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)-γ–inducible protein of 10 kD (IP-10, or CXCL10), IFN-inducible T cell α-chemoattractant (I-TAC; CXCL11), and then monokine induced by IFN-γ (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.

Differential Chemokine and Chemokine Receptor Gene Induction by Ischemia, Alloantigen, and Gene Transfer in Cardiac Grafts

“…They also found that, treatment of recipients with KC antiserum at the time of transplant subsequently decreases intragraft expression of the activated T-cell chemoattractants IP-10 (CXCL10) and MIG (CXCL9). As IP-10 and MIG can play essential roles in allograft rejection (18,19,23,24), these reports demonstrate that innate immune components can have profound effects on subsequent alloantigen-specific rejection. Our data show the induction of this cascade in the transplanted hearts and identify potential candidates that may be antagonized to attenuate rejection of cardiac allografts.…”

“…As shown in Table 2 and Figure 2 (A), multiple chemokines and chemokine receptors were up-regulated in response to alloantigen on day 7, including CCL3, CCL19, CCL21, CCR2, CXCL5, CXCL7, CXCL11, CXCR5, Pumag, and IFNa-gene b. On day 14, when the grafts were undergoing severe rejection and necrosis, more chemokine and receptor mRNA were found, including two potent CXCR3 ligands, CXCL9 and CXCL10, which are known to have strong chemoattractive properties for antigen primed T cells (18,19). Figure 2(B) shows the time course of some representative chemokines in syngeneic and allogeneic grafts.…”

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…We found high induction of IP-10 and MCP-1 8 h after transplantation in NOD mice, as compared with kidney. Interestingly, an early IP-10 production (24-h) was also observed in heart isografts [65]. IP-10 production by these grafts was associated with leukocyte infiltration and graft injury, and the use of anti-IP-10 antibodies prolonged graft survival [65].…”

“…Interestingly, an early IP-10 production (24-h) was also observed in heart isografts [65]. IP-10 production by these grafts was associated with leukocyte infiltration and graft injury, and the use of anti-IP-10 antibodies prolonged graft survival [65]. Besides its chemotactic activities, IP-10 and Mig are potent inhibitors of angiogenesis [66].…”

Up‐regulation of leukocyte CXCR4 expression by sulfatide: An L‐selectin‐dependent pathway on CD4+ T cells

“…They are involved in HIV-1 infection, hematopoiesis, angiogenesis, embryonic de-velopment, tumor metastasis and graft rejection [3][4][5][6]. Stromal-derived factor 1, renamed CXCL12, is a potent chemoattractant for a variety of cells including lymphocytes, monocytes, dendritic cells, and hematopoietic stem cells [3].…”