Mechanisms of Allergen-Specific Immunotherapy and Novel Ways for Vaccine Development
DEVELOPMENT OF DESENSITIZATION OF EFFECTOR CELLS
A number of mechanisms is involved in rendering mast cells and basophils unresponsive to allergens even if these cells are "sensitized" by specific IgE bound to their FcεRI receptor. After the first injections of allergen-SIT, a very early decrease in the susceptibility of basophils to degranulation and systemic anaphylaxis can be observed while all of the treated individuals have high quantities of specific IgE.14 The rapid desensitization of skin mast cells seems to be more difficult to achieve.15 The underlying molecular pathways seem similar to the rapid desensitization of the efector cells in anaphylactic reactions to drugs.16 Histamine is one of the main mediators released upon FcεRI triggering of basophils and mast cells, and it exerts its functions through histamine receptors (HRs).17, 18 We recently demonstrated a rapid upregulation of H2R within the first 6 hours of the build-up phase of venom-SIT.19 H2R strongly suppressed FcεRI-induced activation and mediator release of basophils, including histamine and sulfidoleukotrienes, as well as cytokine production in vitro. These data suggest that immunosilencing of FcεRI-activated basophils by a selective suppression mechanism mediated by H2R is highly relevant for the very early desensitization effect of venom-SIT.19 The release of mediators from mast cells and basophils at low levels, below the "normal" threshold of systemic anaphylaxis is probably taking place during allergen-SIT.20, 21 Thus, successful hyposensitization is associated with the altered magnitude of mediator release from the effector cells.20
INDUCTION OF PERIPHERAL T CELL TOLERANCE TO ALLERGENS
Generation of allergen-specific Treg cells is central in the induction of allergen tolerance during allergen-SIT.22-24 Peripheral tolerance is initiated by IL-10 and TGF-β, which are increasingly secreted by the allergen-specific Treg cells during the course of allergen-SIT.22, 23 Both IL-10-secreting (Tr1) and FOXP3+ (Treg) subsets have been implicated, suggesting that there is an overlap between these subsets of Treg cells in humans.25, 26 The supporting evidence for the central role of Treg cells in the induction of allergen-specific tolerance was provided by the demonstration of the association of increased numbers of FOXP3+CD25+CD3+ cells in the nasal mucosa after immunotherapy with clinical efficacy and the suppression of seasonal allergic inflammation.27 CD4+CD25+ Treg cells from atopic donors are less effective in the inhibition of proliferation of CD4+CD25- T cells, which indicates the failing mechanisms of peripheral allergen tolerance.28 Studies that calculated the frequency of allergen-specific T cell subsets such as Th1, Th2 and Tr1 demonstrated a clonal shift towards Tr1 during allergen tolerance.9, 29 In addition, by using human MHC-class II tetramers to investigate allergen-specific T cells during induction of clinical allergen tolerance showed that this led to a switch in the frequencies of antigen-specific T-cells producing certain cytokines. There was a marked loss of IL-4-producing T-cells and an increase in the number of FOXP3+ and IL-10-producing antigen-specific CD4+ T-cells.30 Along these lines, peptide immunotherapy in asthmatics results in decreased Th2 responses due to IL-10-dependent peripheral T cell tolerance. Injection of peptides of selected T cell epitopes from the major cat allergen Fel d 1 induced suppression of T cell proliferation after stimulation with other "linked" T cell epitopes from the same molecule.31 Some models, such as suppression of germinal center reactions and intestinal lymphoid tissue, show that T cell suppression can take place both in the secondary lymphoid organs and in the affected tissues.32
Studies in human high dose allergen exposure models such as non-allergic bee keepers and cat owners showed that Treg cells specific for the major allergens of venom and cat saliva represent the major T cell subset in healthy individuals.9, 10 They utilize IL-10, TGF-β, cytotoxic T lymphocyte antigen 4, programmed death 1 and a number of other suppressive mechanisms.9, 29 The expression of FOXP3 correlates with the suppressive capacity of Treg cells.33 Consistently, increased FOXP3 expression negatively correlates with IgE, eosinophilia and IFN-γ levels. Remarkably, the ratio of FOXP3+ T cells to total CD4+ T cells is significantly lower in asthmatics or atopic dermatitis patients compared to healthy individuals.34
Investigation of Treg cells in allergic individuals provided further evidence for their role in peripheral allergen tolerance. It has been shown that mucosal tolerance induction against dietary antigens coincides with increased numbers of CD4+CD25+ Treg cells. Children who developed clinical tolerance to milk show suppressed peripheral blood mononuclear cell proliferation to bovine beta-lactoglobulin along with an increased frequency of circulating CD4+CD25+ Treg cells.35 In allergic children, the numbers of Treg cells increase during the pollen season, which provides the mechanism by which other subsets of pollen allergen-specific T cells are controlled.36 Notably, in both healthy and allergic individuals, all three major types of allergen-specific subsets of T cells, the Th1, Th2 and Tr1 cells, are found in different proportions. Thus, the shift in the balance between allergen specific Th2 and Treg cells is central to either development of allergen tolerance or allergic status or even the recovery from allergic disease.9, 29, 37
Breaking of peripheral T-cell tolerance to allergens can lead to the development of allergies, and a recent study showed some insight into these mechanisms. Human tonsils show very low levels of allergen-induced T-cell proliferation, thus representing a very suitable in vivo model to assess mechanisms of breaking allergen-specific T-cell tolerance.38 Triggering of Toll-like receptor 4 or 8 combined with addition of proinflammatory cytokines IL-1beta or IL-6 breaks allergen-specific T-cell tolerance in human tonsils and peripheral blood through a mechanism dependent on the adaptor molecule myeloid differentiation primary response gene 88 (MyD88).38 In particular, myeloid DCs and stimulations that activate these cells mediate the breaking of the tolerant state of allergen-specific CD4+ T cells, whereas plasmacytoid DCs and stimulations that activate these cells did not have any tolerance-breaking effect. Tolerance-breaking conditions induced by different molecular mechanisms were associated with a mixed cytokine profile with a tendency toward increased levels of IL-13 and IL-17, which are Th2 and Th17 cytokines, respectively.
ALLERGEN-SPECIFIC IgE AND IgG RESPONSES
In contrast to the allergen-specific T cells, B cells do not show tolerance or unresponsiveness to allergens but are skewed from IgE-producing to IgG4-producing cells.39 Allergen-SIT induces a transient increase in serum specific IgE followed by a gradual decrease usually visible after 3-6 months of treatment.40 Measurements of the IgG subtype levels during SIT showed specific increases in the range of 10-100 fold in the concentrations of IgG1 and particularly of IgG4.41 Specific IgG4 in serum shows a relatively early and rapid increase and continues to increase during the whole duration of SIT as it generally reflects the total allergen.
The suppressive cytokine IL-10 produced by Treg cells also affects the immunoglobulin synthesis through strong suppression of allergen-specific IgE, while it increases IgG4 production.22, 42 Thus, IL-10 regulates specific isotype formation towards a non-inflammatory phenotype - IgG4.43 IgG4 antibodies are dynamic molecules that exchange Fab arms by swapping heavy-light chain pairs between IgG4 molecules with different specificities. This results in the production of bispecific antibodies with a substantially decreased capacity for cross-linking, because they are functionally monovalent.44 The IgG4 hinge region has specialized structural features that result in a lower affinity for certain Fcγ receptors, and IgG4 does not fix complement and can inhibit immune-complex formation by other antibody isotypes.45 In addition, IgG4 is a blocking antibody that prevents the activation and degranulation of effector cells by competing with allergen binding to the IgE on the Fcε receptors of mast cells and basophils.43, 46 The described shift in immunoglobulin isotype production cannot however, explain the therapeutic effect of SIT. In general, the decrease in serum IgE appears much later than clinical tolerance, which occurs relatively early during the course of SIT and does not correlate with the magnitude of clinical improvement after treatment. The production of IgE by bone marrow-residing plasma cells that show a very long life-span might the a plausible explanation for this discrepancy.47
In a recent study, human inducible IL-10-secreting B regulatory (Br1) cells and their immunoregulatory capacity has been investigated in highly purified IL-10-secreting allergen-specific human B cells.43 Human Br1 cells produced high levels of IL-10 and potently suppressed antigen-specific CD4+ T-cell proliferation. Interestingly, IgG4 was selectively confined to human IL-10+ Br1 cells. Healthy beekeeper-derived B cells specific for the major bee venom allergen phospholipase A2 showed increased expression of IL-10. Furthermore as a major contribution to mechanisms of allergen-SIT, the frequency of IL-10+ PLA-specific B cells was significantly increased in patients receiving allergen-specific immunotherapy after 3 months demonstrating for the first time a functional B regulatory cell subset that may play a role in allergen tolerance in humans.43
SUPPRESSION OF EFFECTOR CELLS OF ALLERGIC INFLAMMATION
Allergen-SIT efficiently modulates IgE-mediated activation and histamine release from mast cells and basophils.48 This process is regulated by Treg cells and their anti-inflammatory cytokines. Several molecular mechanisms have been proposed. Through the direct Treg cell-mast cell contact, Treg cells inhibit FcεRI-dependent mast cell degranulation.49 IL-10 suppresses IL-5 production by human Th2 cells, reduces proinflammatory cytokine release from mast cells and downregulates eosinophil function and activity.50 Mast cells are also involved in immune tolerance and exert suppressive functions in allergic inflammation. They are capable of downregulating allergic inflammation in UV-induced skin injury and venom-induced tissue damage models in which IL-10 plays key role.51, 52 Treg cells are potent suppressors in various models of eosinophilic inflammation including by schistosome infection-induced as well as asthma-like lung inflammation in mice.53 Along these lines, decreased numbers of eosinophils, eosinophil chemoattractants, and their mediators in the nasal mucosa have been observed as a long term effect of SIT.54
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