In addition to recognition of alloantigen, costimulation of T cells primarily by B7 molecules on APCs is important for activating alloreactive T cells. Rejection of allografts, and stimulation of alloreactive T cells in a mixed lymphocyte reaction (described later), can be inhibited by agents that block B7 molecules. Allografts survive for longer periods when they are transplanted into knockout mice lacking B7-1 (CD80) and B7-2 (CD86) compared with transplants into normal recipients. As we will discuss later, blocking of B7 costimulation is a therapeutic strategy to inhibit graft rejection in humans as well. There is experimental evidence, largely from rodents, that several other T cell costimulatory pathways, including ICOS ligand/ICOS and 0x40 ligand/0x40, contribute to acute allograft rejection, but the relevance of these pathways to human transplantation has not yet been examined.
The requirement for costimulation leads to the interesting question of why these costimulators are expressed by graft APCs in the absence of infection, which we have previously discussed as the physiologic stimulus for the expression of costimulators (see Chapter 9). A likely possibility is that the process of organ transplantation is associated with ischemic damage and death of some cells in the graft, during the time the organ is removed from the donor and before it is surgically connected to the circulatory system of the recipient. Several molecules expressed by or released from ischemically damaged cells (so-called damage-associated molecular patterns) stimulate innate immune responses that result in increased expression of costimulators on APCs (see Chapter 4). In fact, the clinical experience is that the ischemia time of an organ is a determinant of the frequency and severity of acute rejection, and one reason for this may be that ischemic death of graft cells stimulates subsequent anti-graft immune responses.
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