title: The transcription factor, T-bet, primes intestine transplantation rejection and is associated with disrupted mucosal homeostasis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA. 2Hillman Center for Pediatric Transplantation of the Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA. 3Histology Core Laboratory, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Sarangarajan
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Chethan
authors.initials: C
authors.lastname: Ashokkumar
authors.forename: Mylarappa
authors.initials: M
authors.lastname: Ningappa
authors.forename: Lori
authors.initials: L
authors.lastname: Schmitt
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sindhi
mesh_terms: D056704:Adaptive Immunity; D018941:Antigens, CD19 / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005404:Fixatives; D005557:Formaldehyde; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007223:Infant; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D007422:Intestines / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D016377:Organ Transplantation / Q000009:adverse effects*; D016612:Paraffin Embedding; D053668:Syndecan-1 / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D013997:Time Factors; D016707:Tissue Fixation / Q000379:methods; D016896:Treatment Outcome; D000098815:T-bet Transcription Factor
chemical_list: D018941:Antigens, CD19; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D005404:Fixatives; C075005:GNLY protein, human; D018950:Lipopolysaccharide Receptors; C508241:SDC1 protein, human; D053668:Syndecan-1; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D005557:Formaldehyde