Observational Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Aug 24, 2017; 7(4): 222-234
Published online Aug 24, 2017. doi: 10.5500/wjt.v7.i4.222
Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant
Francisco Salcido-Ochoa, Susan Swee-Shan Hue, Siyu Peng, Zhaoxiang Fan, Reiko Lixiang Li, Jabed Iqbal, John Carson Allen Jr, Alwin Hwai Liang Loh
Francisco Salcido-Ochoa, Tregs and HLA Research Force and Renal Medicine Department, Singapore General Hospital, Singapore 169856, Singapore
Susan Swee-Shan Hue, Tregs and HLA Research Force and Department of Pathology, National University Hospital, Singapore 119074, Singapore
Siyu Peng, Zhaoxiang Fan, Tregs and HLA Research Force and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore
Reiko Lixiang Li, Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore
Jabed Iqbal, Alwin Hwai Liang Loh, Department of Pathology, Singapore General Hospital, Singapore 169856, Singapore,
John Carson Allen Jr, Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore 169856, Singapore
Author contributions: Salcido-Ochoa F designed the study, revised all the collected data, analysed data, wrote and revised the paper; Hue SSS, Iqbal J and Loh AHL analysed histopathological data and revised the paper; Peng S and Fan Z collected clinical data and plotted the data; Li RL performed the immunohistochemistry experiments and collected clinical data; Allen Jr JC performed and supervised statistical analysis, and revised the paper.
Supported by National Kidney Foundation Singapore, No. NKFRC/2008/07/22; the Medicine Academic Clinical Program (a SingHealth-Duke/National University of Singapore Joint Partnership); and the Khoo Scholar Programme (Duke/National University of Singapore).
Institutional review board statement: The study protocol was approved by the Centralised Institutional Review Board of SingHealth, Singapore (approval No. 2009/615/E).
Informed consent statement: Signed informed consent was taken from all participants before being subjected to a kidney transplant biopsy, which was clinically indicated and not an experimental procedure in our protocol.
Conflict-of-interest statement: There is no conflict of interest among the authors or the participating institutions, and the authors do not have any financial relationships to disclose.
Data sharing statement: De-identified data was shared among few of the authors for the purpose of data analysis. No data was shared to third parties.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Francisco Salcido-Ochoa, MD (Mex), MRCP (UK), MSc (UK), PhD (UK), Consultant and Transplant Immunologist, Tregs and HLA Research Force and Renal Medicine Department, Singapore General Hospital, 20 College Road, Academia, Level 3, Singapore 169856, Singapore. francisco.salcido.ochoa@singhealth.com.sg
Telephone: +65-63266165 Fax: +65-62602308
Received: January 28, 2017
Peer-review started: February 8, 2017
First decision: May 8, 2017
Revised: June 6, 2017
Accepted: June 30, 2017
Article in press: July 3, 2017
Published online: August 24, 2017

To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes.


A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively.


In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3+ regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3+ regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss.


Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.

Keywords: Acute T cell-mediated rejection in the kidney transplant, Banff classification, Cytotoxic T cell, Regulatory T cell, Th17 cell

Core tip: In the clinical setting, acute T cell-mediated rejection in the kidney transplant (ATCMR-KTx) is only confirmed through a kidney transplant biopsy, which is scored according to the Banff classification. The Banff classification is largely based on the estimation of mononuclear cell infiltration instead of the identification and quantification of the actual T cell subsets recruited to mediate rejection. Therefore, a more detailed analysis of the inflammatory infiltrate of ATCMR-KTx is likely to enhance the diagnostic accuracy of the Banff classification. In our analyses, ATCMR-KTx appeared to be characterised by a numerical dominance of cytotoxic T lymphocytes over regulatory T cells in comparison to the absence of acute rejection. We also found an association of the numbers of infiltrating Th17 cells with kidney transplant outcomes. Although this is a small pilot study, it further supports our suspicion that the immune balance in ATCMR-KTx is tilted towards the pro-rejection forces.