Regulatory T cell biomarkers identify patients at risk of developing acute cellular rejection in the first year following heart transplantation
Ji-Young Kim1,2,3,4, Megan K Levings5,6,7, Scott J Tebbutt1,2,3,4.
1Prevention of Organ Failure Centre of Excellence (PROOF), Vancouver, BC, Canada; 2Medicine, University of British Columbia, Vancouver, BC, Canada; 3Heart Lung Innovation, Vancouver, BC, Canada; 4Providence Research, Providence Health Care Research Institute, Vancouver, Vancouver, BC, Canada; 5Surgery, University of British Columbia, Vancouver, BC, Canada; 6BC Children’s Hospital Research Institute, Vancouver, BC, Canada; 7Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
Biomarkers in Transplantation (BiT).
Background: Acute cellular rejection (ACR), an alloimmune response involving CD4+ and CD8+ T cells, is a leading cause of mortality and morbidity following heart transplantation. While immunosuppressive drugs such as corticosteroids and calcineurin inhibitors (e.g., cyclosporine, tacrolimus) have largely reduced ACR events immediately following transplantation, ACR remains a risk factor in the long-term, with outcomes including graft loss and death. The balance between a conventional versus regulatory CD4+ T cell alloimmune response is believed to play a major role in the development of ACR. Therefore tracking these cells following transplantation would elucidate if changes in these cell populations could signal ACR risk. Understanding this link could be an important step towards developing tools that can detect and/or prevent ACR.
Methods: To describe changes in conventional versus regulatory CD4+ T cells during the course of heart transplantation, we used a CD4+ T cell gene signature panel (TGS) that tracks CD4+ T conventional (Tconv) and regulatory cells (Treg) on longitudinal samples from 94 adult heart transplant recipients. We investigated Tconv and Treg levels pre-transplant vs. post-transplant, as well as between non-rejection and ACR samples. Also, we compared TGS with HEARTBiT assay, a gene expression assay for exclusionary diagnosis of ACR in heart transplant patients in the first year following transplantation, on ACR diagnosis performance while also investigating its prognostic utility.
Results: Compared to pre-transplant samples, non-rejection samples showed increased Treg- and decreased Tconv-gene expression while such differences were reduced in ACR samples. Within the post-transplant samples, we saw that the TGS panel could discriminate between ACR and non-rejection samples with comparable performance to the HEARTBiT assay. When HEARTBiT and TGS were combined, they showed improved specificity to HEARTBiT alone (up to 10% increase in specificity at the same sensitivity level). Furthermore, within the first two months following transplantation, Treg genes showed reduced expression in patients who had developed one or more ACR events. Reduced Treg gene expression was positively associated with younger recipient age and higher intra-patient tacrolimus variability.
Conclusion: We demonstrated that expression of genes associated with CD4+ Tconvs and Tregs could identify patients at greater risk of ACR. Also, complementing HEARTBiT with TGS improved the diagnostic performance of HEARTBiT. Taken together, these biomarker tools may have clinical utility in heart transplant care.
This work was supported by the Canadian Institute for Health Research, the Canadian Foundation for Innovation, Genome Canada and British Columbia, the Mathematics of Information Technology and Complex Systems (Mitacs), Michael Smith Health Research BC, the PROOF Centre of Excellence, IBM, Novartis, and Astellas.
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