Jj. Yun et al., Early and late chemokine production correlates with cellular recruitment in cardiac allograft vasculopathy, TRANSPLANT, 69(12), 2000, pp. 2515-2524
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.