Antigen-driven bystander suppression after oral administration of antigens.

Abstract

SummarySuppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8 + T cells that can be isolated from the spleens of MBP-fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8 + T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen-driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.A variety of mechanisms have been described for the maintenance of self-tolerance in the host. These include clonal deletion (1), clonal anergy (2, 3), and active suppression (4; and reviewed in reference 5). We have been studying antigen-driven active suppression after oral administration of antigens as a tolerance mechanism and as a method to downregulate autoimmune diseases in experimental animals (6-11). In the experimental autoimmune encephalomyelitis (EAE) 1 model, oral administration of myelin basic protein (MBP) suppresses clinical, histologic, and immune parameters of the disease (6, 12). This effect is mediated by CD8 + T cells, which can adoptively transfer protection and suppress in vitro proliferative responses (7). Although various mechanisms of active suppression have been demonstrated (5, 13), the precise mechanism(s) by which T cells mediate suppression re1Abbreviations used in this paper: DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; PPD, purified protein derivative. 791 mains t...

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