title: Donor-derived IP-10 initiates development of acute allograft rejection.
abstract: An allograft is often considered an immunologically inert playing field on which host leukocytes assemble and wreak havoc. However, we demonstrate that graft-specific physiologic responses to early injury initiate and promulgate destruction of vascularized grafts. Serial analysis of allografts showed that intragraft expression of the three chemokine ligands for the CXC chemo-kine receptor CXCR3 was induced in the order of interferon (IFN)-gamma-inducible protein of 10 kD (IP-10, or CXCL10), IFN-inducible T cell alpha-chemoattractant (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 prolonged allograft survival, but surprisingly, IP-10-deficient (IP-10(-/-)) mice acutely rejected allografts. However, though allografts from IP-10(+/+) mice were rejected by day 7, hearts from IP-10(-/-) mice survived long term. Compared with IP-10(+/+) donors, use of IP-10(-/-) donors reduced intragraft expression of cytokines, chemokines and their receptors, and associated leukocyte infiltration and graft injury. Hence, tissue-specific generation of a single chemokine in response to initial ischemia/reperfusion can initiate progressive graft infiltration and amplification of multiple effector pathways, and targeting of this proximal chemokine can prevent acute rejection. These data emphasize the pivotal role of donor-derived IP-10 in initiating alloresponses, with implications for tissue engineering to decrease immunogenicity, and demonstrate that chemokine redundancy may not be operative in vivo.
authors: Transplantation Unit, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. whancock@mpi.com
authors: W W
authors: WW
authors: Hancock
authors: W
authors: W
authors: Gao
authors: V
authors: V
authors: Csizmadia
authors: K L
authors: KL
authors: Faia
authors: N
authors: N
authors: Shemmeri
authors: A D
authors: AD
authors: Luster
mesh_terms: D000208:Acute Disease; D000818:Animals; D054357:Chemokine CXCL10; D018925:Chemokines / Q000235:genetics; D019743:Chemokines, CXC / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology; D014185:Transplantation, Isogeneic / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma