Papel dos eventos inflamatórios induzidos pela imunização na manutenção de tolerância oral

Abstract

Oral tolerance is a complex phenomenon defined as a state of systemichyporesponsiveness to an antigen that has been previously administered by the oral route. Many factors affect oral tolerance induction, some of them related to antigen, some related to the animal. Feeding regimen as well as the age of the animal are two of the most important factors that affect oral tolerance induction. Neonatal mice are not susceptible to oral tolerance while 8-week-old mice are fully susceptible. Mice becomeless susceptible with 24 weeks of age and totally refractory with 70 weeks of age. Some reports suggest that aging does not affect oral tolerance induction but its maintenance. According to some authors, oral tolerance is kept for a short period of 21 days to 3 months. Previous studies by our laboratory showed that oral tolerance can be maintained for a period of one and a half year after oral treatment. These contradictory reports can be explained by different experimental protocols that were used. The main difference in those protocols is related to immunization with antigen + adjuvant that is essential to reveal oral tolerance induction or maintenance. Thus, our goal was to study the role of inflammatory events triggered by immunization in the oral tolerance induction and maintenance. BALB/c mice at age of 8-12 weeks were treated orally with20mg of OVA, either by gavage or continuous feeding and immunized withOVA+Al(OH)3 i.p or alternatively with OVA+CFA s.c. Primary immunization varied from 7 to 180 days after oral treatment in mice immunized with OVA+Al(OH)3 or OVA+CFA and booster with OVA varied from 14-360 days after primary immunization (with OVA+Al(OH)3). According to our results, animals immunized up to 30 days after oral treatment either by gavage or continuous feeding, independent of the kind of adjuvant used, were able to sustain oral tolerance. However, mice immunized 90 days after oral treatment with OVA+CFA did not maintain the tolerance status, while those immunized with Al(OH)3 did. This result suggests that the type of adjuvant used affects oral tolerance maintenance. On the other hand, mice immunized 180 days with OVA+Al(OH)3 after oral treatment by gavage become responsive to antigen while those treated by continuous feeding kept tolerant. Our data indicate that the feeding regimen isalso able to affect oral tolerance maintenance. Moreover, mice immunized 7 days after oral treatment either by gavage or continuous feeding are able to keep oral tolerance up to one year after oral treatment. This result suggests that immunization with antigen + adjuvant can work strengthening oral tolerance maintenance. We can conclude thatimmunization with antigen + adjuvant is important for oral tolerance maintenance and that the type of adjuvant used, the interval between oral treatment and primary immunization, as well as the regimen feeding (gavage or continuous feeding) all affect oral tolerance maintenance.