David A. Hafler

Suppression of Organ-Specific Autoimmune Diseases by Oral Administration of Autoantigens

One of the primary goals in developing effective therapy for autoimmune diseases is to specifically suppress autoreactive immune processes without affecting the remainder of the immune system. Autoimmune diseases involve the presence of autoreactive clones that have not been deleted in the thymus and thus these cells must be inactivated in the periphery. We have been investigating antigen-driven peripheral immune tolerance as a means to suppress autoimmune processes using the oral route of antigen-exposure to the immune system because of its inherent clinical applicability. An effective andlong-recognized method of inducing immunologic tolerance is the oral administration of antigen, which was first demonstrated by Wells for hen’s egg protein.[l] The mechanism by which orally administered antigen induces tolerance most probably relates to the interaction of protein antigens with gut-associatedlymphoid tissue (GALT) and the subsequent generationo? regulatory or suppressor T cells. [2] The two primary points of contact of orally administered antigen are Peyer’s patches and gut epithelial cells, thelatter of which overlie intraepitheliallymphocytes. Investigators have reported that specific suppressor cells can be found in the Peyer’s patches following oral administration of antigen and that such cells then migrate systemically.[2] Intestinal epithelial cells express class II antigens on their surface and thus have the capacity to function as antigen-presenting cells.[3] Furthermore, it has been shown that human gut epithelial cells preferentially stimulate CD8+ cells in vitro which can function to suppress in vitro immune responses. [4] Although most investigators have reported that the generation of antigen-specific suppressor T cells is the primary mechanism responsible for mediating oral tolerance, other reported mechanisms include anti-idiotypic antibodies, immune complexes and biologically filtered antigen (reviewed in REF. 5).