Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance

Lin Xie, Naotsugu Ichimaru, Miwa Morita, Jiajie Chen, Ping Zhu, Jihong Wang, Peter Urbanellis, Itay Shalev, Shizuko Nagao, Atsushi Sugioka, Liang Zhong, Norio Nonomura, Shiro Takahara, Gary A. Levy, Xiao Kang Li

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Here we examined whether the expression of a novel immunoregulatory gene set could be used to predict outcomes in murine models of rapamycin-induced cardiac tolerance, spontaneous hepatic tolerance, and cardiac rejection. The expression of the immunoregulatory gene set was assessed with the GeXP multiplex reverse-transcription polymerase chain reaction (RT-PCR) analysis system, and it was correlated to the pathological and biochemical parameters of the allografts. In rejecting cardiac grafts, the increased expression of an inflammatory set of genes, which included CD45, CD4, CD25, suppressor of cytokine signaling 2, cytotoxic T lymphocyte-associated protein 4 (CTLA4), selectin lymphocyte, interferon-γ (IFN-γ), programmed cell death 1 (Pdcd1), and granzyme B (Gzmb), was seen 8 days after transplantation along with histological evidence of severe allograft rejection. In tolerant cardiac allografts, the expression of fibrinogen-like protein 2 (Fgl2), Pdcd1, killer cell lectin-like receptor G1 (Klrg1), CTLA4, and lymphocyte-activation gene 3 was associated with tolerance. In a model of liver allograft tolerance, the increased expression of lectin galactose-binding soluble 1, Fgl2, CD39, phosphodiesterase 3B, Klrg1, forkhead box P3 (Foxp3), and transforming growth factor b as well as the inflammatory set of genes was observed 8 to 14 days after transplantation (ie, when there was severe inflammatory injury). At a later time when the liver allografts had been fully accepted and were histologically normal, the expression of the inflammatory set of genes returned to the baseline, but the expression of the tolerogenic set of genes was still increased. Genes that were expressed in tolerant cardiac and liver allografts included Fgl2, Klrg1, and Foxp3, whereas genes associated with rejection included CD25, Gzmb, and IFN-c. Our data indicate that monitoring the graft expression of a novel biomarker gene set with the GeXP multiplex RT-PCR analysis system may allow differentiation between rejection and tolerance.

Original languageEnglish
Pages (from-to)444-454
Number of pages11
JournalLiver Transplantation
Volume18
Issue number4
DOIs
Publication statusPublished - 01-04-2012

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Transplantation Tolerance
Biomarkers
Sensitivity and Specificity
NK Cell Lectin-Like Receptors
Allografts
Genes
Fibrinogen
Granzymes
Liver
Cytotoxic T-Lymphocytes
Interferons
Reverse Transcription
Programmed Cell Death 1 Receptor
Proteins
Transplantation
Type 3 Cyclic Nucleotide Phosphodiesterases
Galectins
Transplants
Selectins
Polymerase Chain Reaction

All Science Journal Classification (ASJC) codes

  • Surgery
  • Hepatology
  • Transplantation

Cite this

Xie, Lin ; Ichimaru, Naotsugu ; Morita, Miwa ; Chen, Jiajie ; Zhu, Ping ; Wang, Jihong ; Urbanellis, Peter ; Shalev, Itay ; Nagao, Shizuko ; Sugioka, Atsushi ; Zhong, Liang ; Nonomura, Norio ; Takahara, Shiro ; Levy, Gary A. ; Li, Xiao Kang. / Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance. In: Liver Transplantation. 2012 ; Vol. 18, No. 4. pp. 444-454.
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abstract = "Here we examined whether the expression of a novel immunoregulatory gene set could be used to predict outcomes in murine models of rapamycin-induced cardiac tolerance, spontaneous hepatic tolerance, and cardiac rejection. The expression of the immunoregulatory gene set was assessed with the GeXP multiplex reverse-transcription polymerase chain reaction (RT-PCR) analysis system, and it was correlated to the pathological and biochemical parameters of the allografts. In rejecting cardiac grafts, the increased expression of an inflammatory set of genes, which included CD45, CD4, CD25, suppressor of cytokine signaling 2, cytotoxic T lymphocyte-associated protein 4 (CTLA4), selectin lymphocyte, interferon-γ (IFN-γ), programmed cell death 1 (Pdcd1), and granzyme B (Gzmb), was seen 8 days after transplantation along with histological evidence of severe allograft rejection. In tolerant cardiac allografts, the expression of fibrinogen-like protein 2 (Fgl2), Pdcd1, killer cell lectin-like receptor G1 (Klrg1), CTLA4, and lymphocyte-activation gene 3 was associated with tolerance. In a model of liver allograft tolerance, the increased expression of lectin galactose-binding soluble 1, Fgl2, CD39, phosphodiesterase 3B, Klrg1, forkhead box P3 (Foxp3), and transforming growth factor b as well as the inflammatory set of genes was observed 8 to 14 days after transplantation (ie, when there was severe inflammatory injury). At a later time when the liver allografts had been fully accepted and were histologically normal, the expression of the inflammatory set of genes returned to the baseline, but the expression of the tolerogenic set of genes was still increased. Genes that were expressed in tolerant cardiac and liver allografts included Fgl2, Klrg1, and Foxp3, whereas genes associated with rejection included CD25, Gzmb, and IFN-c. Our data indicate that monitoring the graft expression of a novel biomarker gene set with the GeXP multiplex RT-PCR analysis system may allow differentiation between rejection and tolerance.",
author = "Lin Xie and Naotsugu Ichimaru and Miwa Morita and Jiajie Chen and Ping Zhu and Jihong Wang and Peter Urbanellis and Itay Shalev and Shizuko Nagao and Atsushi Sugioka and Liang Zhong and Norio Nonomura and Shiro Takahara and Levy, {Gary A.} and Li, {Xiao Kang}",
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Xie, L, Ichimaru, N, Morita, M, Chen, J, Zhu, P, Wang, J, Urbanellis, P, Shalev, I, Nagao, S, Sugioka, A, Zhong, L, Nonomura, N, Takahara, S, Levy, GA & Li, XK 2012, 'Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance', Liver Transplantation, vol. 18, no. 4, pp. 444-454. https://doi.org/10.1002/lt.22480

Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance. / Xie, Lin; Ichimaru, Naotsugu; Morita, Miwa; Chen, Jiajie; Zhu, Ping; Wang, Jihong; Urbanellis, Peter; Shalev, Itay; Nagao, Shizuko; Sugioka, Atsushi; Zhong, Liang; Nonomura, Norio; Takahara, Shiro; Levy, Gary A.; Li, Xiao Kang.

In: Liver Transplantation, Vol. 18, No. 4, 01.04.2012, p. 444-454.

Research output: Contribution to journalArticle

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AU - Zhu, Ping

AU - Wang, Jihong

AU - Urbanellis, Peter

AU - Shalev, Itay

AU - Nagao, Shizuko

AU - Sugioka, Atsushi

AU - Zhong, Liang

AU - Nonomura, Norio

AU - Takahara, Shiro

AU - Levy, Gary A.

AU - Li, Xiao Kang

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