The Tolerance Phase develop, and these, of course, need to be either deleted True tolerance is achieved when challenge with donor or inactivated in order to maintain the tolerant state. tissues can no longer elicit graft rejection, although third-Alloreactive T cells that escape from the thymus in hosts party tissues are readily rejected (Figure 2). Unless comwith an immature immune system, a circumstance complete central deletion of alloreactive cells is achieved, parable to the state occurring after lymphoablative therperipheral mechanisms are required to maintain the tolapy, are particularly susceptible to induction of periph- erant state, and these can include peripheral deletion eral tolerance (Matzinger and Anderson, 2001). Thus, and/or immunoregulation. There is clear evidence for the conditions involved in lymphocyte repopulation im- peripheral deletion in some models of transplantation mediately following lymphoablative treatment favor but tolerance, although whether or not it continues to occur do not insure tolerance induction. Moreover, following this late in the game is not known. In contrast, immuimmune reconstitution, the new alloreactive cells that noregulatory mechanisms have been unequivocally continue to be exported from the thymus exist in the demonstrated to play a role in maintaining established context of a now mature immune system. Experimental tolerance. CD4 cell-dependent donor tissue–protective models have clearly demonstrated that thymectomized immune responses are present in hosts with nondeleanimals are far more susceptible to tolerance induction tional states of peripheral tolerance (Scully et al., 1994; than euthymic ones. Thus, a principal tenet of transplant Yin and Fathman, 1995). In such circumstances, the tolerimmunologists is the need to disarm or delete newly ant state can be rapidly lost upon removal of the donor produced T cells. A stable system to do so that is self- graft. Hence, peripheral tolerance is maintained as an maintaining (ie, does not require ongoing or periodic active T cell–dependent tissue-protective response, much as normal self-tolerance. therapy) is a prerequisite of tolerance.