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

被引:315
作者
Hancock, WW
Gao, W
Csizmadia, V
Faia, KL
Shemmeri, N
Luster, AD
机构
[1] Millennium Pharmaceut Inc, Transplantat Unit, Cambridge, MA 02139 USA
[2] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA
[3] Harvard Univ, Sch Med, Boston, MA 02114 USA
关键词
chemokine; transplantation; rejection; IP-10; endothelium;
D O I
10.1084/jem.193.8.975
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 chemokine 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.
引用
收藏
页码:975 / 980
页数:6
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