Factors Associated With Fatigue in Persons With Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia affecting over 6 million people in the U.S. Fatigue is a frequent symptom of AF, yet no underlying biological mechanisms have been identified in AF-related fatigue as in other chronic conditions such as cancer or HIV fatigue (inflammation, tissue injury). We aimed to identify biomarkers and correlates of AF-fatigue in ARIC participants. METHODS: Participants with AF from ARIC visit 5 (2011-2013) were included in the study. Multiple linear regression was used to estimate the association of high sensitivity troponin (hs-TnT), N-terminal fragment B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) levels with self-reported fatigue (SF-12 and PROMIS Fatigue Scale), depressive symptoms (Center for Epidemiological Studies Depression survey), and physical functioning (Short Physical Performance Battery) scores. All biomarkers underwent natural-log transformation. RESULTS: There were 446 participants (mean age: 78 y ± 5; 44% women). In adjusted analyses, NT-proBNP was associated with AF-fatigue (ß: 0.11, 95% CI: 0.03, 0.19), increased depressive symptoms (ß: 0.44, 95% CI: 0.19, 0.70), and decreased physical function (ß: -0.48, 95% CI: -0.72, -0.23). Hs-TnT was also associated with elevated AF-fatigue (ß: 0.24, 95% CI: 0.09, 0.39) along with decreased physical function (ß: -1.19, 95% CI: -1.64, -0.75). No significant associations were found with hsCRP and fatigue. CONCLUSION: Increased levels of cardiac injury biomarkers, depressive symptoms, and decreased physical function were associated with AF-fatigue. Inflammation was not associated with AF-fatigue; other physiological pathways, such as cardiac overload or myocardial injury may be more relevant in AF-fatigue.

Heart failure symptom burden, dietary intake, and inflammation: An integrative review of the literature.

Heart failure (HF) is characterized by high symptom burden including, but not limited to fatigue, dyspnea, and edema. Up to 21.5% of HF patients experience significant depressive symptoms, much higher than 7.1% in adults without HF. Diet, metabolites, and other inflammatory mechanisms have gained notable attention in recent studies for contributions to symptoms in HF. Symptoms for black adults (B/As) with HF are often influenced by lifestyle factors, which may influence their higher mortality rates; few studies address these factors. Distinguishing the links between key elements with diet, inflammation, and symptoms may bring clarity for new dietary strategies in HF clinical care. The purpose of this integrative review is to examine the existing literature regarding relationships among physiologic pathways in HF along with physical and emotional symptoms in the context of inflammation, dietary intake, tumor necrosis factor-alpha (TNF-α), a biomarker of inflammation, and trimethylamine-N-Oxide (TMAO). Based on available evidence, inflammation may be a key link between physical symptoms, diet, depression, TMAO, and TNF-α in persons with HF and warrants further examination to clarify pathological links to solidify evidence for better guidance with dietary modifications. The literature reviewed in this study demonstrates that more work is needed to examine dietary planning, social support, and differences between men and women in the B/A community. Results of this literature review call attention to the essential, personalized care needs related to symptom monitoring and dietary planning which is expected to decrease symptom burden in the HF population.

Ablation to Reduce Atrial Fibrillation Burden and Improve Outcomes: JACC Review Topic of the Week.

Atrial fibrillation is the most common atrial arrhythmia and accounts for a significant burden of cardiovascular disease globally. With advances in implanted and wearable cardiac monitoring technology, it is now possible to readily and accurately quantify an individual's time spent in atrial fibrillation. This review summarizes the relationship between atrial fibrillation burden and adverse cardiovascular and cerebrovascular outcomes and discusses the role of catheter ablation to mitigate the morbidity and mortality associated with greater burden of atrial fibrillation.

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.

Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

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.

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.

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.

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.

Dampened Inflammatory Signalling and Myeloid-Derived Suppressor-Like Cell Accumulation Reduces Circulating Monocytic HLA-DR Density and May Associate With Malignancy Risk in Long-Term Renal Transplant Recipients.

Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients. Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks. Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density. Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.

Transplantation Without Overimmunosuppression (TWO) study protocol: a phase 2b randomised controlled single-centre trial of regulatory T cell therapy to facilitate immunosuppression reduction in living donor kidney transplant recipients.

INTRODUCTION: Regulatory T cell (Treg) therapy has been demonstrated to facilitate long-term allograft survival in preclinical models of transplantation and may permit reduction of immunosuppression and its associated complications in the clinical setting. Phase 1 clinical trials have shown Treg therapy to be safe and feasible in clinical practice. Here we describe a protocol for the TWO study, a phase 2b randomised control trial of Treg therapy in living donor kidney transplant recipients that will confirm safety and explore efficacy of this novel treatment strategy. METHODS AND ANALYSIS: 60 patients will be randomised on a 1:1 basis to Treg therapy (TR001) or standard clinical care (control). Patients in the TR001 arm will receive an infusion of autologous polyclonal ex vivo expanded Tregs 5 days after transplantation instead of standard monoclonal antibody induction. Maintenance immunosuppression will be reduced over the course of the post-transplant period to low-dose tacrolimus monotherapy. Control participants will receive a standard basiliximab-based immunosuppression regimen with long-term tacrolimus and mycophenolate mofetil immunosuppression. The primary endpoint is biopsy proven acute rejection over 18 months; secondary endpoints include immunosuppression burden, chronic graft dysfunction and drug-related complications. ETHICS AND DISSEMINATION: Ethical approval has been provided by the National Health Service Health Research Authority South Central-Oxford A Research Ethics Committee (reference 18/SC/0054). The study also received authorisation from the UK Medicines and Healthcare products Regulatory Agency and is being run in accordance with the principles of Good Clinical Practice, in collaboration with the registered trials unit Oxford Clinical Trials Research Unit. Results from the TWO study will be published in peer-reviewed scientific/medical journals and presented at scientific/clinical symposia and congresses. TRIAL REGISTRATION NUMBER: ISRCTN: 11038572; Pre-results.

Trajectories of Recovery after Atrial Fibrillation Ablation.

Ablation procedures are common for patients with atrial fibrillation (AF), yet evidence is limited about patient perceptions of their recovery following ablation. We sought to expand understanding of this recovery process. Twenty participants undergoing their first AF ablation completed semi-structured interviews prior to ablation (baseline) and at one, three, and six months post AF ablation. Pre-procedure education is modeled after education used for other ablation procedures, preparing patients to expect a single recovery trajectory. We identified two recovery trajectories that varied in speed of symptom resolution: sustained improvement and pseudo improvement. Recovery was slower than expected in both trajectories. Moreover, returning to desired activity levels consistently lagged behind other symptom resolution by approximately two months. A more accurate understanding of what patients experience post-ablation, as illustrated in these findings, serves as a beginning step to alter patient education prior to AF ablation to better prepare individuals for the recovery process.

Investigation of the uptake of molybdenum by plants from Argentinean groundwater.

Some regions of Argentina are affected by high concentrations of molybdenum, arsenic and vanadium from natural sources in their groundwater. In particular, Mo levels in groundwater from Eduardo Castex (La Pampa, Argentina) typically exceed the guidelines for drinking water formerly established by WHO at 70 µg/L. Therefore, this study investigated the uptake of Mo in plants, using cress (Lepidium sativum L.) as a model using hydroponic experiments with synthetic solutions and groundwater from La Pampa. Cress grown from control experiments (150 µg/L Mo, pH 7) presented an average Mo concentration of 35.2 mg/kg (dry weight, d.w.), higher than the typical total plant range (0.7-2.5 mg/kg d.w.) in the literature. Using pooled groundwater samples (65.0-92.5 µg/L Mo) from wells of La Pampa (Argentina) as growth solutions resulted in significantly lower cress Mo levels (1.89-4.59 mg/kg d.w.) than were obtained for synthetic solutions of equivalent Mo concentration. This may be due to the high levels in these groundwater samples of As, V, Fe and Mn which are known to be associated with volcanic deposits. This research addressed the hitherto scarcity of data about the effect of various physicochemical parameters on the uptake of Mo in plants.

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.

Authentication of Antibiotics Using Portable Near-Infrared Spectroscopy and Multivariate Data Analysis.

Counterfeit medicines represent a global public health threat warranting the development of accurate, rapid, and nondestructive methods for their identification. Portable near-infrared (NIR) spectroscopy offers this advantage. This work sheds light on the potential of combining NIR spectroscopy with principal component analysis (PCA) and soft independent modelling of class analogy (SIMCA) for authenticating branded and generic antibiotics. A total of 23 antibiotics were measured "nondestructively" using a portable NIR spectrometer. The antibiotics corresponded to six different active pharmaceutical ingredients being: amoxicillin trihydrate and clavulanic acid, azithromycin dihydrate, ciprofloxacin hydrochloride, doxycycline hydrochloride, and ofloxacin. NIR spectra were exported into Matlab R2018b where data analysis was applied. The results showed that the NIR spectra of the medicines showed characteristic features that corresponded to the main excipient(s). When combined with PCA, NIR spectroscopy could distinguish between branded and generic medicines and could classify medicines according to their manufacturing sources. The PCA scores showed the distinct clusters corresponding to each group of antibiotics, whereas the loadings indicated which spectral features were significant. SIMCA provided more accurate classification over PCA for all antibiotics except ciprofloxacin which products shared many overlapping excipients. In summary, the findings of the study demonstrated the feasibility of portable NIR as an initial method for screening antibiotics.

Imlifidase Desensitization in Crossmatch-positive, Highly Sensitized Kidney Transplant Recipients: Results of an International Phase 2 Trial (Highdes).

BACKGROUND: Highly HLA sensitized patients have limited access to life-saving kidney transplantation because of a paucity of immunologically suitable donors. Imlifidase is a cysteine protease that cleaves IgG leading to a rapid decrease in antibody level and inhibition of IgG-mediated injury. This study investigates the efficacy and safety of imlifidase in converting a positive crossmatch test to negative, allowing highly sensitized patients to be transplanted with a living or deceased donor kidney. METHODS: This open-label, single-arm, phase 2 trial conducted at 5 transplant centers, evaluated the ability of imlifidase to create a negative crossmatch test within 24 h. Secondary endpoints included postimlifidase donor-specific antibody levels compared with predose levels, renal function, and pharmacokinetic/pharmacodynamic profiles. Safety endpoints included adverse events and immunogenicity profile. RESULTS: Of the transplanted patients, 89.5% demonstrated conversion of baseline positive crossmatch to negative within 24 h after imlifidase treatment. Donor-specific antibodies most often rebounded 3-14 d postimlifidase dose, with substantial interpatient variability. Patient survival was 100% with graft survival of 88.9% at 6 mo. With this, 38.9% had early biopsy proven antibody-mediated rejection with onset 2-19 d posttransplantation. Serum IgG levels began to normalize after ~3-7 d posttransplantation. Antidrug antibody levels were consistent with previous studies. Seven adverse events in 6 patients were classified as possibly or probably related to treatment and were mild-moderate in severity. CONCLUSIONS: Imlifidase was well tolerated, converted positive crossmatches to negative, and enabled patients with a median calculated panel-reactive antibody of 99.83% to undergo kidney transplantation resulting in good kidney function and graft survival at 6 mo.

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.

Defining the structural basis for human leukocyte antigen reactivity in clinical transplantation.

The current state-of-the-art technology employed to assess anti-human leukocyte antigen antibodies (Anti-HLA Ab) for donor-recipient matching and patient risk stratification in renal transplantation is the single antigen bead (SAB) assay. However, there are limitations to the SAB assay as it is not quantitative and due to variations in techniques and reagents, there is no standardization across laboratories. In this study, a structurally-defined human monoclonal alloantibody was employed to provide a mechanistic explanation for how fundamental alloantibody biology influences the readout from the SAB assay. Performance of the clinical SAB assay was evaluated by altering Anti-HLA Ab concentration, subclass, and detection reagents. Tests were conducted in parallel by two internationally accredited laboratories using standardized protocols and reagents. We show that alloantibody concentration, subclass, laboratory-specific detection devices, subclass-specific detection reagents all contribute to a significant degree of variation in the readout. We report a significant prozone effect affecting HLA alleles that are bound strongly by the test alloantibody as opposed to those bound weakly and this phenomenon is independent of complement. These data highlight the importance for establishing international standards for SAB assay calibration and have significant implications for our understanding of discordance in previous studies that have analyzed its clinical relevance.

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.