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.

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.

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.

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.

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.

CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells.

Regulatory T cells (Tregs) are critical mediators of immune homeostasis. The co-stimulatory molecule CD27 is a marker of highly suppressive Tregs, although the role of the CD27-CD70 receptor-ligand interaction in Tregs is not clear. Here we show that after prolonged in vitro stimulation, a significant proportion of human Tregs gain stable CD70 expression while losing CD27. The expression of CD70 in expanded Tregs is associated with a profound loss of regulatory function and an unusual ability to provide CD70-directed co-stimulation to TCR-activated conventional T cells. Genetic deletion of CD70 or its blockade prevents Tregs from delivering this co-stimulatory signal, thus maintaining their regulatory activity. High resolution targeted single-cell RNA sequencing of human peripheral blood confirms the presence of CD27-CD70+ Treg cells. These findings have important implications for Treg-based clinical studies where cells are expanded over extended periods in order to achieve sufficient treatment doses.

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.

Transiently Activated Human Regulatory T Cells Upregulate BCL-XL Expression and Acquire a Functional Advantage in vivo.

Regulatory T cells (Tregs) can control excessive or undesirable immune responses toward autoantigens, alloantigens, and pathogens. In transplantation, host immune responses against the allograft are suppressed through the use of immunosuppressive drugs, however this often results in life-threatening side effects including nephrotoxicity and an increased incidence of cancer and opportunistic infections. Tregs can control graft-vs.-host disease and transplant rejection in experimental models, providing impetus for the use of Tregs as a cellular therapy in clinical transplantation. One of the major barriers to the widespread use of Treg cellular therapy is the requirement to expand cells ex vivo to large numbers in order to alter the overall balance between regulatory and effector cells. Methods that enhance suppressive capacity thereby reducing the need for expansion are therefore of interest. Here, we have compared the function of freshly-isolated and ex vivo-manipulated human Tregs in a pre-clinical humanized mouse model of skin transplantation. Sorted human CD127loCD25+CD4+ Tregs were assessed in three different conditions: freshly-isolated, following transient in vitro activation with antiCD3/antiCD28 beads or after ex vivo-expansion for 2 weeks in the presence of antiCD3/antiCD28 beads and recombinant human IL2. While ex vivo-expansion of human Tregs increased their suppressive function moderately, transient in vitro-activation of freshly isolated Tregs resulted in a powerful enhancement of Treg activity sufficient to promote long-term graft survival of all transplants in vivo. In order to investigate the mechanisms responsible for these effects, we measured the expression of Treg-associated markers and susceptibility to apoptosis in activated Tregs. Transiently activated Tregs displayed enhanced survival and proliferation in vitro and in vivo. On a molecular level, Treg activation resulted in an increased expression of anti-apoptotic BCL2L1 (encoding BCL-XL) which may be at least partially responsible for the observed enhancement in function. Our results suggest that in vitro activation of human Tregs arms them with superior proliferative and survival abilities, enabling them to more effectively control alloresponses. Importantly, this transient activation results in a rapid functional enhancement of freshly-isolated Tregs, thereby providing an opportunity to eliminate the need for in vitro expansion in select circumstances. A protocol employing this technique would therefore benefit from a reduced requirement for large cell numbers for effective therapy.

Glass Slippers and Glass Cliffs: Fitting In and Falling Off.

BACKGROUND: A glass ceiling effect exists for women in male-dominated professions. Recent studies also show a glass-cliff effect where senior women can more easily fall from positions of leadership. Transplantation remains a male-dominated specialty. This study investigated gender and the perception of adverse clinical incidents in transplantation. METHODS: Prospective randomised web-based survey involving five clinical scenarios presenting two versions of episodes with errors or mistakes, with either a male or female as a randomly named protagonist (Set1 and Set2). To address unconscious bias, the study was described as examining actions following clinical adverse incidents in transplantation. Each scenario was followed by 2 closed questions: (1) clinical performance rating and (2) selection of action required. Reasoning was invited (open-text comments). Responses were analyzed using quantitative and qualitative methods. RESULTS: One hundred ninety-one invitees responded; 134 completed questionnaires. There were no statistically significant differences (P > 0.05) in responses between sets for performance ratings or recommended actions. However, for "first solo laparoscopic surgery" scenario, there was some indication that "No Action" was more likely if surgeon was male (P = 0.056). Male responses rated female performance as significantly worse (P = 0.035) for the laboratory-based scenario. One hundred two participants provided open-text comments. Thematic analysis identified 7 themes. Acceptable levels of risk theme demonstrated engendered leadership beliefs, that is, when clinical judgment proved incorrect, males described as forceful but females as needing support. In cases where things went wrong, respondents were more likely to comment females should not have decided to proceed. CONCLUSIONS: While gender may no longer be an overt issue in perceived performance of senior staff in transplantation, respondents' use of language and their choice of words display elements of unconscious (covert) engendered views.

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.

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 .).

Enhancing human regulatory T cells in vitro for cell therapy applications.

Adoptive cellular therapies are gaining popularity as a means to treat clinical conditions, with potentially fewer risks and greater efficacy than traditional pharmacological strategies. Regulatory T cells (Tregs) are currently undergoing clinical trials in various immune-mediated pathologies, including transplant rejection and autoimmune conditions. In general, cell therapy relies upon ex vivo expansion of the cell product, in order to administer more cells than can be isolated from one person. In vitro manipulation of cell therapy products, prior to administration to patients, offers the opportunity to enhance the efficacy of the final cell therapy product in other ways. For example, cells can be exposed to reagents that enhance their longevity or functional potency after transfer into the patient. Genetic modification strategies can even permit the design of cells with bespoke functionality. Crucially, in vitro manipulation of therapeutic cells in isolation can exert these influences upon the biology of the therapeutic cells, without systemic exposure of the patient to the reagents being used. Quality control assessments can be integrated into the procedure prior to administration, to protect the patient from the risk of adverse events, should the procedure produce undesirable results. With a particular focus on Tregs, this review surveys the diverse strategies that are being employed to enhance the efficacy of cell therapy via in vitro manipulation of cells, and highlights some emerging technologies that may propel this endeavour in the future.

How to Escape the Immune Response: What Tumors Teach to Transplant Physicians/Immunologists.

Recent progress in deciphering the mechanisms underlying the concepts of tumor immunosurveillance and immunoevasion has opened new opportunities for the development of effective antitumor therapies. Transplant physicians and immunologists have much to learn from those direct clinical translations of basic science. The 2016 Beaune Seminar in Transplant research brought together researchers from both fields to explore and discuss significant advances in cancer biology, immunotherapies and their potential impacts for the management of cancer in transplant recipients.

TNFR2: The new Treg switch?

Three recent publications identified the TNF/TNR2 pathway as a new target to reduce graft-versus-host-disease through regulatory T cells activation or to potentially switch on a strong anti-leukemic effect through regulatory T cells blockade in allogeneic hematopoietic stem cell transplantation. This identified the TNF/TNR2 pathway as a swith and as a new target for immune checkpoint therapy to modulate the immune regulation in this clinical setting.

Executive Summary of IPITA-TTS Opinion Leaders Report on the Future of ß-Cell Replacement.

The International Pancreas and Islet Transplant Association (IPITA), in conjunction with the Transplantation Society (TTS), convened a workshop to consider the future of pancreas and islet transplantation in the context of potential competing technologies that are under development, including the artificial pancreas, transplantation tolerance, xenotransplantation, encapsulation, stem cell derived beta cells, beta cell proliferation, and endogenous regeneration. Separate workgroups for each topic and then the collective group reviewed the state of the art, hurdles to application, and proposed research agenda for each therapy that would allow widespread application. Herein we present the executive summary of this workshop that focuses on obstacles to application and the research agenda to overcome them; the full length article with detailed background for each topic is published as an online supplement to Transplantation.