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

The Transcription Factor, T-bet, Primes Intestine Transplantation Rejection and Is Associated With Disrupted Mucosal Homeostasis

“…Mucosal t-bet and granulysin staining of biopsies was assessed with single color immunohistochemistry, as described previously. 2,3 For 17 children, mean (SEM) age at ITx was 3.8 (1.2) years, male-to-female sex distribution was 4:13, ethnicity, white, non-white 12:5, and distribution of isolated ITx: combined liver-ITx was 6:11. Demographics are further shown by outcome groups, rejector and nonrejector, in Table 1.…”

“…2 Eleven children, consisting of seven rejectors and four nonrejectors provided the remaining residual biopsy tissue. These biopsies had provided independent replication of the findings related to CD14+ MDM and CD138+ plasma cells in the two previous studies.…”

“…We have recently described a molecular signature in peripheral blood consisting of several upregulated inflammatory genes, which precedes and follows ITx rejection. 2 This signature includes the inflammatory chemokine, CCL5, the type I inflammatory transcription factor, t-bet, and the cytotoxin, granulysin. Only CCL5 remains upregulated during rejection, when the remaining genes lose their differential expression.…”

Polymorphism in Regulatory T-cell (Treg)-Related Genes Is Associated with Unexplained Recurrent Pregnancy Loss

“…The cell surface protein encoded by this gene is expressed on Tregs and other immune system cells and is a suggested biomarker for immune tolerance. NKG7 up-regulation has been linked to allograft rejection [27] implicating its role in establishment of immune tolerance. SNP rs71358833 is located in the promoter region of NKG7 and the association between AA genotype and RPL may be due to increased expression of NKG7 in RPL cases.…”

A new nucleic acid–based agent inhibits cytotoxic T lymphocyte–mediated immune disorders

“…[13][14][15] Upregulation of GNLY levels in sera and tissues (eg, the gut, liver, and skin) has been found in patients with GVHD. 5,[16][17][18] GNLY might also be involved in the pathogenesis of GVHD. Targeting the GNLY-mediated cytotoxic pathway can give rise to a novel therapeutic strategy for the treatment of SJS/TEN and GVHD.…”