Zelluläre Mechanismen der Toleranzinduktion unter spezifischer Immuntherapie mit inhalativen Allergenen

Over the past decades the incidence of respiratory allergies in industrialized countries has risen continuously. Anaphylactic reactions against aeroallergens like pollen, pet dander or house dust mites are characterized by the production of allergen-specific IgE antibodies, which are bound by specific receptors. Cross-linking of these receptors on the surface of effector cells such as basophilic and eosinophilic granulocytes or mast cells by allergen contact results in consecutive cell activation with the release of histamine and other proinflammatory mediators. These mediators are responsible for the development of IgE-mediated immediate type reactions like allergic rhinitis or bronchial asthma. Specific immunotherapy (SIT), also termed hypo- or desensitization, is known for almost a century as a treatment for immediate type reactions. SIT is the only causative therapy, which is also able to modulate the natural course of respiratory allergies. Both the curative and preventive effect of SIT was demonstrated in various clinical trials. Although the clinical efficacy of SIT is well-established, the immunological mechanisms leading to induction and maintenance of allergen tolerance are still focus of intensive research. To assess the impact of SIT on humoral and cellular immune parameters a cohort of 15 patients allergic to birch pollen was studied during SIT with birch pollen extract. The closely meshed, long-term analysis comprised three years of therapy with emphasis on the induction and maintenance phase as well as on comparing periods during and out of birch pollen season. To distinguish between immunological modifications induced by SIT or natural birch pollen exposure two control groups were included consisting of subjects allergic to birch pollen treated only symptomatically and healthy non-allergic volunteers without manifestation of an IgE-mediated allergy. A major finding was that tolerance induction by SIT is characterized by a distinct temporal dynamic resulting in differential induction of cellular and humoral parameters, which are involved in recovery and maintenance of allergen-specific tolerance. Clinically, SIT resulted in a significant reduction of allergic symptoms in all patients already in the first pollen season after SIT induction, which persisted during the further observation period. In contrast, allergic individuals only treated symptomatically did not experience a similar relief of symptoms. Analysis of allergen-specific T cell frequencies pointed to sequential changes induced by SIT with an early, but transient induction of Bet v 1-specific type 1 regulatory T (Tr1) cells. The highest increase was found during natural allergen exposure, paralleling the typical rise of allergen-specific T helper (Th) 2 cells in the birch pollen season. Coculture assays revealed the suppressive activity of Tr1 cells, mediated by IL-10- and in a cell number-dependent manner. In contrast, Foxp3+ regulatory T cells characterized by the expression pattern of the surface markers CD4, CD25 and CD127 remained relatively constant both during the different phases of SIT and in and out of the pollen season. Other remarkable findings were the SIT-induced modifications in allergen-specific Th cell subsets with SIT-treated patients experiencing a shift of the Th2-dominated to a Th1-mediated immune response. Thus, pronounced dynamic changes among Bet v 1-specific T cell subsets were noticed in the first year of SIT. However, no substantial frequencies of allergen-specific T-cells were detected later on during the further treatment, even when patients were exposed to natural pollen allergens, presumably as a consequence of the induction of peripheral T cell tolerance. Humoral alterations induced by SIT became evident by the third month of therapy through continuously rising birch pollen-specific IgG4 serum concentrations, while in both healthy controls and birch pollen allergic subjects not treated by SIT the amount of allergen-specific IgG4 antibodies remained unchanged. By contrast, allergen-specific IgE and IgA antibody concentrations did not show differences between the three cohorts. These results thus show that SIT-mediated tolerance induction in allergic patients is based on differentiated, multi-factorial immunoregulatory mechanisms.