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  • Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios

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Inflammatory bowel disease
Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios
  1. Jörn-Hendrik Weitkamp1,
  2. Tatsuki Koyama2,
  3. Michael T Rock1,
  4. Hernan Correa3,
  5. Jeremy A Goettel4,5,
  6. Pranathi Matta1,
  7. Kyra Oswald-Richter3,
  8. Michael J Rosen1,
  9. Brian G Engelhardt6,
  10. Daniel J Moore1,
  11. D Brent Polk1,4,7,8
  1. 1Department of Pediatrics, Vanderbilt University School of Medicine, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, Tennessee, USA
  2. 2Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  3. 3Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  4. 4Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  5. 5Division of Gastroenterology and Nutrition, Department of Pediatrics, Harvard Medical School, Children's Hospital Boston, Boston, Massachusetts, USA
  6. 6Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  7. 7Department of Pediatrics, University of Southern California and The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California, USA
  8. 8Department of Biochemistry & Molecular Biology, University of Southern California and The Saban Research Institute of Children's Hospital Los Angeles, Los Angeles, California, USA
  1. Correspondence to Dr Jörn-Hendrik Weitkamp, Division of Neonatology, Department of Pediatrics, Monroe Carell Jr. Children's Hospital at Vanderbilt, 2215 B Garland Ave., 1125 MRB IV/Light Hall, Nashville, TN 37232-0656, USA; hendrik.weitkamp{at}vanderbilt.edu

Abstract

Background Necrotising enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Immaturity of gastrointestinal immune regulation may predispose preterm infants to NEC as FOXP3 T regulatory cells (Treg) are critical for intestinal immune homoeostasis.

Objective To investigate the hypothesis that abnormal developmental regulation of lamina propria Treg would define premature infants with NEC.

Design Lamina propria mononuclear cell populations from surgically resected ileum from 18 patients with NEC and 30 gestational age-matched non-NEC surgical controls were prospectively isolated. Polychromatic flow cytometry was performed to phenotype and analyse lamina propria T cell populations. The cytokine gene expression profile in NEC tissue was compared with that of non-NEC controls.

Results The total number of Treg, CD4, or CD8 T cells in each ileum section was independent of gestational age, age or postmenstrual age and similar between patients with NEC and controls. In contrast, the ratio of Treg to CD4 T cells or Treg to CD8 T cells was significantly lower in NEC ileum than in infants without NEC (medians 2.9% vs 6.6%, p=0.001 and medians 6.6% vs 25.9%, p<0.001, respectively). For any given number of CD4 or CD8 T cells, Treg were, on average, 60% lower in NEC ileum than in controls. NEC tissue cytokine gene expression profiles were characteristic of inhibited Treg development or function. Treg/CD4 and Treg/CD8 ratios recovered between initial resection for NEC and reanastomosis.

Conclusion The proportion of lamina propria Treg is significantly reduced in the ileum of premature infants with NEC and may contribute to the excessive inflammatory state of this disease.

  • Necrotising enterocolitis
  • FOXP3
  • mucosal immunity
  • infant development
  • T-lymphocyte
  • intestinal development
  • surgical resection
  • neonatal gut
  • mucosal immunology
  • Crohn's disease
  • cell signalling
  • gut immunology
  • gut inflammation
  • IBD
  • autoimmunity
  • B cell
  • tolerance
  • cellular immunology
  • T lymphocytes

https://doi.org/10.1136/gutjnl-2011-301551

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    Footnotes

    • Funding The project described was supported by award number K08HD061607 (to JHW) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) and award numbers RO1DK56008and RO1DK066176 (both to DBP) from The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIDDK or the National Institutes of Health (NIH). This work was also supported by the Vanderbilt Physician Scientist Development Program Award (to JHW) and the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH. Support for flow cytometry experiments and biostatistics was provided through the Vanderbilt University Medical Centre's Digestive Disease Research Centre sponsored by NIH grant P30DK058404.

    • Competing interests None.

    • Patient consent Since resected human tissue was used and de-identified before processing, the Vanderbilt IRB designated the study; non-human subject research; and waived the consent.

    • Ethics approval This study was conducted with the approval of the Vanderbilt University Medical Centre Ethics Committee. Vanderbilt Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.