Canadian Health&Care Mall Observes Defective Regulation in Allergic Diseases and Asthma

autoantigens Compromised regulation may provide an explanation for hyperreactivity to allergens and autoantigens. A number of studies have investigated the possibility that allergen-specific Treg function is defective in individuals with allergic diseases about which you may learn more on Canadian Health&Care Mall via http://healthcaremall4you.com/five-facts-about-allergy-together-with-canadian-healthcare-mall.html. (Fig 2). CD4+CD25+ T cells from grass pollen-allergic individuals were less able to suppress proliferative responses and IL-5 production by CD4+CD25-negative T cells. Moreover, suppression by CD4+CD25+ T cells was further compromised during the pollen season, suggesting that increased allergen dose in vivo may provide a strong enough stimulus to override Treg-mediated suppression.

Other similar studies have also found evidence of defective regulation but with some caveats. For example, CD4+CD25+ T-cell function from birch pollen-allergic subjects and nonallergic control subjects was compared in and out of season. While both groups had equivalent suppression of allergen-induced proliferation and similar suppression of IFN-7, suppression of Th2 responses appeared to be compromised in allergic subjects, as both CD4+CD25+ and CD4+CD25-negative T cells made IL-5 and IL-13 to birch pollen. The findings are consistent with the observation40 that Th2 thymocyte clones were more resistant to regulation by either CD4+CD25+ or CD8+CD25+ regulatory human thymocytes than were Th1 thymocyte clones.

A third study41 concluded that in the majority of allergic individuals (predominantly rhinitics sensitive to grass pollen or birch in this study), there are no defects in the ability of CD4+CD25+ T cells to regulate proliferative and cytokine responses. However, a subgroup of allergic subjects who produced high levels of IL-4 and IL-10 were unable to regulate effectively. Further related experiments demonstrated that both dose and type of allergen appear to have important effects on the ability of CD4+CD25+ T cells to suppress responses. In grass pollen-allergic individuals, stimulation of T cells with high concentrations of allergen resulted in a failure in the ability of CD4+CD25+ T cells to suppress proliferative responses of CD4+CD25-neg-ative T cells. Moreover, CD4+CD25+ T cells lost their characteristic anergic phenotype and were able to proliferate. Interestingly, the ability of CD4+CD25+ T cells to suppress Th1 and Th2 cytokine production was retained at high allergen dose, reiterating the differential regulation of cytokine and proliferation responses identified in other studies. In the same study, CD4+CD25+ T cells from wasp venom-allergic individuals were cultured with a range of allergen doses. In contrast to results with grass pollen, CD4+CD25+ T cells from these subjects were unable to suppress either proliferative or cytokine responses. In fact at higher concentrations, stronger proliferative responses were observed as the CD4+CD25+ T cells themselves proliferated. Some of the same subjects were also grass pollen allergic; in these individuals, the ability to suppress grass pollen responses was retained. Finally, CD4+CD25+ T cells from nonvenom-allergic individuals were able to suppress proliferation and cytokine responses but only at low allergen dose. Thus, allergens vary in their ability to override CD4+CD25+ Treg suppression, both by virtue of dose and intrinsic allergen-specific properties that remain to be identified.

There is a dearth of data relating to the status of Tr1s in individuals with asthma. However, numbers of IL-10-secreting CD4+ T cells have been reported to be reduced in severe unstable asthma, as compared to severe-stable asthma and mild asthma. Peripheral blood T cells were stimulated with anti-CD3 and anti-CD28 prior to intracellular staining for IL-10 analyzed by flow cytometry. The numbers of subjects were small in this study, and no differences were seen between the groups in sputum and blood eosinophilia or exhaled nitric oxide. The dose of corticosteroids used to treat the severe asthmatics did not influence IL-10 production. However, larger studies are required in order to fully determine the extent of the deficiency in T-cell regulation in asthma.

Fig2

Figure 2. Treg inhibit the effector phase of the allergic response. Under the appropriate conditions, antigen-presenting cells present allergen in the form of short peptides bound to major histocompatibility complex molecules, to T cells resulting in Th2 activation and differentiation. Thymus-derived CD4+CD25-high Foxp3+ natural Treg inhibit this process through cell contact-dependent mechanisms. Adaptive Treg such as Tr1 and Th3 cells are generated in the periphery and are generally allergen/antigen specific. These cells are also capable of inhibiting the development of effector Th2 responses through both cytokine secretion (TGF-p and/or IL-10) and other less well-defined mechanisms. The function of CD4+CD25+ T cells is thought to be compromised in allergic individuals. High-dose tolerance to bee venom or to cat allergen exposure is associated with the development of IL-10-secreting Tr1-like cells that prevent expression of the allergic response. Individuals treated with allergen immunotherapy have adaptive allergen-specific Tr1s secreting both IL-10 and TGF-p.

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