Drug-protein complexes based on non-covalent bindings can cause
degranulation of sensitized MC.
The necessity of covalent bonds between drug and protein is a
prerequisite for initiating an immune response to the drug/hapten, both
in animal models as well as in humans. It is also observed for eliciting
an MC degranulation in previously sensitized animals using in
vitro prepared hapten-protein adducts. However, it has not been
established, whether a non-covalent bound complex is sufficient for
interaction and cross-linking specific IgE in already sensitized animals
or not. One reason might be, that the experiments with relatively labile
drug-protein complexes did not deliver consistent, reproducible results.
It is an exception that some of the non-covalent bindings between drug
and protein reach an affinity which makes cross-linking of IgE/FcεRI
possible. Thus, symptomatic IgE mediated drug allergy is rare.
The main arguments for the role of non-covalent drug-protein complexes
in drug re-exposure reactions are summarized in table 3. Immediate skin
test reactivity to drugs like beta-lactams (<15 min) occurs
before covalent binding between beta-lactam and protein takes place
(17-19). The necessity of covalent bonds cannot explain the immediate
reactivity seen in BAT (<5 min) and the clinical setting
(anaphylaxis <5 min).
For some drugs, metabolism is required to form the reactive metabolite:
E.g., sulfamethoxazole (SMX) is metabolized in the liver to
sulfamethoxazole hydroxylamine (SMX-NHOH), which is further oxidated in
the tissue to the reactive hapten SMX-NO, able to undergo covalent bonds
(13). This metabolism lasts >6-10 hrs (13). But skin test
reactivity and in-vitro BAT can be observed within 15min with SMX
itself, which does not have hapten characteristics. The IgE detected is
cross-reactive with covalently bound SMX-NO and non-covalently bound
SMX. Such a cross-reactivity of the immune system has already been
observed in T-cell reactions to SMX and SMX-NO (28).