ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION

Francesca Lunardi; Luca Vedovelli; Federica Pezzuto; Jerome Le Pavec; Peter Dorfmuller; Marina Ivanovic; Tahuanty Pena; Katharina Wassilew; Michael Perch; Sandrine Hirschi; Marie-Pierre Chenard; Rebecca A Sosa; Martin Goddard; Desley Neil; Angeles Montero-Fernandez; Alexandra Rice; Emanuele Cozzi; Federico Rea; Deborah J Levine; Antoine Roux; Gregory A Fishbein; Fiorella Calabrese

doi:10.1016/j.healun.2023.10.002

ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION

Francesca Lunardi, Luca Vedovelli, Federica Pezzuto, Jerome Le Pavec, Peter Dorfmuller, Marina Ivanovic, Tahuanty Pena, Katharina Wassilew, Michael Perch, Sandrine Hirschi, Marie-Pierre Chenard, Rebecca A Sosa, Martin Goddard, Desley Neil, Angeles Montero-Fernandez, Alexandra Rice, Emanuele Cozzi, Federico Rea, Deborah J Levine, Antoine RouxGregory A Fishbein, Fiorella Calabrese^*

^*Corresponding author for this work

6 Citations (Scopus)

Abstract

BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients.

METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed.

RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%.

CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

Original language	English
Journal	The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Volume	43
Issue number	3
Pages (from-to)	403-413
Number of pages	11
ISSN	1053-2498
DOIs	https://doi.org/10.1016/j.healun.2023.10.002
Publication status	Published - 2024

Keywords

antibody-mediated rejection
antibody-mediated rejection (AMR)
lung transplantation
mammalian target of rapamycin (mTOR) pathway
phosphorylated s6 ribosomal protein (p-S6RP)

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Lunardi, F., Vedovelli, L., Pezzuto, F., Le Pavec, J., Dorfmuller, P., Ivanovic, M., Pena, T., Wassilew, K., Perch, M., Hirschi, S., Chenard, M.-P., Sosa, R. A., Goddard, M., Neil, D., Montero-Fernandez, A., Rice, A., Cozzi, E., Rea, F., Levine, D. J., ... Calabrese, F. (2024). ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 43(3), 403-413. https://doi.org/10.1016/j.healun.2023.10.002

ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION. / Lunardi, Francesca; Vedovelli, Luca; Pezzuto, Federica et al.
In: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, Vol. 43, No. 3, 2024, p. 403-413.

Research output: Contribution to journal › Journal article › Research › peer-review

Lunardi, F, Vedovelli, L, Pezzuto, F, Le Pavec, J, Dorfmuller, P, Ivanovic, M, Pena, T, Wassilew, K, Perch, M, Hirschi, S, Chenard, M-P, Sosa, RA, Goddard, M, Neil, D, Montero-Fernandez, A, Rice, A, Cozzi, E, Rea, F, Levine, DJ, Roux, A, Fishbein, GA & Calabrese, F 2024, 'ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION', The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, vol. 43, no. 3, pp. 403-413. https://doi.org/10.1016/j.healun.2023.10.002

Lunardi F, Vedovelli L, Pezzuto F, Le Pavec J, Dorfmuller P, Ivanovic M et al. ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2024;43(3):403-413. Epub 2023 Oct 6. doi: 10.1016/j.healun.2023.10.002

@article{5c278683948344da8e97a0c05c1e06ea,

title = "ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION",

abstract = "BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients.METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed.RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25\%.CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.",

keywords = "antibody-mediated rejection, antibody-mediated rejection (AMR), lung transplantation, mammalian target of rapamycin (mTOR) pathway, phosphorylated s6 ribosomal protein (p-S6RP)",

author = "Francesca Lunardi and Luca Vedovelli and Federica Pezzuto and \{Le Pavec\}, Jerome and Peter Dorfmuller and Marina Ivanovic and Tahuanty Pena and Katharina Wassilew and Michael Perch and Sandrine Hirschi and Marie-Pierre Chenard and Sosa, \{Rebecca A\} and Martin Goddard and Desley Neil and Angeles Montero-Fernandez and Alexandra Rice and Emanuele Cozzi and Federico Rea and Levine, \{Deborah J\} and Antoine Roux and Fishbein, \{Gregory A\} and Fiorella Calabrese",

note = "Copyright {\textcopyright} 2023. Published by Elsevier Inc.",

year = "2024",

doi = "10.1016/j.healun.2023.10.002",

language = "English",

volume = "43",

pages = "403--413",

journal = "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",

issn = "1053-2498",

publisher = "Elsevier Inc.",

number = "3",

}

TY - JOUR

T1 - ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION

AU - Lunardi, Francesca

AU - Vedovelli, Luca

AU - Pezzuto, Federica

AU - Le Pavec, Jerome

AU - Dorfmuller, Peter

AU - Ivanovic, Marina

AU - Pena, Tahuanty

AU - Wassilew, Katharina

AU - Perch, Michael

AU - Hirschi, Sandrine

AU - Chenard, Marie-Pierre

AU - Sosa, Rebecca A

AU - Goddard, Martin

AU - Neil, Desley

AU - Montero-Fernandez, Angeles

AU - Rice, Alexandra

AU - Cozzi, Emanuele

AU - Rea, Federico

AU - Levine, Deborah J

AU - Roux, Antoine

AU - Fishbein, Gregory A

AU - Calabrese, Fiorella

PY - 2024

Y1 - 2024

N2 - BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients.METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed.RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%.CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

AB - BACKGROUND: Pulmonary antibody-mediated rejection is still a challenging diagnosis as C4d immunostaining has poor sensitivity. Previous studies have indicated that the phosphorylated S6 ribosomal protein, a component of the mammalian target of rapamycin (mTOR) pathway, is correlated with de novo donor-specific antibodies in lung transplantation. The objective of this study was to evaluate the phosphorylation of S6 ribosomal protein as a surrogate for antibody-mediated rejection diagnosis in lung transplant patients.METHODS: This multicentre retrospective study analyzed transbronchial biopsies from 216 lung transplanted patients, 114 with antibody-mediated rejection and 102 without (19 with acute cellular rejection, 17 with ischemia/reperfusion injury, 18 with infection, and 48 without post-transplant complications). Immunohistochemistry was used to quantify phosphorylated S6 ribosomal protein expression in macrophages, endothelium, epithelium, and inter-pathologist agreement was assessed.RESULTS: Median phosphorylated S6 ribosomal protein expression values were higher in antibody-mediated rejection cases than in controls for all cell components, with the highest sensitivity in macrophages (0.9) and the highest specificity in endothelial expression (0.8). The difference was mainly significant in macrophages compared to other post-lung transplantation complications. Inter-pathologist agreement was moderate for macrophages and endothelium, with higher agreement when phosphorylated S6 ribosomal protein expression was dichotomized into positive/negative. The inclusion of phosphorylated S6 ribosomal protein in the diagnostic algorithm could have increased antibody-mediated rejection certainty levels by 25%.CONCLUSIONS: The study supports the role of the mTOR pathway in antibody-mediated rejection-related graft injury and suggests that tissue phosphorylation of S6 ribosomal protein could be a useful surrogate for a more accurate pathological diagnosis of lung antibody-mediated rejection.

KW - antibody-mediated rejection

KW - antibody-mediated rejection (AMR)

KW - lung transplantation

KW - mammalian target of rapamycin (mTOR) pathway

KW - phosphorylated s6 ribosomal protein (p-S6RP)

UR - https://www.scopus.com/pages/publications/85179721082

U2 - 10.1016/j.healun.2023.10.002

DO - 10.1016/j.healun.2023.10.002

M3 - Journal article

C2 - 37806601

SN - 1053-2498

VL - 43

SP - 403

EP - 413

JO - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

JF - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

IS - 3

ER -

ASSESSING THE ROLE OF PHOSPHORYLATED S6 RIBOSOMAL PROTEIN IN THE PATHOLOGICAL DIAGNOSIS OF PULMONARY ANTIBODY-MEDIATED REJECTION

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Keywords

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