4 DISCUSSION
AIT is the only disease modifying treatment to treat the cause of
allergy. Several immune cells and mediators contribute to various
degrees to the severity of the allergic reaction. Mast cells and
basophils are effector cells of the early phase that are involved in
tissue damage, itching and swelling. However, ablating those cells may
be technically difficult and also be potentially dangerous, as they are
also involved in the fighting against tick and helminth infections,
detoxification of arthropod and reptile venoms, and, as recently shown,
preserving cardiac function after myocardial
infarction43-45. B cells expressing as well as IgE and
Th2 cells specific for the respective allergen are therefore potentially
better targets. However, allergen-specific lymphocytes do not have a
unique characteristic to specifically delete them other than the T cell
receptor which is notoriously difficult to target. AIT focusses on
rendering the body more tolerant to the allergen by changing the immune
environment and induction of IgG antibodies25,46,47.
The high potential of IgG antibodies to reduce the severity of allergic
reactions has been shown in mouse models30,40,32 and
more recently in a clinical study demonstrating that it is possible to
treat cat allergy with monoclonal anti-Fel d 1 IgG
antibodies34. In addition, induction of
allergen-specific IgG4 or allergen-specific IgE/IgG4 ratio are
considered to be the best correlate of AIT efficacy. However, whether
IgG4 is more potent than other IgG subclasses or merely happens to be
the preferred IgG subclass induced by classical AIT remis still a matter
of debate. In fact, induction of IgG4 during classical AIT may actually
reflects to some degree natural allergen exposure as seen in bee keepers
who are not allergic to bee venom but have high serum levels of specific
IgG448,49. Indeed, inducing B cell responses in the
absence of innate stimuli, such as toll-like receptor ligands, may
preferentially drive IgG4 responses12,36.
Nevertheless, the role and importance of the induced IgG subclasses
during AIT may have important consequences, since use of modern
vaccination regimens such as inclusion of stronger adjuvants or
formulation with virus-like particles (VLPs) may favour induction of
IgG1 rather than IgG430. Indeed, a clinical study to
treat house dust mite with Der p 1 coupled to a VLP induced strong IgG1
instead of IgG4 responses26. Another important aspect
of the safety of AIT is the availability, standardization, and
formulation of allergens. Given the fact that allergens coupled to VLPs
do not activate basophils50, but induce strong IgG
responses in compared to other approaches, may render AITs safer and
more efficient in future; however, the ability of IgG1 to block the
allergic reaction remains an important caveat for such new therapies.
To investigate whether IgG4 was more potent than other IgG subclasses at
blocking basophil activation, we expressed 3 different monoclonal
antibodies recognizing distinct epitopes on the allergen Fel d 1 in a
human IgG1 and IgG4 format40. We compared 1) the
ability to neutralize the allergen and block basophil activation, 2) to
inhibit basophil activation via engagement of FcγRIIβ, and 3) the
ability of the IgG1 and IgG4 subclasses to bind to FcγRIIβ. In all 3
types of assays, IgG1 and IgG4 antibodies showed similar efficacy at
blocking basophil activation and engaging FcγRIIβ. Hence, IgG4 does not
have preferable characteristics for the treatment of allergy. This may
indicate that induction of IgG4 is not a pre-requisite for efficient
therapy but that amounts and affinities of total IgG may be more
important.