The ultimate success of xenotransplantation will depend upon our ability to safely protect the xenograft from the damaging consequences of AVR/DXR, as well as T-cell dependent immune responses. Although remarkable prolongation of porcine xenograft survival has been achieved in nonhuman primates, subjects invariable succumb to infectious complications from the protocols used to prevent rejection. Safe prolongation of xenograft survival may depend on modulation of the graft-host interaction such that the xenograft is able to survive despite the presence of ongoing immune responses, a process termed "accomodation". Recent data from rodent studies suggest that accomodation of xenografts may be linked to the expression of so-called "protective genes" by endothelial cells, such as A20 and bcl-2, which prevent upregulation of proinflammatory genes and avert the onset of apoptosis. In addition, enduring xenograft survival has been linked to the induction of a helper type 2 (Th2) cytokine immune response within the graft, while rejected grafts display a Th1 type response. Avoidance of AVR/DXR may therefore require the development of transgenic swine donors not only resistant to HAR by virtue of their possession of human complement regulatory proteins, but also "protected" through enhanced expression of certain genes.

Xenoreactive antibodies have generally been viewed in the context of their importance for induction of HAR. However, it is apparent from available in vitro and in vivo evidence that their pathogenetic effects are potentially much greater. Although some have suggested that AVR/DXR can occur in the absence of

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