Place of Death for Young Adults With Chronic Illness.

BACKGROUND: Little is known about where young adults with chronic illness die in the United States and factors associated with place of death. OBJECTIVES: This study aimed to examine place of death and factors associated with place of death for young adults with chronic illness using the most recent national data. METHODS: Our sample ( N = 405,535) from the National Center for Health Statistics Division of Vital Statistics death certificate data (2003-2018) included young adults (age 18-39 years) who died from chronic conditions common in childhood or young adulthood. Conditions were grouped by underlying pathophysiology (oncological, cardiovascular, neuromuscular, metabolic, hematological/immunological, renal, chromosomal/congenital, gastrointestinal, and respiratory). Place of death was dichotomized into acute care (inpatient, outpatient/emergency room, and dead on arrival) or nonacute care (home, hospice, nursing home/long-term care, other, and unknown). Examined factors were gender, year of death, age, race (White, Black, Asian/Pacific Islander, American Indian/Alaskan Native), cause of death, and city of residence population (100,000 or greater and under 100,000). Descriptive statistics and logistic regression were used to examine factors related to place of death. RESULTS: Over half of young adults died in acute care settings. Young adults who were Asian/Pacific Islander or Black or who died from a respiratory or renal cause of death were most likely to die in an acute care setting. Rates of acute care death decreased over the studied years. DISCUSSION: Many young adults died in an acute care setting. Race and cause of death were the most influential factors associated with place of death. Young adults with an oncological cause of death were less likely to die in an acute care setting than patients with other underlying causes. This may indicate that specific care needs or preferences at the end of life may differ in certain disease populations and may affect place of death. Previous research has shown similar results in other developmental populations; however, given the complex psychosocial concerns that often arise during young adulthood, further research is needed to describe how the young adult status may specifically affect place of death.

Self-reported Sleep Quality Before and After Atrial Fibrillation Ablation.

BACKGROUND: Poor sleep quality is highly prevalent in atrial fibrillation (AF) with reported links between worse sleep quality and higher AF severity. Little research has examined whether sleep quality changes after AF ablation despite it being a routinely performed procedure. OBJECTIVE: The aim of this study was to evaluate self-reported sleep quality before and after AF ablation and to examine whether sleep quality differs by AF severity or sex. METHODS: This longitudinal pilot study assessed sleep using the Pittsburgh Sleep Quality Index at preablation and at 1, 3, and 6 months after ablation. Atrial fibrillation disease severity was assessed by the Canadian Cardiology Society Severity of AF scale. Outcomes were analyzed using descriptive statistics, Spearman ρ correlations, and multilevel longitudinal models. RESULTS: The sample (N = 20) was 55% female with a mean age of 65 (±7) years. Poor sleep quality (mean Pittsburgh Sleep Quality Index scores > 5) was evident at all time points. Improvement was noted at 3 months (moderate effect size d = 0.49); and negligible further improvement, from 3 to 6 months post ablation. Improvement was seen primarily in male subjects (large effect size d = 0.89 at 3 months), with smaller improvements for female subjects. Although Severity of AF scale scores were not correlated with sleep quality, Severity of AF scale severity scores did significantly improve over time. CONCLUSIONS: Patients with AF have poor sleep quality that improves for the first 3 months after AF ablation, with men showing more improvement than women. A more accurate understanding of the sleep challenges after AF ablation could lead to development of more realistic patient education and improve patient self-management.

Sex Differences in Cardiac Risk Factors in Young Adults: A Secondary Analysis and Surveillance Study.

BACKGROUND: Coronary artery disease (CAD) is increasing in young adults, and greater understanding of their cardiac risk factors is essential to ensure effective prevention. Given the sex differences in CAD observed in older adults, understanding sex differences in risk factors for this younger group of adults is important. Having insight of cardiac risk factors and sex differences in the young adult population is essential to creating personalized strategies for prevention in nursing care and in this age group. OBJECTIVES: The aims of this study were to determine the differences in CAD risk factors for young adult men and women and examine which factors are related to CAD early in life, ultimately to guide approaches for CAD prevention in primary care. METHODS: In this secondary analysis, 125 017 community-dwelling young adults were evaluated for health behaviors considered as risk factors for CAD. The 2017 Behavior Risk Factor Surveillance System database from the Center for Disease Control was utilized. This database contains questions asked of young adults that would help with risk management for chronic diseases like CAD. Young adults in this article were defined as being between 18 and 44 years of age. RESULTS: Men reported more cardiovascular risk factors than women and developed risk factors at an earlier age. Women had greater percentages of obesity and low activity levels. In this population, those with hypertension had the highest odds ratio for developing CAD. CONCLUSIONS: Differences between men and women in CAD risk factors included lifestyle and other chronic conditions. Greater prevention efforts should focus on these differences in young men and women to reduce risk factors and prevent the development of CAD.

Is the association between cognitive disease progression and atrial fibrillation modified by sex?

INTRODUCTION: It is unclear if sex differences exist in cognitive disease progression in mild cognitive impairment (MCI) and dementia associated with atrial fibrillation (AF). METHODS: Using a variety of statistical methods, we examined sex differences between AF and neuropsychological tests and cognitive disease progression, using the National Alzheimer's Coordinating Center data (N = 43,630). RESULTS: AF is associated with higher odds of dementia (odds ratio [OR] 3.00, 95% confidence interval [CI] [1.22, 7.37] in women and MCI in women (OR 3.43, 95% CI [1.55, 7.55]) versus men. Women with AF and normal baseline cognition had a higher risk of disease progression (hazard ratio [HR] 1.26, 95% CI [1.06, 1.50]) from normal to MCI and from MCI to vascular dementia (HR3.27, 95% CI [1.89, 5.65]) than men with AF or men and women without AF. DISCUSSION: AF was associated with more rapid progression to MCI and dementia in women, but more research is needed to confirm these findings.

Pacific Islands Cohort on Cardiometabolic Health Study: rationale and design.

BACKGROUND: Pacific Islanders, including those residing in the US Affiliated Pacific Islands (USAPI), experience some of the highest mortality rates resulting from non-communicable diseases (NCDs) worldwide. The Pacific Island Health Officers' Association declared a Regional State of Health Emergency in 2010 due to the epidemic of NCDs in the USAPI. Obesity, a known risk factor for NCDs, has become an epidemic among both children and adults in Micronesia and other parts of the USAPI. There is some recent information about overweight and obesity (OWOB) among young children in the USAPI, but there is no data looking at the relationship between children and their biological parents. The Pacific Islands Cohort on Cardiometabolic Health (PICCAH) Study aims to collect data on NCD lifestyle factors from two generations of families (n = 600 child-parent dyads or 1,200 participants) living in Guam, Pohnpei, and Palau. METHODS: The PICCAH Study is an epidemiological study using community-based convenience sampling to recruit participants in USAPI of Guam, Palau, and Pohnpei. The goal is to recruit participant dyads consisting of 1 child plus their biological parent in Guam (500 dyads or 1,000 participants), Pohnpei (50 dyads or 100 participants), and Palau (50 dyads or 100 participants). All participants are having the following information collected: demographic, health, and lifestyle information; anthropometry; diet; physical activity; sleep; acanthosis nigricans; blood pressure; and serum levels of fasting plasma glucose, fasting insulin, glycated hemoglobin, total cholesterol, triglycerides, LDL, and HDL. DISCUSSION: The PICCAH Study is designed to establish the baseline of a generational epidemiologic cohort with an emphasis on cardiometabolic risk, and to better understand the extent of DM and CVD conditions and related risk factors of those living in the USAPI jurisdictions of Guam, Pohnpei, and Palau. This study also serves to further build research capacity in the underserved USAPI Region.

The Fourth International Workshop on Clinical Transplant Tolerance.

The International Workshop on Clinical Transplant Tolerance is a biennial meeting that aims to provide an update on the progress of studies of immunosuppression minimization or withdrawal in solid organ transplantation. The Fourth International Workshop on Clinical Tolerance was held in Pittsburgh, Pennsylvania, September 5-6, 2019. This report is a summary of presentations on the status of clinical trials designed to minimize or withdraw immunosuppressive drugs in kidney, liver, and lung transplantation without subsequent evidence of rejection. All protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. The workshop also included presentations of mechanistic studies designed to improve understanding of the cellular and molecular basis of tolerance and to identify potential predictors/biomarkers of tolerance. Strategies to enhance the safety of hematopoietic cell transplantation and to improve patient selection/risk stratification for clinical trials were also discussed.

Feasibility, long-term safety, and immune monitoring of regulatory T cell therapy in living donor kidney transplant recipients.

Short-term outcomes in kidney transplantation are marred by progressive transplant failure and mortality secondary to immunosuppression toxicity. Immune modulation with autologous polyclonal regulatory T cell (Treg) therapy may facilitate immunosuppression reduction promoting better long-term clinical outcomes. In a Phase I clinical trial, 12 kidney transplant recipients received 1-10 × 106 Treg per kg at Day +5 posttransplantation in lieu of induction immunosuppression (Treg Therapy cohort). Nineteen patients received standard immunosuppression (Reference cohort). Primary outcomes were rejection-free and patient survival. Patient and transplant survival was 100%; acute rejection-free survival was 100% in the Treg Therapy versus 78.9% in the reference cohort at 48 months posttransplant. Treg therapy revealed no excess safety concerns. Four patients in the Treg Therapy cohort had mycophenolate mofetil withdrawn successfully and remain on tacrolimus monotherapy. Treg infusion resulted in a long-lasting dose-dependent increase in peripheral blood Tregs together with an increase in marginal zone B cell numbers. We identified a pretransplantation immune phenotype suggesting a high risk of unsuccessful ex-vivo Treg expansion. Autologous Treg therapy is feasible, safe, and is potentially associated with a lower rejection rate than standard immunosuppression. Treg therapy may provide an exciting opportunity to minimize immunosuppression therapy and improve long-term outcomes.

Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial.

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.

IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.

BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor. METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound. RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred. CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

Identification, selection, and expansion of non-gene modified alloantigen-reactive Tregs for clinical therapeutic use.

Transplantation is limited by the need for life-long pharmacological immunosuppression, which carries significant morbidity and mortality. Regulatory T cell (Treg) therapy holds significant promise as a strategy to facilitate immunosuppression minimization. Polyclonal Treg therapy has been assessed in a number of Phase I/II clinical trials in both solid organ and hematopoietic transplantation. Attention is now shifting towards the production of alloantigen-reactive Tregs (arTregs) through co-culture with donor antigen. These allospecific cells harbour potent suppressive function and yet their specificity implies a theoretical reduction in off-target effects. This review will cover the progress in the development of arTregs including their potential application for clinical use in transplantation, the knowledge gained so far from clinical trials of Tregs in transplant patients, and future directions for Treg therapy.

Summary of the Third International Workshop on Clinical Tolerance.

The Third International Workshop on Clinical Tolerance was held in Stanford, California, September 8-9, 2017. This is a summary of Workshop presentations of clinical trials designed to withdraw or minimize immunosuppressive (IS) drugs in kidney and liver transplant patients without subsequent evidence of rejection. All clinical protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. Tolerance to HLA matched and mismatched living donor kidney transplants with complete withdrawal of IS drugs without subsequent rejection for up to 14 years of observation was achieved in more than 50 patients enrolled in trials in four medical centers after the establishment of transient or persistent chimerism. Complete IS drug withdrawal without chimerism was reported in a prospective trial of liver transplantation combined with injection of regulatory T cells. IS drug minimization without rejection was reported in recipients of living donor kidney transplants enrolled in the One Study consortium after injection of recipient regulatory T cells, or injection of donor regulatory monocytes or dendritic cells. In conclusion, considerable progress has been made in achieving IS drug withdrawal after cell therapy in recipients of organ transplants.

Understanding Stem Cell Immunogenicity in Therapeutic Applications.

Stem cells and their differentiated progeny offer great hope for treating disease by providing an unlimited source of cells for repairing or replacing damaged tissue. Initial studies suggested that, unlike 'normal' transplants, specific characteristics of stem cells enabled them to avoid immune attack. However, recent findings have revealed that the immunogenicity of stem cells may have been underestimated. Here, we review the current understanding of the mechanisms of immune recognition associated with stem cell immunogenicity, and discuss the relevance of reprogramming and differentiation strategies used to generate cells or tissue from stem cells for implantation in eliciting an immune response. We examine the effectiveness of current strategies for minimising immune attack in light of our experience in the transplantation field and, in this context, outline important challenges moving forward.

Quality of life benefits from arrhythmia ablation: A longitudinal study using the C-CAP questionnaire and EQ5D.

AIMS: To investigate long-term efficacy of cardiac ablation for symptomatic arrhythmia by gathering generic and arrhythmia-related quality of life data using patient-reported outcome measures before and after ablation. METHODS: Consecutive patients undergoing cardiac ablation procedures at three sites in the United Kingdom were enrolled (n = 561). Data were collected at baseline, at 8-16 weeks, and 12 months after the ablation with responses from 390 patients received at all three time points. Nonparametric tests were used to identify any changes in patient outcomes due to nonnormal data. RESULTS: There were significant improvements in symptom severity, impact on life scores, EQ-5D-5L indices, and visual analogue score (VAS) scores at pre- versus 3 months and at preablation versus 1 year. Impact on life score showed additional improvement at 1 year versus 3 months, while improvements in symptom severity, EQ-5D-5L indices, and VAS scores continued to be maintained between 3 months and 1 year. CONCLUSION: Cardiac ablation provides patients with arrhythmias relief from symptoms, and results in an improvement in quality of life. Improvements observed at 3 months are maintained at 1 year follow-up.

Questions remain regarding the long-term efficacy of cardiac ablation. We enrolled 561 consecutive patients undergoing ablation procedures at three UK sites. Data were collected at baseline, and at 3 and 12 months. Improvement in symptoms was reported following treatment, with patients continuing to maintain or show continued improvement at 1 year.

Nursing Leadership in Guam.

Guam, an unincorporated territory of the United States, is one of the ten (10) US Affiliated Pacific Islands. The geographic location in the western Pacific Ocean, as well as the ties to the US position Guam as a strategic hub between the continental US, Asia, and the Pacific region. Health disparities in Guam and the Micronesian region are significant, and the non-communicable disease crisis is worsening, threatening the existing poor health infrastructure on the islands. Migration of islanders from the Micronesian region, whose countries also suffer health disparities, adds to the burden of the weak health care system on Guam. A critical nursing workforce shortage plagues the health care community, and strong nursing leadership is needed to address the problems. Nurse leaders, through many organizations, are working to implement strategies to address the issues facing the islands. Increased collaboration with partners on the island, on the US mainland, and globally, are necessary to effectively address Guam's health care concerns.

Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients.

Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+ ) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.

Induction of transplantation tolerance through regulatory cells: from mice to men.

Organ transplantation results in the activation of both innate and adaptive immune responses to the foreign antigens. While these responses can be limited with the use of systemic immunosuppressants, the induction of regulatory cell populations may be a novel strategy for the maintenance of specific immunological unresponsiveness that can reduce the severity of the detrimental side effects of current therapies. Our group has extensively researched different regulatory T-cell induction protocols for use as cellular therapy in transplantation. In this review, we address the cellular and molecular mechanisms behind regulatory T-cell suppression and their stability following induction protocols. We further discuss the use of different hematopoietically derived regulatory cell populations, including regulatory B cells, regulatory macrophages, tolerogenic dendritic cells, and myeloid-derived suppressor cells, for the induction of transplantation tolerance in light of new clinical trials developing therapies with some of these populations.

CD8+ Immunosenescence Predicts Post-Transplant Cutaneous Squamous Cell Carcinoma in High-Risk Patients.

Most morbidity associated with malignancy in long-term renal transplant recipients is due to cutaneous squamous cell carcinoma (SCC). Previously identified measures to stratify SCC risk have limited use, however. We hypothesized that an increased proportion of senescent, terminally differentiated CD8(+) T cells would identify renal transplant recipients at elevated SCC risk. Peripheral blood lymphocytes were isolated from 117 stable transplant recipients at high risk of SCC and analyzed phenotypically by flow cytometry. Participants were followed up prospectively for SCC development. The predictive value of variables was assessed using Cox regression. Age at transplant and enrollment, dialysis duration, and previous disease were predictive of SCC development during follow-up. Previously published clinical phenotype-based risk scores lost predictive value with the removal of age as a covariate. The percentage of CD57-expressing CD8(+) T cells was the strongest immunologic predictor of future SCC and correlated with increasing CD8(+) T cell differentiation. We dichotomized participants into those with a majority (CD57hi) and a minority (CD57lo) of CD8(+) T cells expressing CD57; CD57hi participants were more likely to develop SCC during follow-up (hazard ratio, 2.9; 95% confidence interval, 1.0 to 8.0), independent of potential confounders, and tended to develop earlier recurrence. The CD57hi phenotype was stable with time and associated with increasing age and cytomegalovirus seropositivity. Our results show that the CD57hi phenotype is a strong predictor of SCC development and recurrence in this cohort of long-term, high-risk renal transplant recipients. This information may allow identification of recipients who may benefit from intensive dermatologic screening and immunosuppression reduction.

CD57 expression in CD8 T cells and development of cutaneous squamous cell carcinoma in renal transplant recipients: a prospective cohort study.

BACKGROUND: Cutaneous squamous cell carcinoma is the most common malignancy in renal transplant recipients and a major cause of morbidity and mortality. Various measures have been proposed to identify recipients at increased risk of developing this cancer to allow targeted intervention. CD57 expression might represent a marker of T-cell exhaustion; we hypothesised that expression could predict development of squamous cell carcinoma in renal transplant recipients, and undertook a prospective cohort study to assess its predictive value. METHODS: Renal transplant recipients with and without previous squamous cell carcinoma (matched by race, age, sex, and immunosuppression duration) were recruited at routine clinical follow-up. Peripheral blood lymphocytes were analysed by flow cytometry. Three previously developed risk scores (Harden, Urwin, and Harwood), based on clinical phenotype, were also evaluated. The outcome event was histologically diagnosed squamous cell carcinoma during the study. Ethics approval was granted by local committee. Hazard ratios (HR) were calculated by Cox regression. FINDINGS: 57 renal transplant recipients with and 53 without previous squamous cell carcinoma were recruited. During a median follow-up of 309 days (IQR 223-409), 20 recipients developed this cancer (including four with a first diagnosis). On univariate analysis increasing age at enrolment, previous squamous cell carcinoma, having the CD57hi phenotype (≥50% of CD8 T cells expressing CD57), and increasing clinical risk score were predictive of cancer development. However, all three clinical risk scores were no longer predictive when adjusted for age. By contrast, transplant recipients displaying CD57hi were at significantly increased risk of future squamous cell carcinoma compared with CD57lo recipients (≤50% of CD8 T cells expressing CD57) (HR 5·0, 95%CI 1·11-22·3; p=0·04); risk remained significant after adjustment for both age (1·1, 1·0-1·1; p=0·04) and history of previous squamous cell carcinoma (3·5, 1·12-11·2; p=0·04). INTERPRETATION: Our results show that the CD57hi phenotype is a stronger predictor of squamous cell carcinoma development in long-term, at-risk renal transplant recipients than previously identified clinical phenotypes. This finding could help in the identification of renal transplant recipients at high risk of this cancer, who would benefit from intensive dermatological screening and immunosuppression reduction. FUNDING: Wellcome Trust, Oxford University Hospitals Research Services Committee.

Alloreactive regulatory T cells generated with retinoic acid prevent skin allograft rejection.

CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells mediate immunological self-tolerance and suppress immune responses. Retinoic acid (RA), a natural metabolite of vitamin A, has been reported to enhance the differentiation of Treg cells in the presence of TGF-ß. In this study, we show that the co-culture of naive T cells from C57BL/6 mice with allogeneic antigen-presenting cells (APCs) from BALB/c mice in the presence of TGF-ß, RA, and IL-2 resulted in a striking enrichment of Foxp3(+) T cells. These RA in vitro-induced regulatory T (RA-iTreg) cells did not secrete Th1-, Th2-, or Th17-related cytokines, showed a nonbiased homing potential, and expressed several cell surface molecules related to Treg-cell suppressive potential. Accordingly, these RA-iTreg cells suppressed T-cell proliferation and inhibited cytokine production by T cells in in vitro assays. Moreover, following adoptive transfer, RA-iTreg cells maintained Foxp3 expression and their suppressive capacity. Finally, RA-iTreg cells showed alloantigen-specific immunosuppressive capacity in a skin allograft model in immunodeficient mice. Altogether, these data indicate that functional and stable allogeneic-specific Treg cells may be generated using TGF-ß, RA, and IL-2. Thus, RA-iTreg cells may have a potential use in the development of more effective cellular therapies in clinical transplantation.