Page 1273 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 91 Immunotherapy of Allergic Disease 1233

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greater for pollens than for HDM allergies. Local side effects be possible to manipulate allergens and reduce their ability to
are common with SLIT but are generally well tolerated. Systemic bind to IgE or to create peptide fragments, which will modulate
side effects of SLIT are very rare but have been reported, especially T cells without the risk of anaphylaxis. Cross-linking allergen
in patients who have previously had systemic reactions to injection proteins with aldehydes reduces their ability to bind antibodies.
SIT. SLIT is now being used routinely in some parts of Europe Such allergoids do not degranulate the basophils of sensitized
(especially Italy and France), but the doses and regimes being individuals in vitro but are recognized by allergen-specific T
prescribed are often different from those that were used in the cells. Clinically, allergoids have shown efficacy in rhinitis caused
clinical trials. Overall SLIT should widen the scope of SIT and by grass pollen or HDM. 36
allow more patients to be treated. As with all forms of immu- Short peptide sequences that should not be recognized by
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notherapy, patient selection remains the key to ensuring that IgE antibodies can be used as vaccines as well. Peptide vaccines
therapy is targeted to those who are likely to benefit from it. can be either natural sequences or altered peptide ligands. If
high doses of natural peptides are given, these deceive the T cell
FUTURE DIRECTIONS into high dose tolerance. Altered peptide ligands induce anergy
by providing an incomplete activation signal. Both approaches
There is clearly scope to improve conventional SIT. Possible are affected by the MHC type of the individual undergoing
avenues include the use of recombinant allergens, which should treatment. By sequential alteration of HDM allergen Der p
make it easier to standardize allergen vaccines and may allow peptides, it is possible to suppress proliferation of T-cell clones
fine-tuning of vaccines for patients with unusual patterns of recognizing native Der p peptides, as well as suppressing their
reactivity. Most patients with allergies react to the same com- expression of CD40 ligand and their production of IL-4, IL-5,
ponents of an allergen extract, the so-called major allergens, and IFN-γ. These anergic T cells do not provide help to B cells
which are defined as those allergens recognized by over 50% of to switch class to make IgE; importantly, this anergy cannot be
sera from a pool of patients with clinically significant allergy to reversed by providing exogenous IL-4. In humans, the main
the material in question. However, not all patients recognize all focus has been on cat allergen (Fel d1) peptides, which can reduce
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major allergens, and some patients only recognize allergens that the level of symptoms on exposure to cat dander. Similar studies
are not recognized by the majority of sera of patients with allergies. with the peptides of phospholipase A2 (PLA2, a major allergen
This latter group may not respond to standard extracts but might in bee venom) have also been reported. However, to date, peptide
be better treated by a combination of allergens to which they vaccines have not shown any greater efficacy compared with
are sensitive. Until the advent of molecular cloning, this has conventional vaccines.
been impossible to achieve. Now that recombinant allergens for In an animal model, intranasal application of genetically
SIT are available, the range of sensitivities can be better character- produced hypoallergenic fragments of Bet v1 produced mucosal
ized, and this may lead to patient-tailored vaccine products. tolerance with significant reduction of IgE and IgG1 antibody
Thus far, clinical trials have confirmed that recombinant allergen responses, as well as reduced cytokine production in vitro (IL-5,
cocktails are effective, but these have not yet shown superiority IFN-γ, IL-10). These reduced immunological responses were
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over conventional vaccines. Regulations are the major barrier accompanied by inhibition of the cutaneous and airway responses
to this development: Under current regulations, each combination that were seen with the complete Bet v 1 allergen. The mechanisms
of allergen components would have to be developed as a freestand- of immunosuppression seemed to be different for the allergen
ing pharmaceutical. Until a different regulatory framework is fragments and the whole molecule, in that tolerance induced
agreed upon, recombinant allergens will only be tested as fixed with the whole Bet v 1 molecule was transferable with spleen
combination cocktails. cells, whereas that induced by the fragments was not. 38
Another alternative approach is to inject allergens directly From epidemiological and experimental studies, we know
into lymph nodes, under ultrasound guidance. Proponents that vaccines with mycobacteria have antiallergic properties. In
of this approach argue that after subcutaneous injection, less Japan, early vaccination with the Bacille Calmette-Guérin (BCG)
than 1% of the injected material reaches the lymphatic system; vaccine was associated with a substantial reduction in the risk
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therefore if the benefit of SIT is driven by the dose, then direct of developing allergy, although similar associations were not
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intranodal administration should be more efficient and also safer evident in studies in Sweden. In an animal model, administration
than conventional SIT. Early studies with doses of about 1% of of the BCG vaccine before or during sensitization to ovalbumin
standard SIT showed immunological efficacy, with some signs reduced the degree of airway eosinophilia that followed subse-
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of clinical efficacy and reduced risks of side effects. However, quent challenge with ovalbumin. This effect was not mediated
subsequent clinical trials by other groups have not demonstrated through any direct effect on IgE production or blood eosinophil
efficacy. 33,34 numbers but was mediated through IFN-γ and could be reversed
Novel forms of allergenic molecules may be created: for by exogenous IL-5. 41
example, a recombinant trimer consisting of three covalently Two new approaches using DNA vaccines are also undergoing
linked copies of the major birch pollen allergen, Bet v 1 has been serious consideration. The first of these is a general approach,
made. This trimer is much less allergenic, even though it contains using CpG oligodeoxynucleotides (ODN), which mimic bacterial
the same B-cell and T-cell epitopes as the native molecules and DNA, binding to T-cell receptor-9 (TCR-9) and stimulating a
induces Th1 cytokine release and IgG antibodies, analogous to Th1-type cytokine response. This technology is essentially a
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the antibody response to standard SIT. Folding variants and refinement of vaccination adjuvant technology, since CpG ODN
other modifications of the physical structure may also improve have been shown to be the principal activity from complete
the safety of SIT. Freund adjuvant. In a mouse model of asthma, preadministration
Since the epitopes recognized by IgE molecules are usually of CpG ODN prevented both airway eosinophilia and bronchial
three-dimensional, while epitopes recognized by T cells are short hyperresponsiveness. Moreover, these effects were sustained for
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linear peptide fragments of the antigen (Chapter 6), it should at least 6 weeks after CpG ODN administration. Alternatively,