The transcription factor, T-bet, primes intestine transplantation rejection and is associated with disrupted mucosal homeostasis

• Published in: Transplantation Vol. 99; no. 4; p. 890
• Main Authors: Ranganathan, Sarangarajan, Ashokkumar, Chethan, Ningappa, Mylarappa, Schmitt, Lori, Higgs, Brandon W, Sindhi, Rakesh
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Adaptive Immunity; Antigens, CD19 - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; Biomarkers - metabolism; Biopsy; Child; Child, Preschool; Female; Fixatives; Formaldehyde; Graft Rejection - immunology; Graft Rejection - pathology; Homeostasis; Humans; Immunity, Innate; Immunity, Mucosal; Infant; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestinal Mucosa - transplantation; Intestines - immunology; Intestines - metabolism; Intestines - pathology; Intestines - transplantation; Lipopolysaccharide Receptors - metabolism; Male; Organ Transplantation - adverse effects; Paraffin Embedding; Syndecan-1 - metabolism; T-Box Domain Proteins - metabolism; Time Factors; Tissue Fixation - methods; Treatment Outcome
• ISSN: 1534-6080
• DOI: 10.1097/TP.0000000000000445

The transcription factor, t-bet, promotes inflammatory polarization and intestinal homing of many inflammatory cells. In previous studies, the t-bet and granulysin genes were upregulated in peripheral blood before and after intestine transplantation (ITx) rejection, but not during rejection, possibly because of sequestration in allograft mucosa. Mucosal sequestration of t-bet and granulysin may also explain the presence of inflammatory CD14+ monocyte-derived macrophages (MDM) and immunoglobulin G+ B-cell lineage cells, and loss of mature non-inflammatory CD138+ plasma cells in allograft mucosa during ITx rejection in these previous studies. T-bet-stained and granulysin-stained cells, MDM and CD138+ plasma cells were evaluated with immunohistochemistry in serial biopsies from 17 children, in whom changes in MDM and CD138+ plasma cells were observed previously. T-bet-positive mucosal cells were significantly higher in postperfusion (P = 0.035) and early posttransplant biopsies (P = 0.016) among rejectors, compared with nonrejectors. T-bet-positive cell counts per high-power field (hpf) were (a) positively correlated with MDM counts/hpf in postperfusion (Spearman r = 0.73; P = 0.01) and early posttransplant biopsies (r = 0.54, r = 0.046), and (b) negatively correlated with CD138+B-/pre-plasma cells in early posttransplant biopsies (r = 0.63, P = 0.038). T-bet expression in CD14+ monocytes, CD19+B cells, and several other leukocyte subsets was higher in random blood samples from two rejectors, compared with those from five normal human subjects and three nonrejectors. Scant granulysin-stained mucosal cells precluded additional evaluation of this cytotoxin and its role in ITx rejection. The transcription factor, t-bet, primes ITx rejection, and associates with disrupted homeostatic relationships between innate and adaptive immune cells in the allograft mucosa during rejection.