Early and late chemokine production correlates with cellular recruitment in cardiac allograft vasculopathy

Background. Cardiac allograft vasculopathy (CAV) remains the leading cause of late mortality in heart transplant recipients. Activated T lymphocytes a nd macrophages infiltrate the donor heart before vascular intimal thickenin g develops, but the specific mediators of mononuclear cell recruitment lead ing to CAV are unknown. Therefore, we sought to define the relationship bet ween chemokine gene expression and production, T lymphocyte and macrophage recruitment, and intimal thickening in a murine model of CAV. Methods. B10.A or B10.BR strain hearts were transplanted heterotopically in to B10.BR mice. Recipients were killed at 1, 4, 7, 14, and 30 days. Donor h earts were assayed for chemokine gene expression with ribonuclease protecti on and for protein with ELISA. Intragraft cellular infiltration was defined immunohistochemically, Intimal thickening was quantitated morphometrically . Results. Early and late patterns of intragraft chemokine expression associa ted with distinct cellular infiltration were identified. First, transient M IP-2 and MCP-1/JE production in isografts and allografts correlated with ne utrophil and macrophage infiltration. MCP-1/JE production and macrophage in filtration was greater in allografts than isografts, Second, allografts dem onstrated sustained lymphotactin, RANTES, and IP-10 expression, beginning a t day 4, correlating with persistent macrophage and T lymphocyte infiltrati on. Intimal thickening became evident at 14 days. Isografts did not display the late pattern of sustained chemokine gene expression, cellular infiltra tion, or intimal thickening. Conclusions. Transient, early MIP-2, and MCP-1/JE production in isografts a nd allografts correlated with neutrophil and macrophage recruitment, and is likely related to ischemia-reperfusion. In allografts, the delayed inducti on of chemokines specific for macrophages and T lymphocytes correlated with mononuclear cell infiltration and preceded intimal thickening. This study thus demonstrates a dual pattern of chemokine induction correlating with in tragraft mononuclear cell recruitment, associated with ischemia-reperfusion and CAV development. Chemokine-directed interventions may interfere with l eukocyte trafficking and inhibit CAV development.