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Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

ABSTRACT: 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.

SUBMITTER: Dedeoglu B

PROVIDER: S-EPMC4780739 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

Dedeoglu Burç B Meijers Ruud W J RW Klepper Mariska M Hesselink Dennis A DA Baan Carla C CC Litjens Nicolle H R NH Betjes Michiel G H MG

PloS one 20160307 3

<h4>Background</h4>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).<h4>Methods</h4>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 cir ...[more]

PMID: 26950734

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Project description:IntroductionAboriginal and Torres Strait Islander peoples (hereafter respectfully termed Indigenous Australians) experience a 3-fold increased risk of acute rejection after transplantation compared to non-Indigenous Australians. We investigated whether acute rejection explains the association between Indigenous status, infection-related deaths, and all-cause deaths after kidney transplantation, and whether acute rejection mediates the relationship between Indigenous status and overall graft loss.MethodsThis cohort study included all recipients who received their first kidney transplant between 2005 and 2018 in Australia, using data from the Australia and New Zealand Dialysis and Transplant registry. Multivariable Cox regression models determined the associations between Indigenous status, graft loss, infection-related deaths, and all-cause deaths. Mediation analyses examined if acute rejection mediated these relationships. Primary outcome was infection-related death. Secondary outcomes included all-cause death and overall graft loss.ResultsThere were 9993 patients (n = 390 (3.9%) Indigenous Australians) who received a kidney transplant between 2005 and 2018, and they were followed-up with for 56,876 patient-years. A total of 1165 died (12%) (211 infection-related deaths) and 1957 (20%) lost their allografts. Compared with non-Indigenous recipients, the adjusted hazard ratio (HR) (95% confidence interval [CI]) for graft loss, infection-related deaths and all-cause deaths among Indigenous Australians were 2.27 (1.90-2.71), 3.01 (1.90-4.77) and 2.36 (1.89-2.94), respectively. The mediation analysis showed the association between Indigenous status and graft loss (but not infection-related death or all-cause death) was partially mediated by acute rejection (1.06 [1.03-1.09]), and the proportion of effects mediated by acute rejection was 0.10.ConclusionIndigenous Australians experienced a higher risk of graft loss, a relationship mediated partially through acute rejection. The higher risk of infection-related death was independent of acute rejection.

Project description:Background and objectivesDefinition of individual risk profile is the first step to implement strategies to keep the delicate balance between under- and overimmunosuppression after kidney transplantation.Design, setting, participants, & measurementsWe used data from the Efficacy Limiting Toxicity Elimination Symphony Study (1190 patients between 2002 and 2004) to model risk of rejection and infection in the first year after kidney transplantation. External validation was performed in a study population from the Fixed-Dose Concentration-Controlled Trial (630 patients between 2003 and 2006).ResultsDespite different temporal dynamics, rejections and severe infections had similar overall incidences in the first year after transplantation (23.4% and 25.5%, respectively), and infections were the principal cause of death (43.2% of all deaths). Recipient older age, deceased donor, higher number of HLA mismatches, and high risk for cytomegalovirus disease were associated with infection; deceased donor, higher number of HLA mismatches, and immunosuppressive therapy including cyclosporin A (compared with tacrolimus), with rejection. These factors were integrated into a two-dimensional risk stratification model, which defined four risk groups: low risk for infection and rejection (30.8%), isolated risk for rejection (36.1%), isolated risk for infection (7.0%), and high risk for infection and rejection (26.1%). In internal validation, this model significantly discriminated the subgroups in terms of composite end point (low risk for infection/rejection, 24.4%; isolated risk for rejection and isolated risk for infection, 31.3%; high risk for infection/rejection, 54.4%; P<0.001), rejection episodes (isolated risk for infection and low risk for infection/rejection, 13.0%; isolated risk for rejection and high risk for infection/rejection, 24.2%; P=0.001), and infection episodes (low risk for infection/rejection and isolated risk for rejection, 12.0%; isolated risk for infection and high risk for infection/rejection, 37.6%; P<0.001). External validation confirmed the applicability of the model to an independent cohort.ConclusionsWe propose a two-dimensional risk stratification model able to disentangle the individual risk for rejection and infection in the first year after kidney transplantation. This concept can be applied to implement a personalized immunosuppressive and antimicrobial treatment approach.

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Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

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Loss of CD28 on Peripheral T Cells Decreases the Risk for Early Acute Rejection after Kidney Transplantation.

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