Activated CD8 T-cell Hepatitis in Children with Indeterminate Acute Liver Failure: Results from a Multicenter Cohort

Catherine A. Chapin*, Hector Melin-Aldana, Portia A. Kreiger, Thomas Burn, Katie Neighbors, Sarah A. Taylor, Lorena Ostilla, Joshua B. Wechsler, Simon P. Horslen, Mike A. Leonis, Kathleen M. Loomes, Edward M. Behrens, Robert H. Squires, Estella M. Alonso

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Objectives:In many pediatric acute liver failure (PALF) cases, a diagnosis is not identified, and the etiology is indeterminate (IND-PALF). Our pilot study found dense CD8 T-cell infiltrates and increased T-cell clonality in liver specimens from IND-PALF patients. We aimed to validate these findings in a multicenter cohort with investigators blinded to diagnosis.Methods:PALF Study Group registry subjects with IND-PALF (n = 37) and known diagnoses (DX-PALF) (n=18), ages 1 to 17 years, with archived liver tissue were included. Liver tissue slides were stained for T cells (CD8 and CD4), B cells (CD20), macrophages (CD163), perforin, and tissue resident-memory T cells (Trm, CD103), and scored as minimal, moderate, or dense. Lymphocytes were isolated from frozen liver tissue for T-cell receptor beta (TCRβ) sequencing.Results:Dense hepatic CD8 staining was found in significantly more IND-PALF (n=29, 78%) compared with DX-PALF subjects (n=5, 28%) (P=0.001). IND-PALF subjects were more likely to have dense or moderate perforin (88% vs 50%, P=0.03) and CD103 (82% vs 40%, P=0.02) staining compared with DX-PALF subjects. TCRβ sequencing of 15 IND-PALF cases demonstrated increased clonal overlap compared with 6 DX-PALF cases (P=0.002).Conclusions:Dense infiltration of effector Trm CD8 T cells characterizes liver tissue from IND-PALF subjects. Increased clonality suggests the T-cell expansion is antigen(s)-driven as opposed to a nonspecific inflammatory response. These findings support CD8 staining as a new biomarker of the activated CD8 T-cell PALF phenotype. Future studies are needed to characterize potential antigens, host risk factors, and inflammatory pathways with the goal of developing targeted therapies.

Original languageEnglish (US)
Pages (from-to)713-719
Number of pages7
JournalJournal of pediatric gastroenterology and nutrition
Volume71
Issue number6
DOIs
StatePublished - Dec 1 2020

Keywords

  • acute hepatitis
  • aplastic anemia
  • fulminant hepatic failure
  • immune dysregulation

ASJC Scopus subject areas

  • Gastroenterology
  • Pediatrics, Perinatology, and Child Health

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