• biomarkers
• dd-cfDNA
• immunity
• infection
• molecular diagnostics
• non-invasive
• rejection
• transplant

• Humans
• Graft Rejection/immunology
• Graft Rejection/diagnosis
• Biomarkers
• Risk Assessment
• Risk Factors
• Organ Transplantation/adverse effects
• Infections/etiology
• Infections/diagnosis
• Infections/immunology
• Biopsy

• Humans
• CD8-Positive T-Lymphocytes/immunology
• Animals
• Graft Rejection/immunology
• Organ Transplantation/adverse effects
• Graft Survival/immunology

• R01 AI113142 NIAID NIH HHS
• R01 AI160740 NIAID NIH HHS

• alloreactivity
• kidney transplantation
• operational tolerance
• regulatory B cells

• Humans
• Kidney Transplantation
• Male
• Female
• Middle Aged
• T-Lymphocytes, Regulatory/immunology
• Adult
• Immunologic Memory
• Memory T Cells/immunology
• B-Lymphocytes, Regulatory/immunology
• Graft Rejection/immunology
• Aged
• CD8-Positive T-Lymphocytes/immunology
• Transplantation Tolerance/immunology
• Prospective Studies
• Transplant Recipients
• Immune Tolerance
• Graft Survival/immunology

• 952512 European Union's Horizon
• European Union’s Horizon

• Chronic kidney disease
• Genetic associations
• Immune cell phenotypes
• Inflammatory proteins
• Mendelian randomization

• Humans
• Mendelian Randomization Analysis
• Renal Insufficiency, Chronic/genetics
• Renal Insufficiency, Chronic/immunology
• Genome-Wide Association Study
• Inflammation Mediators/metabolism
• Genetic Predisposition to Disease

• 82370724 National Natural Science Foundation of China

• TCR repertoire
• thymoglobulin
• transplant

• Kidney Transplantation/adverse effects
• Humans
• Antilymphocyte Serum/therapeutic use
• CD8-Positive T-Lymphocytes/immunology
• Male
• Tissue Donors
• Graft Rejection/immunology
• Graft Rejection/etiology
• Middle Aged
• Female
• Adult
• Receptors, Antigen, T-Cell/metabolism
• Receptors, Antigen, T-Cell/genetics
• Animals
• CD4-Positive T-Lymphocytes/immunology
• Prognosis
• Follow-Up Studies
• Kidney Failure, Chronic/surgery
• Kidney Failure, Chronic/immunology
• Rabbits
• Graft Survival/immunology
• Lymphocyte Depletion

• U01 AI063594 NIAID NIH HHS

• Humans
• Aged
• Kidney Transplantation/adverse effects
• Graft Rejection
• Immunosuppressive Agents/adverse effects
• Immunosuppression Therapy/adverse effects
• Immunosenescence
• Risk Assessment
• Renal Insufficiency, Chronic/drug therapy
• Inflammation/drug therapy

• age
• antibody-mediated rejection
• elderly
• graft survival
• kidney transplantation

• Aged
• Middle Aged
• Humans
• Adolescent
• Young Adult
• Adult
• Incidence
• Kidney Transplantation/adverse effects
• Antibodies
• Death
• Multivariate Analysis

• Clinical
• Outcomes
• Senescence
• T-cell
• Transplant

• Humans
• Organ Transplantation
• Heart Transplantation
• Liver Transplantation
• Lung Transplantation
• Transplant Recipients
• Aging
• Graft Rejection/diagnosis

• EIA-2017-013 Health Research Board

• T cell-mediated rejection
• age
• antibody-mediated rejection
• donor-specific antibodies
• graft survival
• immune suppression
• kidney transplantation
• mortality

• CD4+/CD8+ ratio
• HMGB1
• free light chains
• hemodialysis
• uremic toxin

• Glycolysis
• Glycometabolism
• Memory CD8(+)T cell
• mTOR

Biopsy-proven causes of graft loss many years after kidney transplantation are scarcely documented.

Patients transplanted between 1995 and 2005 (n = 737) in a single center were followed on a regular basis until 2021. The recipients were divided according to age at transplantation into 3 groups; 18–39 years (young), 40–55 years (middle age), and older than 55 years (elderly). For cause biopsies of renal transplants were clustered into the categories, rejection, IFTA, return original disease, and diagnosis of de novo kidney disease.

Rejection was the main cause of graft failure censored for death at every time period after transplantation. The incidence of T cell-mediated rejection (TCMR) became rare 6 years after transplantation while the cumulative incidence of antibody-mediated rejection (ABMR) increased over time (1.1% per year). ABMR was not diagnosed anymore beyond 15 years of follow-up in recipients without pre-transplant donor-specific antibodies (DSA). An episode of TCMR was associated with an increased incidence of ABMR diagnosis in the short-term but did not increase the overall incidence of AMBR not in the long-term. Death as a cause of graft failure was an important competitive risk factor long after transplantation and resulted in a significantly lower frequency of rejection-related graft loss in the elderly group (11 vs. 23% in the young group at 15 year follow-up).

Rejection is a major cause of graft loss but recipient’s age, time after transplantation, and the presence of DSA before transplantation determine the relative contribution to overall graft loss and the type of rejection involved.

• Nierstichting

• Jeanssons Stiftelser
• Magnus Bergvalls Stiftelse
• NOMIS Stiftung
• Max Planck Society

• Adaptive immunity
• Cytokines
• Cytotoxic T lymphocytes (CTLs)
• Cytotoxic-associated transcripts (CATs)
• Immunosuppression
• Kidney transplantation
• Rejection

Accelerated thymic involution is a main feature of end-stage renal disease (ESRD)-associated immune senescence. Recent evidences suggest that ESRD-associated immune senescence is associated with adverse outcomes in dialysis patients. However, no study focused on the association between pre-transplant thymic function and patient survival after transplantation. We conducted a prospective, multicenter study to assess whether pre-transplant thymic function measured by recent thymic emigrants (RTE) may predict death after first kidney transplantation. Results were tested in a validation cohort. Nine hundred and sixty-seven incident kidney transplant recipients were included in the prospective study. Mean follow up was 5.1 + 2.9 years. Eighty two patients (8.5%) died during follow up. Lower RTE levels were associated with a higher risk of death (2.53; 95%CI, 1.54–4.39 for each decrease of 1 log in RTE; p < 0.001). Cancer-related death was particularly increased in patients with low RTE levels (4.23; 95%CI, 1.43–12.13; p = 0.007). One hundred and thirty-six patients having received a first kidney transplantation were included in the validation cohort. Lower TREC levels were associated with higher risk of death (1.90; 95%CI, 1.11–3.51 for each decrease of 1 log in RTE; p = 0.025). RTE were not associated with death-censored graft loss. Pre-transplant thymic function is strongly associated with death after transplantation. Attempt to reverse ESRD-related thymic loss may prevent premature death.

• cancer
• death
• immune senescence
• kidney transplantation
• thymus

• Adult
• CD28 Antigens/genetics
• CD28 Antigens/immunology
• CD57 Antigens/genetics
• CD57 Antigens/immunology
• CD8-Positive T-Lymphocytes/classification
• CD8-Positive T-Lymphocytes/immunology
• Cross-Sectional Studies
• Female
• Gene Expression Profiling
• Graft Rejection/etiology
• Graft Rejection/genetics
• Graft Rejection/immunology
• Healthy Volunteers
• Humans
• Immunophenotyping
• In Vitro Techniques
• Kidney Transplantation/adverse effects
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Phenotype
• Receptors, CCR7/genetics
• Receptors, CCR7/immunology
• T-Lymphocyte Subsets/classification
• T-Lymphocyte Subsets/immunology

• Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea
• Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT

Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Naïve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. The expanding populations of memory T cells have a pro-inflammatory phenotype, add to low-grade inflammation already present in ESRD patients and destabilize atherosclerotic plaques. The effect of loss of renal function on the thymus is not reversed after restoring renal function by kidney transplantation and constitutes a long-term mortality risk factor. Promising results from animal experiments have shown that rejuvenation of the thymus is a possibility, although not yet applicable in humans.

• adaptive immunity
• chronic kidney disease
• immunological ageing
• lymphopenia
• thymus
• uremia

The hypothesis was tested that parameters of an aged T-cell compartment associate with the risk for late rejection after kidney transplantation.

Recipients of a kidney transplant in the period 2007–2013 were (N = 365) were included. T cells were characterized prior to transplantation by flow cytometry as naive (CD45RO^-CCR7⁺), central-memory (CD45RO⁺CCR7⁺), effector-memory (CD45RO^-CCR7^-) or terminally differentiated CD8⁺ Temra (CD45RO^-/CCR7^-/CD28^-) cells. T cell telomere length and thymic output were assessed prior to transplantation in 202 recipients. Follow-up was until December 2018. The date of the first time of biopsy-proven late rejection (>6 months after transplantation) was used to calculate the rejection-free survival time.

Fifty cases of biopsy-proven rejection were recorded. Thymic output and T cell telomere length did not associate with late rejection-free survival. However, the percentage and absolute numbers of CD8⁺Temra and CD28null CD8⁺ T cells were significantly lower in patients with late rejection. Specifically, in the highest tertile of percentages of CD28null CD8⁺ T cells, the cumulative incidence of late rejection at 5 and 10 years was only 5% and 8% compared to 16% and 20% in the middle to lowest tertile (p = 0.002). Multivariate proportional hazard analysis showed that percentage and absolute number of CD28null CD8⁺ T cells remained significantly associated with late rejection and rejection-related graft loss.

High numbers of differentiated CD28null CD8⁺ T cells decrease the risk for late rejection and rejection-related graft loss after kidney transplantation.

• Adult
• Aged
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/virology
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/virology
• Epstein-Barr Virus Infections/epidemiology
• Epstein-Barr Virus Infections/immunology
• Epstein-Barr Virus Infections/virology
• Female
• France/epidemiology
• Herpesvirus 4, Human/immunology
• Humans
• Kidney Transplantation/adverse effects
• Lymphopenia/etiology
• Lymphopenia/pathology
• Male
• Middle Aged
• Retrospective Studies
• Transplant Recipients/statistics & numerical data

• Ligue Contre le Cancer

Background: A previously proposed immune risk profile (IRP), based on T cell phenotype and CMV serotype, is associated with mortality in the elderly and increased infections post-kidney transplant. To evaluate if NK cells contribute to the IRP and if the IRP can be predicted by a clinical T cell functional assays, we conducted a cross sectional study in renal transplant candidates to determine the incidence of IRP and its association with specific NK cell characteristics and ImmuKnow® value.

Material and Methods: Sixty five subjects were enrolled in 5 cohorts designated by age and dialysis status. We determined T and NK cell phenotypes by flow cytometry and analyzed multiple factors contributing to IRP.

Results: We identified 14 IRP+ [CMV seropositivity and CD4/CD8 ratio < 1 or being in the highest quintile of CD8+ senescent (28CD–/CD57+) T cells] individuals equally divided amongst the cohorts. Multivariable linear regression revealed a distinct IRP+ group. Age and dialysis status did not predict immune senescence in kidney transplant candidates. NK cell features alone could discriminate IRP– and IRP+ patients, suggesting that NK cells significantly contribute to the overall immune status in kidney transplant candidates and that a combined T and NK cell phenotyping can provide a more detailed IRP definition. ImmuKnow® value was negatively correlated to age and significantly lower in IRP+ patients and predicts IRP when used alone or in combination with NK cell features.

Conclusion: NK cells contribute to overall immune senescence in kidney transplant candidates.

• BK virus
• NK cells
• dialysis
• end stage renal disease
• immune risk profile
• immune senescence
• kidney transplant

• biomarker
• immune system
• kidney transplantation

The positive long-term effects of conversion to everolimus (EVL) after heart transplantation (HT) have been evaluated in several studies. However, the timing of EVL initiation, the best way to combine it with other immunosuppressive treatments, and the impact of these combinations on the immune response are poorly understood aspects. Here, we analyzed the immune phenotype and function of HT patients (n = 56) at short and long terms (prospective and retrospective cohorts), taking into account the time of EVL initiation: early (3 months post-transplant, EVL-E group) or late (>1 year post-transplant, EVL-L group) compared with mycophenolate mofetil treatment (MMF group). We show that early EVL conversion from MMF allows the increase of cytotoxic (CD56^dim CD16⁺) NK and effector-memory (EM, CD45RA⁻ CCR7⁻) CD8⁺ T cell subsets, which show a significantly higher level of expression of cytotoxic molecules, IFN-γ production and degranulation ability under activation. NK cell expansion is accompanied by an altered balance of receptor expression, increasing the activation state, and lytic activity of those cells. Those changes are detected after as little as 1 month after EVL conversion in association with the expansion of regulatory T cells and the decrease in B cell frequency. However, no changes in the immune cells subsets were observed after late EVL initiation (EVL-L) compared with the MMF group. Our results imply that only early EVL conversion induces key changes in the post-transplant immune response, preserving an efficient anti-viral response, but simultaneously showing a limited ability to counteract the cytotoxic response to the allograft.

• CD8+ T cells
• DNA methylation
• NK cells
• cytotoxicity
• everolimus
• heart transplantation
• mTOR inhibitors

Singh et al. show that expression of B cell adaptor for PI3-kinase (BCAP) is induced upon T cell activation and that this helps control effector and memory CD8⁺ T cell differentiation.

CD8⁺ T cells respond to signals via the T cell receptor (TCR), costimulatory molecules, and immunoregulatory cytokines by developing into diverse populations of effector and memory cells. The relative strength of phosphoinositide 3-kinase (PI3K) signaling early in the T cell response can dramatically influence downstream effector and memory T cell differentiation. We show that initial PI3K signaling during T cell activation results in up-regulation of the signaling scaffold B cell adaptor for PI3K (BCAP), which further potentiates PI3K signaling and promotes the accumulation of CD8⁺ T cells with a terminally differentiated effector phenotype. Accordingly, BCAP-deficient CD8⁺ T cells have attenuated clonal expansion and altered effector and memory T cell development following infection with Listeria monocytogenes. Thus, induction of BCAP serves as a positive feedback circuit to enhance PI3K signaling in activated CD8⁺ T cells, thereby acting as a molecular checkpoint regulating effector and memory T cell development.

• Acute rejection
• Dialysis
• Immune senescence
• Inflammation
• Iron overload

• LABEX Lipstic

The regulatory function of CCR7⁺CD8⁺ T cells against effector T-cells involved in T-cell mediated rejection (TCMR) in kidney transplant recipients was investigated. In vitro experiments explored the ability of CCR7⁺CD8⁺ T cells to suppress T-cell proliferation under T-cell activation conditions or during coculture with human renal proximal tubular epithelial cells (HRPTEpiC). In an ex vivo experiment, the proportion of CCR7⁺/CD8⁺, FOXP3⁺/CCR7⁺CD8⁺ T and effector T-cell subsets were compared between the normal biopsy control (NC, n = 17) and TCMR group (n = 17). The CCR7⁺CD8⁺ T cells significantly suppressed the proliferation of CD4⁺ T cells and significantly decreased the proportion of IFN-γ⁺ and IL-17⁺/CD4⁺ T cells and inflammatory cytokine levels (all p < 0.05). After coculturing with HRPTEpiC, CCR7⁺CD8⁺ T cells also suppressed T-cell differentiation into IL-2⁺, IFN-γ⁺, and IL-17⁺/CD4⁺ T cells (all p < 0.05). The TCMR group had significantly fewer CCR7⁺/CD8⁺ and FOXP3⁺/CCR7⁺CD8⁺ T in comparison with the NC group, but the proportions of all three effector T-cell subsets were increased in the TCMR group (all p < 0.05). The proportion of CCR7⁺/CD8⁺ T was inversely correlated with those of effector T-cell subsets. The results indicate that CCR7⁺CD8⁺ T cells may regulate effector T-cells involved in TCMR in an in vitro and in an ex vivo transplant model.

Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C⁺ NK and Vδ2^negγδ T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2^negγδ T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2^negγδ T cells and terminally differentiated TCRαβ⁺ T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ⁺ T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.

• cytomegalovirus infections
• hematopoietic stem cell transplantation
• leukemia
• solid organ transplantation
• tolerance

The T-cell composition within the lymph node (LN) of end-stage renal disease (ESRD) patients differs from the composition within the circulation. Activation of the alloreactive T-cell response within secondary lymphoid organs is important after organ transplantation. However, to date no data are present on LN T-cell subsets and the risk for acute rejection after kidney transplantation.

T cells from LNs of ESRD patients were analyzed for frequency of recent thymic emigrants, relative telomere length, expression of differentiation markers, and were related to the development of early acute rejection (EAR), occurring within 3 months after renal transplantation (RT). Furthermore, the alloreactive potential of mononuclear cells isolated from the LN and peripheral blood of 10 patients was analyzed. Measures of alloreactive potential included proliferation, cytokine production, frequencies of interferon-gamma-producing cells, and the presence of cytotoxic molecules.

Patients with EAR were younger (p = 0.019), cytomegalovirus-seropositive (p = 0.037) and usually received dialysis prior to RT (p = 0.030). Next to this, patients with EAR showed a lower CD4:CD8 ratio (p = 0.027) within the LN. T cells from the LN were similar with regard to alloreactive capacity compared with those within the circulation. Univariate regression analysis showed that the CD4:CD8 ratio (OR: 0.67, p = 0.039), patient age (OR: 0.93, p = 0.024), and preemptive RT (OR: 0.11, p = 0.046) were associated with EAR. After a multivariate analysis, only the CD4:CD8 ratio (OR: 0.58, p = 0.019) and preemptive RT (OR:0.05, p = 0.012) were associated with EAR.

A lower CD4:CD8 ratio in the LN is associated with a higher risk for the development of rejection within 3 months after RT.

• T cells
• T-cell composition
• kidney transplantation
• lymph nodes
• rejection

• basic (laboratory) research/science
• flow cytometry
• immunobiology
• kidney (allograft) function/dysfunction
• kidney transplantation/nephrology
• macrophage/monocyte biology: activation
• macrophage/monocyte biology: trafficking
• pathology/histopathology
• rejection
• translational research/science

• Biomarker
• kidney transplantation
• lymphocyte
• personalized medicine
• rejection

BK polyomavirus (BKPyV) reactivation in kidney transplant recipients can lead to allograft damage and loss. The elements of the adaptive immune system that are permissive of reactivation and responsible for viral control remain incompletely described. We performed a prospective study evaluating BKPyV-specific T-cell response, humoral response and overall T-cell phenotype beginning pre-transplant through one year post-transplant in 28 patients at two centers. We performed an exploratory analysis of risk factors for the development of viremia and viruria as well as compared the immune response to BKPyV in these groups and those who remained BK negative. 6 patients developed viruria and 3 developed viremia. BKPyV-specific CD8⁺ T-cells increased post-transplant in viremic and viruric but not BK negative patients. BKPyV-specific CD4⁺ T-cells increased in viremic, but not viruric or BK negative patients. Anti-BKPyV IgG antibodies increased in viruric and viremic patients but remained unchanged in BK negative patients. Viremic patients had a greater proportion of CD8⁺ effector cells pre-transplant and at 12 months post-transplant. Viremic patients had fewer CD4⁺ effector memory cells at 3 months post-transplant. Exploratory analysis demonstrated lower CD4 and higher total CD8 proportions, higher anti-BKPyV antibody titers and the cause of renal failure were associated BKPyV reactivation. In conclusion, low CD4, high CD8 and increased effector CD8 cells were found pre-transplant in patients who became viremic, a phenotype associated with immune senescence. This pre-transplant T-cell senescence phenotype could potentially be used to identify patients at increased risk of BKPyV reactivation.

• Adult
• Aged
• Antibodies, Viral/biosynthesis
• BK Virus/genetics
• BK Virus/immunology
• BK Virus/physiology
• CD4-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/immunology
• DNA, Viral/analysis
• Female
• Humans
• Immunophenotyping
• Kidney Diseases/immunology
• Kidney Diseases/surgery
• Kidney Transplantation
• Male
• Middle Aged
• Prospective Studies
• Virus Activation

• R21 NS090951 NINDS NIH HHS

• chronic kidney disease
• t cell
• kidney transplant
• rejection

• Animals
• Graft Rejection/immunology
• Humans
• Kidney Transplantation/methods
• Renal Insufficiency, Chronic/immunology
• T-Lymphocytes/immunology

• K12 HD072245 NICHD NIH HHS
• R01 AI073707 NIAID NIH HHS
• R01 AI104699 NIAID NIH HHS

The role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included.

CpGs in the promoter regions of both IFNγ and PD1 were significantly (p < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNγ and PD1 inversely correlated with the percentage of IFNγ or PD1-producing cells. Before transplantation, the methylation status of both IFNγ and PD1 was not significantly different from healthy donors. At 3 months after transplantation, irrespective of rejection and subsequent anti-rejection therapy, the IFNy methylation was significantly higher in the differentiated effector memory CD45RA+ (EMRA) CD8+ T cells (p = 0.01) whereas the PD1 methylation was significantly higher in all memory CD8+ T cell subsets (CD27+ memory; p = 0.02: CD27− memory; p = 0.02: EMRA; p = 0.002). Comparing the increase in methylation in the first 3 months after transplantation between rejectors and non-rejectors demonstrated a significantly more prominent increase in the PD1 methylation in the CD27− memory CD8+ T cells in rejectors (increase in rejectors 14%, increase in non-rejectors 1.9%, p = 0.04). The increase in DNA methylation in the other memory CD8+ T cells was not significantly different between rejectors and non-rejectors. At 12 months after transplantation, the methylation of both IFNγ and PD1 returned to baseline levels.

The DNA methylation of both IFNγ and PD1 increases the first 3 months after transplantation in memory CD8+ T cells in kidney transplant recipients. This increase was irrespective of a rejection episode indicating that general factors of the kidney transplantation procedure, including the use of immunosuppressive medication, contribute to these variations in DNA methylation.

• Allograft rejection
• CD8 T-cell subset
• DNA methylation
• IFNγ
• Kidney transplant recipients
• PD1

• T cell biology
• basic (laboratory) research/science
• kidney transplantation/nephrology
• kidney transplantation: living donor

• CMV
• immune risk phenotype
• immune senescence
• infection
• transplantation

End-stage renal disease patients have a dysfunctional, prematurely aged peripheral T-cell system. Here we hypothesized that the degree of premature T-cell ageing before kidney transplantation predicts the risk for early acute allograft rejection (EAR).

222 living donor kidney transplant recipients were prospectively analyzed. EAR was defined as biopsy proven acute allograft rejection within 3 months after kidney transplantation. The differentiation status of circulating T cells, the relative telomere length and the number of CD31⁺ naive T cells were determined as T-cell ageing parameters.

Of the 222 patients analyzed, 30 (14%) developed an EAR. The donor age and the historical panel reactive antibody score were significantly higher (p = 0.024 and p = 0.039 respectively) and the number of related donor kidney transplantation was significantly lower (p = 0.018) in the EAR group. EAR-patients showed lower CD4⁺CD28null T-cell numbers (p<0.01) and the same trend was observed for CD8⁺CD28null T-cell numbers (p = 0.08). No differences regarding the other ageing parameters were found. A multivariate Cox regression analysis showed that higher CD4⁺CD28null T-cell numbers was associated with a lower risk for EAR (HR: 0.65, p = 0.028). In vitro, a significant lower percentage of alloreactive T cells was observed within CD28null T cells (p<0.001).

Immunological ageing-related expansion of highly differentiated CD28null T cells is associated with a lower risk for EAR.

• Adult
• Age Factors
• CD28 Antigens/deficiency
• CD28 Antigens/metabolism
• CD4-Positive T-Lymphocytes/cytology
• CD4-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/cytology
• CD8-Positive T-Lymphocytes/metabolism
• Cell Count
• Cell Differentiation
• Cellular Senescence
• Female
• Graft Rejection/immunology
• Humans
• Kidney Transplantation/adverse effects
• Male
• Middle Aged
• Risk
• T-Lymphocytes/cytology
• T-Lymphocytes/metabolism
• Telomere/genetics
• Thymus Gland/immunology

• basic (laboratory) research/science
• flow cytometry, monitoring: immune, T cell biology
• immunobiology

• CD28 Antigens/immunology
• CD28 Antigens/metabolism
• CD8-Positive T-Lymphocytes/classification
• CD8-Positive T-Lymphocytes/cytology
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Cell Differentiation
• Female
• Flow Cytometry
• Follow-Up Studies
• Humans
• Immunologic Memory/immunology
• Kidney Failure, Chronic/immunology
• Kidney Failure, Chronic/metabolism
• Kidney Failure, Chronic/surgery
• Kidney Transplantation
• Leukocyte Common Antigens/immunology
• Leukocyte Common Antigens/metabolism
• Male
• Middle Aged
• Prognosis
• Prospective Studies
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism
• Transplant Recipients

The study was aimed at assessing T cell subsets of peripheral blood from recipients of long-term functioning (more than 60 months) biological and mechanical heart valve prostheses. The absolute and relative number of CD4 and CD8 T cell subsets was analyzed: naïve (N, CD45RA⁺CD62L⁺), central memory (CM, CD45RA⁻CD62L⁺), effector memory (EM, CD45RA⁻CD62L⁻), and terminally differentiated CD45RA-positive effector memory (TEMRA, CD45RA⁺CD62L⁻) in 25 persons with biological and 7 with mechanical prosthesis compared with 48 apparently healthy volunteers. The relative and absolute number of central memory and naïve CD3⁺CD8⁺ in patients with biological prosthesis was decreased (p < 0.001). Meanwhile the number of CD45RA⁺CD62L⁻CD3⁺CD8⁺ and CD3⁺CD4⁺ was increased (p < 0.001). Patients with mechanical prosthesis had increased absolute and relative number of CD45RA⁺CD62L⁻CD3⁺CD8⁺ cells (p = 0.006). Also the relative number of CD3⁺CD4⁺ cells was reduced (p = 0.04). We assume that altered composition of T cell subsets points at development of xenograft rejection reaction against both mechanical and biological heart valve prostheses.

• cancer
• cytomegalovirus
• immunology
• renal transplantation
• risk factors

Infiltration of effector CD8 T cells plays a major role in allograft rejection, and increases in memory and terminally differentiated effector memory CD8 T cells are associated with long-term allograft dysfunction. Alternatively, CD8 regulatory T cells suppress the inflammatory responses of effector lymphocytes and induce allograft tolerance in animal models. Recently, there has been a renewed interest in the field of immunometabolics and its important role in CD8 function and differentiation. The purpose of this review is to highlight the key metabolic pathways involved in CD8 T cells and to discuss how manipulating these metabolic pathways could lead to new immunosuppressive strategies for the transplantation field.

• CD8 lymphocytes
• glycolysis
• metabolism
• mitochondria
• regulation
• therapeutics
• transplantation

• Cytomegalovirus (CMV)
• T cell biology
• donor-specific hyporesponsiveness
• hepatology
• immunobiology
• infection and infectious agents
• infectious disease
• liver transplantation
• rejection
• science
• tolerance
• translational research
• viral

End-stage renal disease (ESRD) patients have a defective T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated pro-inflammatory milieu, created by loss of renal function. Therefore, ESRD patients are highly susceptible for infections, have an increased risk for virus-associated cancers, respond poorly to vaccination and have an increased risk for atherosclerotic diseases. Three ageing parameters can be used to assess an immunological T-cell age. First, thymic output can be determined by assessing the T-cell receptor excision circles-content together with CD31 expression within the naïve T cells. Second, the telomere length of T cells and third the T-cell differentiation status are also indicators of T-cell ageing. Analyses based on these parameters in ESRD patients revealed that the immunological T-cell age is increased by on average 20 years compared to the chronological age. After kidney transplantation (KTx) the aged T-cell phenotype persists although the pro-inflammatory milieu is diminished. This might be explained by epigenetic modifications at hematopoietic stem cells level. Assessment of an immunological T-cell age could be an important tool to identify KTx recipients who are at risk for allograft rejection or to prevent over-immunosuppression.

• End-stage renal disease patients
• Kidney transplantation
• T-cell ageing
• T-cell differentiation
• Uremia