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For over a century, specific immunotherapy (SIT), also known as hypo- or desensitization, has been used to treat immediate-type allergies. In this type of allergy, repeated allergen contact results in cross-linking of IgE-antibodies bound to the surface of basophilic and eosinophilic granulocytes or mast cells with consecutive cell activation and release of histamine or other pro-inflammatory mediators ultimately leading to typical allergic symptoms. Particularly, in the case of insect venom allergy stings of e.g. bees or wasps can lead to life-threatening anaphylactic reactions.
To date, SIT is still the only causal treatment capable of positively affecting the natural course of the disease in patients suffering from immediate-type allergies. Numerous clinical studies have demonstrated the curative efficacy of SIT. However, the underlying immunological mechanisms of this therapy have been subject of research for decades. While the immune alterations leading to induction of allergen tolerance are already being investigated, the mechanisms responsible for maintenance of tolerance even after SIT remain largely unexplained. Although it has been shown that approximately 90-95% of insect venom allergic patients will gain tolerance during SIT, however, it is also known that approximately 15% will lose the acquired tolerance within a few years after cessation of therapy. So far, there are no laboratory biomarkers which reliably predict either a continuing tolerance or an imminent tolerance loss, which may be associated with recurring life-threatening anaphylaxis.
The present study was conducted to fill this "diagnostic gap". Patients allergic to bee or venom who have completed SIT between 4-13 years ago were examined for different cellular and humoral immune parameters. Depending on the time period since termination of SIT, patients were divided into four cohorts. In addition, a control population consisting of healthy subjects without manifestation of an IgE-mediated allergy was compared to the allergic groups.
The analysis of different T-cell populations showed significant deviations in allergen-specific T-cell frequencies for T-helper (Th) 2, Th1 and Type 1 regulatory T (Tr1) cells between patients and healthy control subjects. In contrast, there were no significant changes of Th1 or Tr1 cells comparing the patient groups after finishing SIT. Only for allergen-specific Th2 cells an increase by trend could be observed (which was actually significant for a subpopulation of the allergic patients) the longer the SIT dated back. The frequency of non-specific Foxp3+ regulatory T cells, as determined by the expression pattern of the surface markers CD4, CD25 and CD127, remained unchanged in both the patient cohorts and in comparison to the control group.
In order to characterize the humoral immune response after completion of SIT, serum concentrations of allergen-specific IgE, IgG and IgG4 antibodies were determined for the individual patient groups as well as the respective ratios of the different antibody classes. Significant differences could be demonstrated for the insect venom-allergic patients in comparison to the healthy controls, however, among the four patient cohorts serum concentrations were constant. In further subgroup analyses between patients who reacted again to a field sting several years after the end of SIT, and those who had no anaphylactic sting reaction after a re-experienced field sting (i.e. patients who were still tolerant), showed no alterations in the investigated parameters.
Thus, the data showed that both maintenance and loss of allergen tolerance after SIT is not only dependent on the immunological parameters determined quantitatively in this study, but rather essentially based on other, qualitative factors such as Allergen-blocking serum activity.