Differential regulation of allergen-specific antibodies in allergy and specific immunotherapy.

Allergen-specific immunotherapy (SIT) aims to specifically skew an allergic response into a normal immune reaction against an allergen. The response to bee venom (BV) provides an especially suited model to study the immunological mechanisms of SIT in human. The BV-phospholipase A2 (PLA) represents the major antigen/allergen of BV. In SIT of BV allergy both whole BV and T cell epitope peptides of PLA were successfully applied. It appeared that the induction of specific anergy in peripheral T cells and reactivation of the T cells by microenvironmental cytokines represent the basic key steps in the immunological mechanism of SIT. The proliferative and cytokine responses by specific T cells were significantly suppressed simultaneously with an increase in IL-10 after 7 days. The anergic state was fully established after 4 weeks. Neutralization of IL-10 in PBMC by a specific antibody reconstituted the original proliferative and cytokine responses. Intracytoplasmatic cytokine staining revealed that IL-10 was initially produced by activated allergen-specific T cells. IL-10-producing B cells and monocytes were involved at a later stage of SIT and in maintenance of the anergy. The addition of IL-10 to stimulated PBMC or purified B cells inhibited IgE synthesis and enhanced the IgG4 antibody formation. Thus, SIT generates IL-10, which in turn induces specific anergy by autokrine interaction in T cells and counter-regulates IgE and IgG4 production. Particular cytokines from the tissue microenvironment reactivate the T cells to produce distinct Th1 or Th2 cytokine patterns respectively and by this way direct SIT towards successful or unsuccessful treatment. High amounts of allergen administered in SIT preferentially generate Th1 cytokines in T cells and IgG4 antibodies in memory B cells. Further investigations demonstrated that suppression of T cells by IL-10 is an active process, which depends on the expression and participation of CD28.