Vigorous allograft rejection in the absence of danger

Tolerance to self is a necessary attribute of the immune system. Pt is thou ght that most autoreactive T cells are deleted in the thymus during the pro cess of negative selection. However, peripheral tolerance mechanisms also e xist to prevent development of autoimmune diseases against peripheral self- Ags, It :has been proposed that T cells develop tolerance to peripheral sel f-rigs encountered in the absence of inflammation or "danger" signals. We h ave used immunodeficient Rag 1(-/-) mice to study the response of T cells t o neo-self peripheral Ags in the form of well-healed skin and vascularized cardiac allografts. In this paper we report that skin and cardiac allograft s without evidence of inflammation are vigorously rejected by transferred T cells or when recipients are reconstituted with T cells at a physiologic r ate by nude bone graft transplantation. These results provide new insights into the role of inflammation or "danger" in the initiation of T cell-depen dent immune responses. These findings also have profound implications in or gan transplantation and suggest that in the absence of central deletional t olerance, peripheral tolerance mechanisms are not sufficient to inhibit all oimmune responses even in the absence of inflammation or danger.