Donor-derived IP-10 initiates development of acute allograft rejection

An allograft is often considered an immunologically inert playing field on which host leukocytes assemble and wreak havoc. However, we demonstrate tha t graft-specific physiologic responses to early injury initiate and promulg ate destruction of vascularized grafts. Serial analysis of allografts showe d that intragraft expression of the three chemokine ligands for the CXC che mokine receptor CXCR3 was induced in the order of interferon (IFN)-gamma -i nducible protein of 10 kD (IP-10, or CXCL10), IFN-inducible T cell alpha -c hemoattractant (I-TAC; CXCL11). and then monokine induced by IFN-gamma (Mig , CXCL9). Initial IP-10 production was localized to endothelial cells, and only IP-10 was induced by isografting. Anti-IP-10 monoclonal antibodies pro longed allograft survival, but surprisingly, IP-10-deficient (IP-10(-/-)) m ice acutely rejected allografts. However, though allografts from IP-10(+/+) mice were rejected by day 7, hearts from IP-10(-/-) mice survived long ter m. Compared with IP-10(+/+) donors, use of IP-10(-/-) donors reduced intrag raft expression of cytokines, chemokines and their receptors, and associate d leukocyte infiltration and graft injury. Hence, tissue-specific generatio n of a single chemokine in response to initial ischemia/reperfusion can ini tiate progressive graft infiltration and amplification of multiple effector pathways, and targeting of this proximal chemokine can prevent acute rejec tion. These data emphasize the pivotal role of donor-derived IP-10 in initi ating alloresponses, with implications for tissue engineering to decrease i mmunogenicity, and demonstrate that chemokine redundancy may not be operati ve in vivo.