Intravenous administration of acetylcholine receptor (AChR)-coupled syngeneic spleen cells induced AChR-specific tolerance in Lewis rats. Injection of 20 x 10(6) AChR-coupled spleen cells resulted in a significant reduction of the antibody response to AChR when the animals were subsequently immunized with AChR (up to 66% inhibition). Tolerance induced by AChR-coupled cells was antigen-specific: challenge with AChR plus an unrelated antigen, ovalbumin (OVA), resulted in significantly reduced serum antibody titers to AChR but normal or enhanced titers to OVA, compared to controls. Lymphocytes from these rats showed substantially reduced proliferative responses in vitro to AChR, and normal or enhanced responses to OVA. To investigate the role of Ia antigens in tolerance induction, AChR was coupled to Ia-positive or Ia-negative spleen cells. Injection of AChR-coupled Ia-positive cells induced antigen-specific tolerance to AChR; challenge with AChR plus OVA resulted in reduced serum antibody titers and lymphoproliferative responses to AChR, and normal or enhanced titers and cellular responses to OVA. Injection of AChR-coupled Ia-negative cells did not induce tolerance to AChR. These results demonstrate that AChR, which is known to be highly immunogenic, can be rendered tolerogenic without denaturation or linkage to toxic substances. The possible mechanisms of tolerance induced by AChR-coupled spleen cells are discussed.