A role of TLRs in inducing systemic tolerance to oral antigens comes from two lines of evidence. Unlike conventionally raised animals, germ-free BALB/c mice given sheep RBC via gastric gavage were able to induce potent systemic immune responses as determined by detection of high frequencies of antigen-specific antibody (IgG, IgM, and IgA)-producing splenocytes on intraperitoneal immunization with antigen. When these germ-free mice were given a single oral dose of LPS, they became hyporesponsive to systemic challenge (Michalek et al. 1982; Wannemuehler et al. 1982). The role of LPS in the induction of oral tolerance was further suggested by similar studies in which tolerance could not be induced in C3H/HeJ (LPS insensitive) compared with C3H/HeN (LPS-sensitive) mice (Kiyono et al. 1982; Mowat et al. 1986). Both the lack of oral tolerance in germ-free mice and the role of LPS in mediating this tolerance were challenged by studies in germ-free and conventionalized C3H/HeJ mice (Moreau and Corthier 1988) using OVA as fed antigen. However, these studies used a high dose of OVA, which is known to induce T cell deletion rather than induction of regulatory T cells (Chen et al. 1995) and may have been the mode of action in experiments using SRBC.
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