Aging is reported to be associated with decline in oral tolerance induction, which is initiated at the intestinal mucosal surface. Herein, we examined the effect of aging in T cells and cytokines at the intestinal mucosa that might be involved in oral tolerance induction. Frequencies of regulatory-type IEL subsets such as TCRγδ+ and TCRαβ+CD8αα+ were lower in aged mice. Mucosal CD4+CD25+Foxp3+ and CD4+LAP+ T cells increased with aging but activated CD44+CD4+ mucosal T cells also augmented. Production of TGF-β and IL-10 in the small intestine of old mice was reduced. Moreover, the ability of mucosal dendritic cells of aged mice to stimulate TGF-β secretion and differentiation of CD4+LAP+ T cells in co-culture studies also declined with aging. Reduction in these regulatory-type cytokines and T cells may help to explain the decline in susceptibility to oral induction during aging. However, not all mucosal regulatory elements were altered by aging and CD4+CD25+Foxp3+ T cells were especially resistant to changes. Persistence of some mechanisms of regulation might play a critical role in maintaining mucosal homeostasis during aging.
Anti-DNP antibody formation resulting from intraperitoneal (i.p.) immunization with DNP-KLH may be blocked by simultaneous (i.p.) injection of DNP-Ova or native Ova in mice orally tolerant to Ova, but not in normal mice. In Ova-tolerant mice the inhibition of anti-DNP antibody formation also occurred when DNP-Ova and DNP-KLH were given by separate routes of immunization: subcutaneous (s.c.) and i.p. A second exposure to Ova by gastric intubation (gavage) or intravenous administration simultaneously with i.p. immunization with DNP-KLH failed to inhibit anti-DNP antibody formation. There was inhibition of responses to DNP-KLH i.p. by DNP-Ova given 24 h before, but not 24 h after, and in the Ova-tolerant mice, addition of DNP-Ova only to the primary immunization with DNP-KLH inhibited secondary and tertiary responses to DNP-KLH in the absence of further exposures to DNP-Ova. These results suggest that the indirect effects of parenteral exposure of tolerant mice to the tolerated immunogen may inhibit unrelated immune responses. This inhibition is not due to 'innocent bystanding' suppression, i.e., to inhibitory cytokines provided locally by specific suppressor lymphocytes; it may derive from more durable perturbations of immune system.
Carvalho CR, Verdolin BA, Vaz NM. Indirect Effects of Oral Tolerance Cannot be Ascribed to Bystander Suppression. Scand J Immunol 1997;45:276-281 The addition of tolerated antigens to immunizing doses of unrelated antigens blocks antibody responses to these unrelated antigens. This inhibition, which the authors have called the indirect effects of tolerated antigens, occurs even when the mixture of proteins is injected as soon as 24 h after the oral tolerance induction. The indirect effects also do not require the simultaneous injection of the two proteins: they are still present 72 h after an injection of Ova in Ova tolerant mice, but do not occur if the unrelated protein is injected 24 h before the tolerated protein. In addition, indirect effects do not block secondary responses to unrelated proteins if the primary immunization is made in the absence of the tolerated protein. These results cannot be explained by innocent bystander suppression, which is believed to result from the action of suppressive cytokines released by specific tolerant lymphocytes upon unrelated lymphocytes that would otherwise respond to the second, non-tolerated antigen. Indirect effects may be better understood in terms of network models.
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