Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.
2011
Recurrent rejection shortens graft survival after
intestinal transplantation(ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors:
TBX21,
CCL5,
GNLY,
SLAMF7, TGFBR3 , NKG7 , SYNE1 , and GK5 . Only
CCL5was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors,
CD14+ monocytes expressed the
CCL5protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating
CCL5+
CD14+ monocytes and intragraft
CD14+ monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with
CD154+ T-cytotoxic memory cells correlated with the
CCL5gene and intragraft
CD14+ monocyte-derived macrophages at graft reperfusion and early post-ITx.
CCL5gene up-regulation and
CD14+ macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with
CD14+ macrophages may predict rejection events.
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