Tregs and allergic disease

Abstract

Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

Figure 1

Peripheral blood CD4⁺CD25⁺ T cells from atopic volunteers show reduced suppressive ability in allergen-stimulated T cell cultures. CD4⁺CD25^– T cells were separated from peripheral blood by immunomagnetic separation, then cultured with allergen extracts either alone or mixed with CD4⁺CD25⁺ T cells. Proliferation was assessed by incorporation of tritiated thymidine (shown as cpm), and IL-5 was measured in supernatants at day 6 of cultures by Luminex bead array. Data shown are means and standard errors for cpm and IL-5 from 9 separate nonatopic donors, showing almost complete suppression of responses of CD4⁺CD25^– T cells when CD4⁺CD25⁺ T cells were added. When these data were expressed as percentage suppression (reduction in counts in the mixed culture compared with those in CD4⁺CD25^– T cells alone), suppression was significantly less when cells were obtained from atopic donors or volunteers with hay fever studied in or out of season (IS or OS). Suppression out of season was significantly more than that seen in season but still significantly less than in nonatopic controls. Figure adapted from Lancet (54), with permission from Elsevier.

Figure 2

Immunological changes after allergen immunotherapy. Following 2-year grass pollen immunotherapy (closed circles), there were significant increases in (A) allergen-stimulated PBMC production of IL-10 (78); (B) serum concentrations of grass pollen (Phleum P5) allergen-specific IgG4 (84); and (C) serum inhibitory activity for allergen-IgE binding to B cells (88) compared with controls (open circles). These changes were accompanied by a reduction in symptoms and rescue medication use during the pollen season (83); inhibition of the allergen (grass pollen) induced late cutaneous response.

Figure 3

Potential mechanisms of conventional allergen immunotherapy. High-dose allergen exposure during immunotherapy results in both immune deviation of Th2 responses in favor of a Th0/Th1 response and in the generation of IL-10– and TGF-β–producing CD4⁺CD25⁺ T cells, possibly Tregs. IFN-γ–induced activation of bystander macrophages and/or other cells represents an alternative source of these inhibitory cytokines. During subsequent natural environmental exposure to allergens, the activation and/or maintenance of the usual atopic Th2 T cell response is inhibited. Additionally, these cytokines induce preferential switching of B cell responses in favor of IgG and IgG4 antibodies (and possibly IgA antibodies under the influence of TGF-β). IgG may also inhibit IgE-facilitated allergen binding to antigen-presenting cells with subsequent downregulation of IgE-dependent Th2 T lymphocyte responses. Blue arrows represent immune response pathway to natural exposure (low-doses Ag and IgE); green arrows represent immune response pathway to immunotherapy (high-dose Ag); red blocked lines represent inhibition (high-dose Ag); dotted lines represent possible means of action not yet proven.

Figure 4

Peptide immunotherapy is associated with allergen-specific hyporesponsiveness and the induction of IL-10. (A) Cat-allergic asthmatic subjects (n = 6) were challenged intradermally with a mixture of 12 peptides (5 μg each) from the sequence of Fel d 1 or vehicle alone. Lung function was measured by spirometry for 6 hours. Challenges were separated by 14 days or more. Challenge with vehicle (circles) did not significantly modify forced expiratory volume in one second (FEV₁). Initial peptide challenge (squares) resulted in an isolated LAR that significantly differed from baseline (P = 0.02 area under the curve; AUC). A second challenge (triangles) with the same dose of peptide was associated with an attenuated or absent LAR. Values are mean of 6 individuals with standard error. (B) Cat-allergic asthmatic subjects underwent intradermal allergen challenge (volar aspect of the forearm) before and after administration of a mixture of 11 peptides in incremental divided doses. Peptide treatment significantly reduced the magnitude of the cutaneous late-phase reaction. (C) Treatment of 16 cat-allergic asthmatic individuals with a mixture of 12 peptides (incremental divided doses) resulted in elevated production of IL-10 by peripheral blood mononuclear cells at both 4–6 weeks and 3–9 months after the completion of treatment. Data presented as median and interquartile range.