Suggestive evidence of oral tolerance in humans

The concept of oral tolerance is mainly based on feeding experiments in rodents and has a long history (Brandtzaeg, 1996a). The understanding of this mucosally-induced down-regulatory or suppressive phenomenon has been hampered by an overwhelming mechanistic complexity. Identifiable experimental variables include genetics, age, dose and timing of post-natal feeding, anti-genic structure and composition of fed protein, epithelial barrier integrity and the degree of concurrent local immune activation, as reflected by microenviron-mental cytokine profiles and the expression of co-stimulatory molecules on mucosal APCs (Brandtzaeg, 1996a; Nagler-Anderson, 2000; Mayer et al., 2001). Also, rodent studies suggest that the commensal microflora is important both for induction of oral tolerance and for reconstitution of this mechanism after its experimental abrogation (Helgeland and Brandtzaeg, 2000). This effect is probably mediated mainly through immune stimulation of GALT, as discussed above.

Although there is little direct evidence that oral tolerance operates in humans, it seems justified to believe that this is the case. Circumstantial evidence is provided by the fact that, in the normal state, the vulnerable gut mucosa, which is separated only by a monolayered epithelium from the enormous intestinal load of live and dead antigenic material, exhibits no substantial IgG response (Brandtzaeg et al., 1987, 1999a) and contains very few T-cells with markers of hyperactivation, such as CD25 (the IL-2 receptor) (Brandtzaeg et al., 1998). Moreover, the systemic IgG response to dietary antigens tends to decrease in humans with increasing age (Rothberg and Farr, 1965; Scott et al., 1985), and direct evidence for a hyporesponsive state in regard to bovine serum albumin has been obtained by intradermal testing with this antigen in adults (Korenblat et al., 1968).

Interestingly, experimental feeding in healthy adults with a protein to which humans are not normally exposed, keyhole limpet haemocyanin (KLH), did result in down-regulation of the peripheral T-cell response, although stimulation of local as well as systemic humoral immunity was observed (Husby et al., 1994). Conversely, intranasal application of KLH tended to suppress both cellmediated and humoral peripheral immunity to this antigen (Waldo et al., 1994). The mechanisms remain unclear, however, and sequestration of specific immune cells into the antigen-exposed mucosae or regional lymph nodes is an alternative possibility, which may be difficult to refute because local immunity was enhanced in both studies. Such a mechanism has been suggested in untreated coeliac-disease patients whose circulating T-cells show a decreased response to gluten compared with treated patients on a gluten-free diet (Scott et al., 1983). Nevertheless, feeding humans with KLH was recently repeated with parallel systemically immunized controls, and mucosally-induced T-cell tolerance was indeed confirmed in peripheral blood (Mayer et al., 2001, and their unpublished observations). Also notably, feeding low doses of myelin basic protein to patients with multiple sclerosis resulted in a higher frequency of circulating T-cells with a potency for production of the down-regulatory cytokine TGF-p, compared with T-cells from placebo-fed patients (Fukaura et al., 1996).

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Gluten Free Living Secrets

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