Frontiers in Immunology (May 2021)

Sensing Acute Cellular Rejection in Liver Transplant Patients Using Liver-Derived Extracellular Particles: A Prospective, Observational Study

  • Kaan Kamali,
  • Moritz Schmelzle,
  • Can Kamali,
  • Philipp Brunnbauer,
  • Katrin Splith,
  • Annekatrin Leder,
  • Nadja Berndt,
  • Karl-Herbert Hillebrandt,
  • Karl-Herbert Hillebrandt,
  • Nathanael Raschzok,
  • Linda Feldbrügge,
  • Matthäus Felsenstein,
  • Matthäus Felsenstein,
  • Joseph Gaßner,
  • Paul Ritschl,
  • Paul Ritschl,
  • Georg Lurje,
  • Wenzel Schöning,
  • Christian Benzing,
  • Johann Pratschke,
  • Felix Krenzien,
  • Felix Krenzien

DOI
https://doi.org/10.3389/fimmu.2021.647900
Journal volume & issue
Vol. 12

Abstract

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Acute cellular rejection (ACR) after liver transplantation (LT) goes along with allograft dysfunction, which is diagnosed by liver biopsy and concomitant histological analysis, representing the gold standard in clinical practice. Yet, liver biopsies are invasive, costly, time-intensive and require expert knowledge. Herein we present substantial evidence that blood plasma residing peripheral liver-derived extracellular particles (EP) could be employed to diagnose ACR non-invasively. In vitro experiments showed organ-specific EP release from primary human hepatocytes under immunological stress. Secondly, analysis of consecutive LT patients (n=11) revealed significant heightened EP concentrations days before ACR. By conducting a diagnostic accuracy study (n = 69, DRKS00011631), we explored the viability of using EP as a liquid biopsy for diagnosing ACR following LT. Consequently, novel EP populations in samples were identified using visualization of t-distributed stochastic neighbor embedding (viSNE) and self-organizing maps (FlowSOM) algorithms. As a result, the ASGR1+CD130+Annexin V+ EP subpopulation exhibited the highest accuracy for predicting ACR (area under the curve: 0.80, 95% confidence interval [CI], 0.70–0.90), with diagnostic sensitivity and specificity of 100% (95% CI, 81.67–100.0%) and 68.5% (95% CI, 55.3–79.3%), respectively. In summary, this new EP subpopulation presented the highest diagnostic accuracy for detecting ACR in LT patients.

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