EVIDENCE THAT TOLERANCE TO CULTURED THYROID ALLOGRAFTS IS AN ACTIVE IMMUNOLOGICAL PROCESS - PROTECTION OF 3RD-PARTY GRAFTS BEARING NEW ANTIGENS WHEN ASSOCIATED WITH TOLEROGENIC ANTIGENS

We studied the tolerance phenomenon that develops in long-term recipients of cultured thyroid allografts. Allogeneic mouse thyroids were cultured under hyperbaric oxygen or acidic conditions and then transplanted beneath the kidney capsule of C57BL/6 recipients. Donors differed from the recipients in minor antigens alone, major histocompatibility complex antigens alone, or both. At 35-77 weeks after the first cultured graft, recipients received two more cultured grafts under the capsule of the opposite kidney and were immunized with donor spleen cells (SC). At 5 weeks after the second transplantation, we observed that whereas second grafts carrying new antigens alone were rejected, second grafts carrying new antigens in association with antigens in the first graft were significantly protected. In another set of experiments, normal mice became tolerant to cultured allografts after 2 weeks in parabiosis with tolerant individuals. Tolerant mice showed reduced specific in vivo and in vitro cytotoxic T lymphocyte responses. However, the frequency of CTL precursors of tolerant mice was the same as in normal mice. The reduced in vitro CTL responses were restored to normal levels by the addition of a lymphokine rich medium. Also, we observed that the injection of specifically activated immune SC caused the rejection of cultured allografts in normal but not in tolerant recipients. We conclude that the tolerance that develops in recipients of cultured allografts is an active immunological process that affects the activation and effector function of CTL.