Dataset Information

Sirolimus Increases T-Cell Abundance in the Sun Exposed Skin of Kidney Transplant Recipients.

ABSTRACT: BACKGROUND:Kidney transplant recipients (KTRs) receiving the mammalian target of rapamycin inhibitor sirolimus may display a reduced risk of skin cancer development compared to KTRs receiving calcineurin inhibitors. Despite studies investigating the effects of these 2 drug classes on T cells in patient blood, the effect these drugs may have in patient skin is not yet known. METHODS:Fifteen patients with chronic kidney disease (not recipients of immunosuppressive drugs), and 30 KTRs (15 receiving a calcineurin inhibitor, and 15 receiving sirolimus) provided matched samples of blood, sun exposed (SE) and non-SE skin. The abundance of total CD8+ and CD4+ T cells, memory CD8+ and CD4+ T cells, and regulatory T (Treg) cells in each sample was then assessed by flow cytometry. RESULTS:Sirolimus treatment significantly increased absolute numbers of CD4+ T cells, memory CD8+- and CD4+ T cells, and Treg cells in SE skin versus paired samples of non-SE skin. No differences were found in the absolute number of any T cell subset in the blood. Correlation analysis revealed that the percentage of T cell subsets in the blood does not always accurately reflect the percentage of T-cell subsets in the skin of KTRs. Furthermore, sirolimus significantly disrupts the balance of memory CD4+ T cells in the skin after chronic sun exposure. CONCLUSIONS:This study demonstrated that immunosuppressive drug class and sun exposure modify the abundance of multiple T-cell subsets in the skin of KTRs. Correlation analysis revealed that the prevalence of Treg cells in KTR blood does not accurately reflect the prevalence of Treg cells in KTR skin.

SUBMITTER: Burke MT

PROVIDER: S-EPMC5498012 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Sirolimus Increases T-Cell Abundance in the Sun Exposed Skin of Kidney Transplant Recipients.

Burke Michael Thomas MT Sambira Nahum Lauren C LC Isbel Nicole M NM Carroll Robert P RP Soyer Hans Peter HP Francis Ross R Bridge Jennifer Anne JA Hawley Carmel C Oliver Kimberly K Staatz Christine E CE Wells James William JW

Transplantation direct 20170606 7

<h4>Background</h4>Kidney transplant recipients (KTRs) receiving the mammalian target of rapamycin inhibitor sirolimus may display a reduced risk of skin cancer development compared to KTRs receiving calcineurin inhibitors. Despite studies investigating the effects of these 2 drug classes on T cells in patient blood, the effect these drugs may have in patient skin is not yet known.<h4>Methods</h4>Fifteen patients with chronic kidney disease (not recipients of immunosuppressive drugs), and 30 KTR ...[more]

PMID: 28706974

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Project description:Background and aimsAs conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal.Approach and resultsWe performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group.ConclusionsThis study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.

Project description:BackgroundSkin cancer is among the most common cancer types with an increasing global trend of incidence rate. This study explores the spatial distribution of skin cancer, considering body sites exposed and not exposed to sunshine separately.MethodsWe used 4302 skin cancer cases recorded by Fars Cancer Registry in south-western Iran for over 6 years (2011-2017). The variables included in the study were patients' residence address, gender, age, report date, and final topographical code. The patients' addresses were geocoded to the counties of the study area. Skin cancer sites were categorized based on sun exposure in male and female cases. We used the empirical Bayesian smoothing approach to smooth the skin cancer incidence rate at the county level to remove any potential population size bias. Finally, Anselin's Local Moran's Index and Getis Ord G* were used to identify the clustered and high-risk skin cancer geographical areas.ResultsThe incidence rates had an increasing trend from 14.28 per 100,000 people in 2011 to 17.87 per 100,000 people in 2016, however, it was decreased to 13.05 per 100,000 people in 2017. Out of 4302 patients with skin cancer, 2602 cases (60%) were male. The cancer cumulative incidence rate in males and females who were not exposed to sunshine was 7.80 and 14.18 per 100,000, respectively. The rates increased to 86.22 and 48.20 in males and females who were exposed to the sun. There were some high-risk spatial clusters of skin cancer in the study area. Further investigations are required to identify the underlying cause of the formation of these clusters.ConclusionsPatients exposed to sunshine, especially among the male group, experienced much higher rates of cancer occurrence as compared to unexposed individuals. With a heterogeneous spatial pattern, hotspots were identified in non-sun-exposed and sun-exposed categories in the study area. Researchers and policymakers can significantly benefit from the spatial analyses of skin cancer incidence. These analyses can provide useful and timely prevention policies as well as tailored monitoring techniques in high-risk regions.

Project description:Background and objectivesGraft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.Design, setting, participants, & measurementsUrine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.ResultsMean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules.ConclusionHigher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.

Dataset Information

Sirolimus Increases T-Cell Abundance in the Sun Exposed Skin of Kidney Transplant Recipients.

Publications

Sirolimus Increases T-Cell Abundance in the Sun Exposed Skin of Kidney Transplant Recipients.

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