title: Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.
abstract: 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 CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14(+) monocytes expressed the CCL5 protein 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 CCL5 gene and intragraft CD14(+) monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14(+) macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14(+) macrophages may predict rejection events.
authors.affiliation: Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pennsylvania Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.forename: Mylarappa
authors.initials: M
authors.lastname: Ningappa
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Qing
authors.initials: Q
authors.lastname: Sun
authors.forename: Lori
authors.initials: L
authors.lastname: Schmitt
authors.forename: Sara
authors.initials: S
authors.lastname: Snyder
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dobberstein
authors.forename: Maria
authors.initials: M
authors.lastname: Branca
authors.forename: Ronald
authors.initials: R
authors.lastname: Jaffe
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
authors.forename: Robert
authors.initials: R
authors.lastname: Squires
authors.forename: Feras
authors.initials: F
authors.lastname: Alissa
authors.forename: Benjamin
authors.initials: B
authors.lastname: Shneider
authors.forename: Kyle
authors.initials: K
authors.lastname: Soltys
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bond
authors.forename: Kareem
authors.initials: K
authors.lastname: Abu-Elmagd
authors.forename: Abhinav
authors.initials: A
authors.lastname: Humar
authors.forename: George
authors.initials: G
authors.lastname: Mazariegos
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007223:Infant; D007249:Inflammation / Q000235:genetics; D007422:Intestines / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D007962:Leukocytes / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D018655:Lymphocyte Count; D008264:Macrophages / Q000378:metabolism / Q000637:transplantation*; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D018950:Lipopolysaccharide Receptors