. 2023 Aug 1;107(8):1810-1819.

doi: 10.1097/TP.0000000000004607. Epub 2023 Jul 20.

Regulatory T Cell Biomarkers Identify Patients at Risk of Developing Acute Cellular Rejection in the First Year Following Heart Transplantation

Ji-Young V Kim^{1

2

3

4}, Sara Assadian^{1

3

4}, Zsuzsanna Hollander^{1

3

4}, Paloma Burns^{1

3

4}, Casey P Shannon^{1

3

4}, Karen Lam^{1

3

4}, Mustafa Toma⁵, Andrew Ignaszewski⁵, Ross A Davies⁶, Diego Delgado⁷, Haissam Haddad⁸, Debra Isaac⁹, Daniel Kim⁹, Alice Mui¹⁰, Miroslaw Rajda¹¹, Lori West¹², Michel White¹³, Shelley Zieroth¹⁴, Paul A Keown¹⁵, W Robert McMaster¹⁶, Raymond T Ng^{1

17}, Bruce M McManus^{1

18}, Megan K Levings^{10

19

20}, Scott J Tebbutt^{1

2

3

4}

Affiliations

¹ Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, BC, Canada.
² Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
⁴ Providence Research, Providence Health Care Research Institute, Vancouver, BC, Canada.
⁵ Department of Cardiology, University of British Columbia, Vancouver, BC, Canada.
⁶ Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁷ University Health Network/Mount Sinai Hospital, Toronto, ON, Canada.
⁸ Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
⁹ Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹⁰ Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Medicine, Dalhousie University, Halifax, NS, Canada.
¹² Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
¹³ Institut de Cardiologie de Montréal, Montréal, QC, Canada.
¹⁴ Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.
¹⁵ Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada.
¹⁶ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.
¹⁸ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁹ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
²⁰ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.

PMID: 37365692
DOI: 10.1097/TP.0000000000004607

Regulatory T Cell Biomarkers Identify Patients at Risk of Developing Acute Cellular Rejection in the First Year Following Heart Transplantation

Ji-Young V Kim et al. Transplantation. 2023.

. 2023 Aug 1;107(8):1810-1819.

doi: 10.1097/TP.0000000000004607. Epub 2023 Jul 20.

Authors

Affiliations

¹ Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, BC, Canada.
² Department of Medicine, Division of Respiratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Centre for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
⁴ Providence Research, Providence Health Care Research Institute, Vancouver, BC, Canada.
⁵ Department of Cardiology, University of British Columbia, Vancouver, BC, Canada.
⁶ Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁷ University Health Network/Mount Sinai Hospital, Toronto, ON, Canada.
⁸ Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
⁹ Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹⁰ Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Medicine, Dalhousie University, Halifax, NS, Canada.
¹² Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
¹³ Institut de Cardiologie de Montréal, Montréal, QC, Canada.
¹⁴ Department of Medicine, University of Manitoba, Winnipeg, MB, Canada.
¹⁵ Department of Medicine, Division of Nephrology, University of British Columbia, Vancouver, BC, Canada.
¹⁶ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Computer Science, University of British Columbia, Vancouver, BC, Canada.
¹⁸ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁹ BC Children's Hospital Research Institute, Vancouver, BC, Canada.
²⁰ School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.

PMID: 37365692
DOI: 10.1097/TP.0000000000004607

Abstract

Background: Acute cellular rejection (ACR), an alloimmune response involving CD4+ and CD8+ T cells, occurs in up to 20% of patients within the first year following heart transplantation. The balance between a conventional versus regulatory CD4+ T cell alloimmune response is believed to contribute to developing ACR. Therefore, tracking these cells may elucidate whether changes in these cell populations could signal ACR risk.

Methods: We used a CD4+ T cell gene signature (TGS) panel that tracks CD4+ conventional T cells (Tconv) and regulatory T cells (Treg) on longitudinal samples from 94 adult heart transplant recipients. We evaluated combined diagnostic performance of the TGS panel with a previously developed biomarker panel for ACR diagnosis, HEARTBiT, while also investigating TGS' prognostic utility.

Results: Compared with nonrejection samples, rejection samples showed decreased Treg- and increased Tconv-gene expression. The TGS panel was able to discriminate between ACR and nonrejection samples and, when combined with HEARTBiT, showed improved specificity compared with either model alone. Furthermore, the increased risk of ACR in the TGS model was associated with lower expression of Treg genes in patients who later developed ACR. Reduced Treg gene expression was positively associated with younger recipient age and higher intrapatient tacrolimus variability.

Conclusions: We demonstrated that expression of genes associated with CD4+ Tconv and Treg could identify patients at risk of ACR. In our post hoc analysis, complementing HEARTBiT with TGS resulted in an improved classification of ACR. Our study suggests that HEARTBiT and TGS may serve as useful tools for further research and test development.

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Conflict of interest statement

The authors declare no conflicts of interest.

References

1. Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010;25:61–74.
1. Khush KK, Cherikh WS, Chambers DC, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report—2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38:1056–1066.
1. San Segundo D, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4 CD25 FOXP3 regulatory T cells in renal transplant recipients. Transplantation. 2006;82:550–557.
1. Loupy A, Aubert O, Orandi BJ, et al. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019;366:l4923.
1. Chung BH, Oh HJ, Piao SG, et al. Clinical significance of the ratio between FOXP3 positive regulatory T cell and interleukin-17 secreting cell in renal allograft biopsies with acute t-cell-mediated rejection. Immunology. 2012;136:344–351.

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Regulatory T Cell Biomarkers Identify Patients at Risk of Developing Acute Cellular Rejection in the First Year Following Heart Transplantation

Affiliations

Regulatory T Cell Biomarkers Identify Patients at Risk of Developing Acute Cellular Rejection in the First Year Following Heart Transplantation

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials