch (immune deviation) and production
of IFN-
has been shown (5).
In parallel with the elucidation of the immunologic regulation
of the allergic inflammatory reaction, the importance of a comprehensive
knowledge of allergen extracts has emerged. The problems of currently
used natural allergens are the inborn capacity to induce anaphylaxis
due to cross-linking of IgE and the subsequent release of allergic
mediators. Allergens may be modified as allergoids, isoforms or
by side-directed mutagenesis to have a reduced IgE-binding capacity
while retaining the immunologic activity and consequently allow
the administration of larger doses implying improvement in clinical
efficacy without compromising the crucial safety aspects (6).
Animal experiments suggest that the clinical efficacy may be reinforced
by combining allergens with cytokines (IFN-,
IL-12) (7).
Local immunotherapy
Due to the small but still potential risk of inducing
anaphylaxis by injection immunotherapy, several attempts to alternative
administration of more safe allergen-specific treatment have been
investigated. As allergic inflammation is expressed predominantly
on mucosal surfaces, local as opposed to systemic immunotherapy
is an attractive therapeutic option. The most popular and promising
are sublingual immunotherapy. The clinical efficacy of sublingual
immunotherapy has been convincingly documented in controlled studies
(8, 9). The major questions to be answered are the long-term efficacy
(does the clinical effect persist after terminating treatment?)
and the preventive capacity (prevention of new sensitizations
and deteriorations of disease severity). Among the advantages
are the safety profile allowing patients to be treated outside
the doctors office that might imply dissemination of specific
treatment to more patients. However, the precise role in the treatment
strategy of sublingual immunotherapy still has to be defined.
Peptide-based immunotherapy
The rationale for peptide-based immunotherapy is to induce
peripheral T cell tolerance (anergy) without cross linking IgE
and thus avoid the problem of anaphylaxis potentially associated
with traditional whole protein-based allergen immunotherapy (6).
Animal studies have demonstrated that peptides derived from the
major cat allergen Fel d I can induce T cell tolerance and that
the failure of T lymphocytes to respond to subsequent allergen
challenge may be due to an absence of T lymphocyte co-stimulation.
Clinical studies showed that subcutaneous injection of two
peptides derived from Fel d I resulted in a modest improvement
in symptom scores in cat allergic subjects (10). Furthermore,
a considerable frequency of systemic reactions to the injections
of Fel d I peptides suggest that the potential for anaphylaxis
to peptides is still significant (11). More recently, shorter
Fel d 1 peptides (16 residues vs 27 residues in the earlier studies)
have been investigated to determine whether these peptides will
be clinically effective without side effects. Preliminary studies
suggest that a single injection of 12 of the shorter Fel d I peptides
can inhibit the cutaneous late-phase response to whole allergen,
and that multiple peptide administrations could reduce the IgE-mast
cell-dependent early response in cat allergic asthmatics (12).
The mechanisms of action of peptide immunotherapy seem to be related
to down-regulation of cells and cytokines through the induction
of IL-10 (anergy or tolerance) (13).
Specific immunotherapy combined with anti-IgE
Injection of monoclonal anti-IgE antibody reduced IgE-mediated
symptoms independently of the allergen specificity. A controlled
study combining specific immunotherapy in birch and grass pollen
rhinitic patients with anti-IgE or placebo showed an additional
symptom/medication score reduction of anti-IgE of about 50% over
specific immunotherapy alone when administered after the induction
treatment (during seasons) (14). Side effects related to treatment
were more common in the specific immunotherapy plus anti-IgE groups
(25%) versus 16% in the immunotherapy plus placebo groups indicating
that the addition of anti-IgE does nor eliminate side effects
during maintenance treatment. Of considerably interest would have
been to elucidate if anti-IgE could reduce immunotherapy-induced
anaphylactic side effects during the induction phase.
DNA Vaccines
The potential of immunostimulatory DNA sequences containing
a CpG motif to inhibit the Th2 immune response and associated
airway reactivity has been demonstrated in animal models of asthma
(15). The immunostimulatory DNA sequences (unmethylated CpG motifs)
mediate this effect indirectly by activating the innate immune
system to generate cytokines (IL-12, IFN-)
which redirect the immune response from a Th2 to a Th1 response.
Additional studies have utilized conjugation of the immunostimulatory
DNA sequences to an allergen protein such as ragweed to target
the immunostimulatory DNA sequence and the allergen protein to
the same antigen presenting cell and enhance the Th1 immune response
to the allergen. Preliminary studies in humans utilizing a ragweed
protein (Amb a I) conjugated to immunostimulatory DNA have demonstrated
that the conjugate is less allergenic than the ragweed protein
alone based on basophil histamine release assays in vitro,
and skin test reactivity in vivo (16). Ongoing clinical
studies with immunostimulatory DNA and immunostimulatory DNA conjugated
to protein allergens will determine the safety and efficacy of
this immunomodulatory approach in subjects with allergic rhinitis
and asthma.
Conclusion
In the discussion of the applicability of immunologic treatment
of allergic diseases, several aspects have to be taken into consideration.
Although the clinical efficacy of conventional anti-allergic drugs
is high (under optimal conditions), the low compliance and the
emotional unwillingness to use prophylactic drugs limit the usefulness
in daily clinical practice. The prospects of interfering causally
in the pathophysiologic mechanisms involved in the allergic inflammatory
reactions and the potential for preventing new sensitizations
and progression of disease severity are important elements to
be considered in the debate of the optimal disease management.
Allergen-specific approaches to therapy offer the best change
of modifying the disease processes without impinging negatively
on the rest of the immune system. The optimal anti-allergic treatment
implies a therapy that is safe, inexpensive, easy to administer,
effective and preferable with a capacity to interfere fundamentally
with the immunologic regulation of the allergic inflammation.
Failure to develop disease-modifying approaches to therapy will
give rise to greater morbidity, mortality and economic burden
due to the rapidly increasing incidence of allergic diseases.
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