Differential Expression of the IFN-γ-Inducible CXCR3-Binding Chemokines, IFN-Inducible Protein 10, Monokine Induced by IFN, and IFN-Inducible T Cell α Chemoattractant in Human Cardiac Allografts: Association with Cardiac Allograft Vasculopathy and Acute Rejection

Abstract

CXCR3 chemokines exert potent biological effects on both immune and vascular cells. The dual targets suggest their important roles in cardiac allograft vasculopathy (CAV) and rejection. Therefore, we investigated expression of IFN-inducible protein 10 (IP-10), IFN-inducible T cell α chemoattractant (I-TAC), monokine induced by IFN (Mig), and their receptor CXCR3 in consecutive endomyocardial biopsies (n = 133) from human cardiac allografts and corresponding normal donor hearts (n = 11) before transplantation. Allografts, but not normal hearts, contained IP-10, Mig, and I-TAC mRNA. Persistent elevation of IP-10 and I-TAC was associated with CAV. Allografts with CAV had an IP-10-GAPDH ratio 3.7 ± 0.8 compared with 0.8 ± 0.2 in those without CAV (p = 0.004). Similarly, I-TAC mRNA levels were persistently elevated in allografts with CAV (6.7 ± 1.9 in allografts with vs 1.5 ± 0.3 in those without CAV, p = 0.01). In contrast, Mig mRNA was induced only during rejection (2.4 ± 0.9 with vs 0.6 ± 0.2 without rejection, p = 0.015). In addition, IP-10 mRNA increased above baseline during rejection (4.1 ± 2.3 in rejecting vs 1.8 ± 1.2 in nonrejecting biopsies, p = 0.038). I-TAC did not defer significantly with rejection. CXCR3 mRNA persistently elevated after cardiac transplantation. Double immunohistochemistry revealed differential cellular distribution of CXCR3 chemokines. Intragraft vascular cells expressed high levels of IP-10 and I-TAC, while Mig localized predominantly in infiltrating macrophages. CXCR3 was localized in vascular and infiltrating cells. CXCR3 chemokines are induced in cardiac allografts and differentially associated with CAV and rejection. Differential cellular distribution of these chemokines in allografts indicates their central roles in multiple pathways involving CAV and rejection. This chemokine pathway may serve as a monitor and target for novel therapies to prevent CAV and rejection.

Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4+ T Cells to HIV-1-Infected Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes

“…It is noteworthy that just as CXCL10 and CXCL11 were, and CXCL9 was not, induced by infection with HIV-1 in vitro, CXCL10 and CXCL11 were expressed in an identical pattern in vivo, which differed from the pattern that we saw for CXCL9 (36). These observations are analogous to those by Zhao et al (58), who reported that CXCL10 and CXCL11 were both expressed by vessels in endomyocardial biopsies from human cardiac allografts, which was not the case for CXCL9. To our knowledge, our study is the first demonstration of the expression of chemokines by venules of HIV-1-infected lymph node, providing candidates mediating the enhanced recruitment of T cells to these tissues.…”

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.…”

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

“…Although a number of clinical investigations focused on other putative indicators of alloreaction like IL-2, MCP-1, or granzyme B (27)(28)(29), more recently transplantation studies in animals (8,24,30) and measurements of chemokine mRNA in biopsy specimens (11,12,31,32) have stressed the prominent role of IFN-␥-dependent chemokines, especially MIG, for the acute phase of allograft rejection. Urinary measurements of MIG in a small number of pediatric patients (33) and in adult renal allograft patients support our data (34,35).…”