A CHOLERA TOXOID-INSULIN CONJUGATE AS AN ORAL VACCINE AGAINST SPONTANEOUS AUTOIMMUNE DIABETES

Mucosally induced immunological tolerance is an attractive strategy Fo r preventing or treating illnesses resulting from untoward inflammator y immune reactions against self- or non-self-antigens. Oral administra tion of relevant autoantigens and allergens has been reported to delay or suppress onset of clinical disease in a number of experimental aut oimmune and allergic disorders, However, the approach often requires r epeated feeding of large amounts of tolerogens over long periods and i s only partly effective in animals already systemically sensitized to the ingested antigen such as in animals already harboring autoreactive T cells, and thus presumably also in humans with an autoimmune diseas e, We have recently shown that oral administration of microgram amount s of antigen coupled to cholera toxin B subunit (CTB), can effectively suppress systemic T cell reactivity in naive as well as in immune ani mals, We nom report that feeding small amounts (2-20 mu g) of human in sulin conjugated to CTB can effectively suppress beta cell destruction and clinical diabetes in adult nonobese diabetic (NOD) mice, The prot ective effect could be transferred by T cells from CTB-insulin-treated animals and mas associated with reduced lesions of insulitis. Further more, adoptive co-transfer experiments involving injection of Thy-1,2 recipients with diabetogenic T cells from syngeneic mice and T cells f rom congenic Thy-l,1 mice fed with CTB-insulin demonstrated a selectiv e recruitment of Thy-1,B donor cells in the peripancreatic lymph nodes concomitant with reduced islet cell infiltration, These results sugge st that protection against autoimmune diabetes can be achieved by feed ing minute amounts of a pancreas islet cell autoantigen linked to CTB and appears to involve the selective migration and retention of protec tive T cells into lymphoid tissues draining the site of organ injury.