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Published in: Clinical and Experimental Nephrology 2/2018

01-04-2018 | Original article

Allo-specific immune response profiles indicative of acute rejection in kidney allografts using an in vitro lymphocyte culture-based model

Authors: Sobhana Mahakur, Biman Saikia, Mukut Minz, Ranjana W. Minz, Ritambhra Nada, Shashi Anand, Ashish Sharma, Vivekanand Jha, Neha Joshi, Lekha Goel, Amit Arora, Kusum Joshi

Published in: Clinical and Experimental Nephrology | Issue 2/2018

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Abstract

Background

Ability to predict the manner in which a recipient’s immune system would respond to a transplanted graft by analyzing cytokine profiles of the “allograft antigen sensitized” recipient lymphocytes in vitro might provide a means to identify patients at risk to adverse clinical endpoints.

Methods

Cytokine/chemokine gene expression profiles of peripheral blood mononuclear cells co-cultured with allograft antigen-pulsed macrophages were studied in 49 renal transplant recipients—12 with acute cellular rejection (ACR) with or without antibody-mediated rejection (AMR), 7 with AMR (without ACR), and 30 with stable allografts (SA). An 86-gene inflammatory cytokines and receptors PCR array was used to measure fold changes in gene expression between pulsed and un-pulsed cultures.

Results

On linear discriminant analysis and multivariate analysis of variance, a gene set comprising C3, CCL3, IL1B, TOLLIP, IL10, CXCL5, ABCF1, CCR3, IL10RB, CXCL1, and IL1R1 differentiated the ACR–AMR from the SA group. Similarly, a gene set comprising IL10, C3, IL37, IL1B, CCL3, CARD18, and TOLLIP differentiated the AMR from the SA group. No significant difference was found between the ACR–AMR vs AMR groups.

Conclusion

Distinct post in vitro stimulation cytokine profiles at the time of transplantation thus correlated with the occurrence of post-transplantation rejection episodes which indicated feasibility of this in vitro model to assess the recipient’s anti-graft response at an early stage.
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Literature
1.
go back to reference Strehlau J, Pavlakis M, Lipman M, et al. Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation. Proc Natl Acad Sci USA. 1997;94:695–700.CrossRefPubMedPubMedCentral Strehlau J, Pavlakis M, Lipman M, et al. Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation. Proc Natl Acad Sci USA. 1997;94:695–700.CrossRefPubMedPubMedCentral
2.
go back to reference Suthanthiran M. Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction. Am J Med Sci. 1997;313:264–7.PubMed Suthanthiran M. Clinical application of molecular biology: a study of allograft rejection with polymerase chain reaction. Am J Med Sci. 1997;313:264–7.PubMed
3.
go back to reference Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identifies by DNA micro-array profiling. N Eng J Med. 2003;349:125–38.CrossRef Sarwal M, Chua MS, Kambham N, et al. Molecular heterogeneity in acute renal allograft rejection identifies by DNA micro-array profiling. N Eng J Med. 2003;349:125–38.CrossRef
4.
go back to reference Flechner SM, Kurian SM, Head SR, et al. Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes. Am J Transplant. 2004;4:1475–89.CrossRefPubMedPubMedCentral Flechner SM, Kurian SM, Head SR, et al. Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes. Am J Transplant. 2004;4:1475–89.CrossRefPubMedPubMedCentral
5.
go back to reference Saint-Mezard P, Berthier CC, Zhang H, et al. Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection. Transplant Inter. 2009;22:293–302.CrossRef Saint-Mezard P, Berthier CC, Zhang H, et al. Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection. Transplant Inter. 2009;22:293–302.CrossRef
6.
go back to reference Alakulppi Noora, Seikku Paula, Jaatinen Taina, et al. Feasibility of diagnosing subclinical renal allograft rejection in children by whole blood gene expression analysis. Transplantation. 2008;86:1222–8.CrossRefPubMed Alakulppi Noora, Seikku Paula, Jaatinen Taina, et al. Feasibility of diagnosing subclinical renal allograft rejection in children by whole blood gene expression analysis. Transplantation. 2008;86:1222–8.CrossRefPubMed
7.
go back to reference Reevea J, Sellarés J, Mengela M, et al. Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies. Am J Transplant. 2013;13:645–55.CrossRef Reevea J, Sellarés J, Mengela M, et al. Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies. Am J Transplant. 2013;13:645–55.CrossRef
8.
go back to reference Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014;14:255–71.CrossRefPubMedPubMedCentral Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014;14:255–71.CrossRefPubMedPubMedCentral
9.
go back to reference Thomas KA, Valenzuela NM, Reed EF. The perfect storm: HLA antibodies, complement, FCγRs, and endothelium in transplant rejection. Trends Mol Med. 2015;21(5):319–29.CrossRefPubMedPubMedCentral Thomas KA, Valenzuela NM, Reed EF. The perfect storm: HLA antibodies, complement, FCγRs, and endothelium in transplant rejection. Trends Mol Med. 2015;21(5):319–29.CrossRefPubMedPubMedCentral
10.
go back to reference Vijayagopal P, Srinivasan SR, Radhakrishnamurthy B, et al. Lipoprotein-proteoglycan complexes from atherosclerotic lesions promote cholesteryl ester accumulation in human monocytes/macrophages. Arterioscler Thromb Vasc Biol. 1992;12:237–49.CrossRef Vijayagopal P, Srinivasan SR, Radhakrishnamurthy B, et al. Lipoprotein-proteoglycan complexes from atherosclerotic lesions promote cholesteryl ester accumulation in human monocytes/macrophages. Arterioscler Thromb Vasc Biol. 1992;12:237–49.CrossRef
11.
go back to reference Huang D, Quan Y, He M, Zhao B. Comparison of linear discriminant analysis methods for the classification of cancer based on gene expression data. J Exp Clin Can Res. 2009;28:149. doi:10.1186/1756-9966-28-149.CrossRef Huang D, Quan Y, He M, Zhao B. Comparison of linear discriminant analysis methods for the classification of cancer based on gene expression data. J Exp Clin Can Res. 2009;28:149. doi:10.​1186/​1756-9966-28-149.CrossRef
12.
go back to reference Avihingsanon Y, Ma N, Pavlakis M, et al. On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes. J Am Soc Nephrol. 2005;16:1542–8.CrossRefPubMedPubMedCentral Avihingsanon Y, Ma N, Pavlakis M, et al. On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes. J Am Soc Nephrol. 2005;16:1542–8.CrossRefPubMedPubMedCentral
13.
go back to reference Suthanthiran M, Schwartz JE, Ding R, et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Eng J Med. 2013;369:20–31.CrossRef Suthanthiran M, Schwartz JE, Ding R, et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Eng J Med. 2013;369:20–31.CrossRef
14.
go back to reference He H, Stone JR, Perkins DL. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation. Immunology. 2003;109:185–96.CrossRefPubMedPubMedCentral He H, Stone JR, Perkins DL. Analysis of differential immune responses induced by innate and adaptive immunity following transplantation. Immunology. 2003;109:185–96.CrossRefPubMedPubMedCentral
15.
go back to reference Segerer S, Cui Y, Eitner F, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis. 2001;37:518.CrossRefPubMed Segerer S, Cui Y, Eitner F, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis. 2001;37:518.CrossRefPubMed
16.
go back to reference Ruster M, Sperschneider H, Funfstuck R, et al. Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol. 2004;61:30.CrossRefPubMed Ruster M, Sperschneider H, Funfstuck R, et al. Differential expression of beta-chemokines MCP-1 and RANTES and their receptors CCR1, CCR2, CCR5 in acute rejection and chronic allograft nephropathy of human renal allografts. Clin Nephrol. 2004;61:30.CrossRefPubMed
17.
go back to reference Mayer V, Hudkins KL, Heller F, et al. Expression of the chemokine receptor CCR1 in human renal allografts. Nephrol Dial Transplant. 2007;22:1720.CrossRefPubMed Mayer V, Hudkins KL, Heller F, et al. Expression of the chemokine receptor CCR1 in human renal allografts. Nephrol Dial Transplant. 2007;22:1720.CrossRefPubMed
18.
go back to reference D’Ambrosio D, Panina-Bordignon P, Sinigaglia F. Chemokine receptors in inflammation: an overview. J Immunol Methods. 2003;273:3.CrossRefPubMed D’Ambrosio D, Panina-Bordignon P, Sinigaglia F. Chemokine receptors in inflammation: an overview. J Immunol Methods. 2003;273:3.CrossRefPubMed
20.
go back to reference Mao Y, Wang M, Zhou Q, et al. CXCL10 and CXCL13 expression were highly upregulated in peripheral blood mononuclear cells in acute rejection and poor response to anti-rejection therapy. J Clin Immunol. 2011;31:414–8.CrossRefPubMed Mao Y, Wang M, Zhou Q, et al. CXCL10 and CXCL13 expression were highly upregulated in peripheral blood mononuclear cells in acute rejection and poor response to anti-rejection therapy. J Clin Immunol. 2011;31:414–8.CrossRefPubMed
21.
go back to reference Saxena A, Panigrahi A, Gupta S, et al. Frequency of T cell expressing Th1 and Th2 associated chemokine receptor in patients with renal allograft dysfunction. Transpl Proc. 2012;44:290–5.CrossRef Saxena A, Panigrahi A, Gupta S, et al. Frequency of T cell expressing Th1 and Th2 associated chemokine receptor in patients with renal allograft dysfunction. Transpl Proc. 2012;44:290–5.CrossRef
23.
go back to reference Kirk AD, Bollinger RR, Finn OJ. Rapid, comprehensive analysis of human cytokine mRNA and its application to the study of acute renal allograft rejection. Hum Immunol. 1995;43(2):113–28.CrossRefPubMed Kirk AD, Bollinger RR, Finn OJ. Rapid, comprehensive analysis of human cytokine mRNA and its application to the study of acute renal allograft rejection. Hum Immunol. 1995;43(2):113–28.CrossRefPubMed
24.
go back to reference van Geffen EW, van Caam AP, van Beuningen HM, Vitters EL, Schreurs W, van de Loo FA, et al. IL37 dampens the IL1β-induced catabolic status of human OA chondrocytes. Rheumatology (Oxford). 2017;56(3):351–61. van Geffen EW, van Caam AP, van Beuningen HM, Vitters EL, Schreurs W, van de Loo FA, et al. IL37 dampens the IL1β-induced catabolic status of human OA chondrocytes. Rheumatology (Oxford). 2017;56(3):351–61.
25.
go back to reference Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1-beta generation by pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001;8:649–57.CrossRefPubMed Druilhe A, Srinivasula SM, Razmara M, Ahmad M, Alnemri ES. Regulation of IL-1-beta generation by pseudo-ICE and ICEBERG, two dominant negative caspase recruitment domain proteins. Cell Death Differ. 2001;8:649–57.CrossRefPubMed
Metadata
Title
Allo-specific immune response profiles indicative of acute rejection in kidney allografts using an in vitro lymphocyte culture-based model
Authors
Sobhana Mahakur
Biman Saikia
Mukut Minz
Ranjana W. Minz
Ritambhra Nada
Shashi Anand
Ashish Sharma
Vivekanand Jha
Neha Joshi
Lekha Goel
Amit Arora
Kusum Joshi
Publication date
01-04-2018
Publisher
Springer Singapore
Published in
Clinical and Experimental Nephrology / Issue 2/2018
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-017-1469-7

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