A two-step model for the induction of organ-specific autoimmunity.

Peripheral tolerance is considered to be a safeguard against autoimmunity but the mere existence of anergic T cells renders them potentially dangerous. Using transgenic mice that were tolerant to a foreign MHC class I antigen (Kb) exclusively expressed in the liver, we investigated whether reversal of tolerance in vivo would directly result in autoimmunity. Breaking of tolerance was achieved by application of tumour cells expressing both Kb and interleukin 2. Despite the fact that the respective mice were now able to reject Kb-positive grafts, the reversed T cells did not infiltrate and attack the Kb-positive liver. However, when the liver was 'conditioned' through an inflammatory reaction either by irradiation or by infection with Listeria, massive T cell infiltration and liver damage were observed in the reversed mice. The results show that at least two steps are required for autoimmunity: (1) activation of antigen-specific T cells, and (2) conditioning of the target organ. It will be important to determine the factors leading to conditioning but it is likely that adhesion molecules are involved. These experiments are not only of relevance for treatment of autoimmune disease but also for tumour therapy.