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CD45RC Expression of Circulating CD8⁺ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

ABSTRACT: Predictive biomarkers of acute rejection (AR) are lacking. Pre-transplant expression of CD45RC on blood CD8⁺ T cells has been shown to predict AR in kidney transplant (KT) patients. The objective of the present study was to study CD45RC expression in a large cohort of KT recipients exposed to modern immunosuppressive regimens. CD45RC expression on T cells was analyzed in 128 KT patients, where 31 patients developed AR, of which 24 were found to be T-cell mediated (TCMR). Pre-transplant CD4⁺ and CD8⁺ CR45RC^high T cell proportions were significantly higher in patients with AR. The frequency of CD45RC^high T cells was significantly associated with age at transplantation but was not significantly different according to gender, history of transplantation, pre-transplant immunization, and de novo donor specific anti-Human Leucocyte Antigen (HLA) antibody. Survival-free AR was significantly better in patients with CD8⁺ CD45RC^high T cells below 58.4% (p = 0.0005), but not different according to CD4⁺ T cells (p = 0.073). According to multivariate analysis, CD8⁺ CD45RC^high T cells above 58.4% increased the risk of AR 4-fold (HR 3.96, p = 0.003). Thus, pre-transplant CD45RC expression on CD8⁺ T cells predicted AR, mainly TCMR, in KT patients under modern immunosuppressive therapies. We suggest that CD45RC expression should be evaluated in a prospective study to validate its usefulness to quantify the pre-transplant risk of AR.

SUBMITTER: Lemerle M

PROVIDER: S-EPMC6723395 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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CD45RC Expression of Circulating CD8<sup>+</sup> T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

Lemerle Marie M Garnier Anne-Sophie AS Planchais Martin M Brilland Benoit B Subra Jean-François JF Blanchet Odile O Blanchard Simon S Croue Anne A Duveau Agnès A Augusto Jean-François JF

Journal of clinical medicine 20190801 8

Predictive biomarkers of acute rejection (AR) are lacking. Pre-transplant expression of CD45RC on blood CD8<sup>+</sup> T cells has been shown to predict AR in kidney transplant (KT) patients. The objective of the present study was to study CD45RC expression in a large cohort of KT recipients exposed to modern immunosuppressive regimens. CD45RC expression on T cells was analyzed in 128 KT patients, where 31 patients developed AR, of which 24 were found to be T-cell mediated (TCMR). Pre-transplan ...[more]

PMID: 31374966

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Project description:BackgroundBiological biomarkers to stratify cancer risk before kidney transplantation are lacking. Several data support that tumor development and growth is associated with a tolerant immune profile. T cells expressing low levels of CD45RC preferentially secrete regulatory cytokines and contain regulatory T cell subset. In contrast, T cells expressing high levels of CD45RC have been shown to secrete proinflammatory cytokines, to drive alloreactivity and to predict acute rejection (AR) in kidney transplant patients. In the present work, we evaluated whether pre-transplant CD45RClow T cell subset was predictive of post-transplant cancer occurrence.MethodsWe performed an observational cohort study of 89 consecutive first time kidney transplant patients whose CD45RC T cell expression was determined by flow cytometry before transplantation. Post-transplant events including cancer, AR, and death were assessed retrospectively.ResultsAfter a mean follow-up of 11.1±4.1 years, cancer occurred in 25 patients (28.1%) and was associated with a decreased pre-transplant proportion of CD4+CD45RChigh T cells, with a frequency below 51.9% conferring a 3.7-fold increased risk of post-transplant malignancy (HR 3.71 [1.24-11.1], p = 0.019). The sensibility, specificity, negative predictive and positive predictive values of CD4+CD45RChigh<51.9% were 84.0, 54.7, 89.8 and 42.0% respectively. Confirming our previous results, frequency of CD8+CD45RChigh T cells above 52.1% was associated with AR, conferring a 20-fold increased risk (HR 21.7 [2.67-176.2], p = 0.0004). The sensibility, specificity, negative predictive and positive predictive values of CD8+CD45RChigh>52.1% were 94.5, 68.0, 34.7 and 98.6% respectively. Frequency of CD4+CD45RChigh T cells was positively correlated with those of CD8+CD45RChigh (p<0.0001), suggesting that recipients with high AR risk display a low cancer risk.ConclusionHigh frequency of CD45RChigh T cells was associated with AR, while low frequency was associated with cancer. Thus, CD45RC expression on T cells appears as a double-edged sword biomarker of promising interest to assess both cancer and AR risk before kidney transplantation.

Project description:Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential.

Dataset Information

CD45RC Expression of Circulating CD8⁺ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

Publications

CD45RC Expression of Circulating CD8<sup>+</sup> T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

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Dataset Information

CD45RC Expression of Circulating CD8+ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

Publications

CD45RC Expression of Circulating CD8<sup>+</sup> T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD45RC Expression of Circulating CD8⁺ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients.