The Role of Coinhibitory Signaling Pathways in Transplantation and Tolerance

Negative costimulatory molecules, acting through so-called inhibitory pathways, play a crucial role in the control of T cell responses. This negative “second signal” opposes T cell receptor activation and leads to downregulation of T cell proliferation and promotes antigen specific tolerance. Much interest has focused upon these pathways in recent years as a method to control detrimental alloresponses and promote allograft tolerance. However, recent experimental data highlights the complexity of negative costimulatory pathways in alloimmunity. Varying effects are observed from molecules expressed on donor and recipient tissues and also depending upon the activation status of immune cells involved. There appears to be significant overlap and redundancy within these systems, rendering this a challenging area to understand and exploit therapeutically. In this article, we will review the literature at the current time regarding the major negative costimulation pathways including CTLA-4:B7, PD-1:PD-L1/PD-L2 and PD-L1:B7-1, B7-H3, B7-H4, HVEM:BTLA/CD160, and TIM-3:Galectin-9. We aim to outline the role of these pathways in alloimmunity and discuss their potential applications for tolerance induction in transplantation

Nanodelivery of Mycophenolate Mofetil to the Organ Improves Transplant Vasculopathy.

Inflammation occurring within the transplanted organ from the time of harvest is an important stimulus of early alloimmune reactivity and promotes chronic allograft rejection. Chronic immune-mediated injury remains the primary obstacle to the long-term success of organ transplantation. However, organ transplantation represents a rare clinical setting in which the organ is accessible ex vivo, providing an opportunity to use nanotechnology to deliver therapeutics directly to the graft. This approach facilitates the directed delivery of immunosuppressive agents (ISA) to target local pathogenic immune responses prior to the transplantation. Here, we have developed a system of direct delivery and sustained release of mycophenolate mofetil (MMF) to treat the donor organ prior to transplantation. Perfusion of a donor mouse heart with MMF-loaded PEG-PLGA nanoparticles (MMF-NPs) prior to transplantation abrogated cardiac transplant vasculopathy by suppressing intragraft pro-inflammatory cytokines and chemokines. Our findings demonstrate that ex vivo delivery of an ISA to donor organs using a nanocarrier can serve as a clinically feasible approach to reduce transplant immunity

Targeted Delivery of Immunomodulators to Lymph Nodes

SUMMARY Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node address in molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo

Effect of dapagliflozin on cause-specific mortality in patients with heart failure across the spectrum of ejection fraction

Importance: In 2 trials enrolling patients with heart failure (HF) across the spectrum of ejection fraction (EF), dapagliflozin has been shown to reduce the rate of the composite of worsening HF events or death from cardiovascular (CV) causes. Objective: To examine the effects of dapagliflozin on cause-specific CV and non-CV mortality across the spectrum of EF. Design, Setting, and Participants: This was a participant-level, pooled, prespecified secondary analysis of data from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure, or DAPA-HF trial (participant left ventricular EF [LVEF] ≤40%), and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure, or DELIVER trial (participant LVEF >40%), to assess the effects of randomized treatment on cause-specific mortality. The trials assigned adjacent populations of patients with chronic HF, New York Heart Association class II-IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The primary outcome for each study was a composite of worsening HF events (hospitalization or urgent heart failure visits) or CV death. Clinical outcomes, including all deaths, were adjudicated as to cause by clinical end points committees blinded to treatment assignment. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to baseline EF was examined, as well as the effect of randomized treatment on cause-specific death in Cox regression models. Relationships with continuous EF were modeled using Poisson regression. Results: Of 11 007 patients in the pooled data set, there were 1628 deaths during follow-up (mean [SD] age, 71.7 [10.3] years; 1139 male [70.0%]). Of those who died, 872 (53.5%) were ascribed to CV deaths, 487 (29.9%) to non-CV deaths, and 269 (16.5%) to undetermined causes. Of CV deaths, 289 (33.1%; this represented 17.8% of total deaths) were due to HF, 441 (50.6%; 27.1% of total deaths) were sudden, 69 (7.9%; 4.2% of total deaths) were due to stroke, 47 (5.4%; 2.9% of total deaths) to myocardial infarction, and 26 (3.0%; 1.6% of total deaths) were due to other CV causes. The proportion of non-CV deaths was higher in those with higher EF. In the pooled population, across the spectrum of EF, treatment with dapagliflozin was associated with lower rates of CV death (hazard ratio [HR], 0.86; 95% CI, 0.75-0.98; P = .02), principally due to lower rates of sudden death (HR, 0.84; 95% CI, 0.70-1.01; P = .07) and HF death (HR, 0.88; 95% CI, 0.70-1.11; P = .30), with little difference in rates of death from stroke or MI. Conclusions and Relevance: In a pooled analysis of patients with HF in the DAPA-HF and DELIVER randomized clinical trials, across the full spectrum of LVEF, dapagliflozin significantly reduced risks of CV death with contributions from lower rates of sudden death and death from progressive HF. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124, NCT0361921

Angiotensin-neprilysin inhibition and renal outcomes in heart failure with preserved ejection fraction

Background: In patients with heart failure, chronic kidney disease (CKD) is common and associated with a higher risk of renal events than in patients without CKD. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure and preserved ejection fraction (HFpEF) enrolled in PARAGON-HF. Methods: In this randomized, double-blind, event-driven trial, we assigned 4,822 patients with HFpEF to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein we present the results of the pre-specified renal composite outcome (time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 ml/min/1.73m2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio [HR], 0.50; 95%CI, 0.33 to 0.77; P=0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan compared with valsartan (-1.8 [95%CI, -2.0 to -1.6] vs. -2.4 [95%CI, -2.6 to - 2.2] ml/min/1.73m2/year). Conclusions: In patients with HFpEF, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan

CRISIS AFAR: an international collaborative study of the impact of the COVID-19 pandemic on mental health and service access in youth with autism and neurodevelopmental conditions

BackgroundHeterogeneous mental health outcomes during the COVID-19 pandemic are documented in the general population. Such heterogeneity has not been systematically assessed in youth with autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDD). To identify distinct patterns of the pandemic impact and their predictors in ASD/NDD youth, we focused on pandemic-related changes in symptoms and access to services.MethodsUsing a naturalistic observational design, we assessed parent responses on the Coronavirus Health and Impact Survey Initiative (CRISIS) Adapted For Autism and Related neurodevelopmental conditions (AFAR). Cross-sectional AFAR data were aggregated across 14 European and North American sites yielding a clinically well-characterized sample of N = 1275 individuals with ASD/NDD (age = 11.0 ± 3.6 years; n females = 277). To identify subgroups with differential outcomes, we applied hierarchical clustering across eleven variables measuring changes in symptoms and access to services. Then, random forest classification assessed the importance of socio-demographics, pre-pandemic service rates, clinical severity of ASD-associated symptoms, and COVID-19 pandemic experiences/environments in predicting the outcome subgroups.ResultsClustering revealed four subgroups. One subgroup-broad symptom worsening only (20%)-included youth with worsening across a range of symptoms but with service disruptions similar to the average of the aggregate sample. The other three subgroups were, relatively, clinically stable but differed in service access: primarily modified services (23%), primarily lost services (6%), and average services/symptom changes (53%). Distinct combinations of a set of pre-pandemic services, pandemic environment (e.g., COVID-19 new cases, restrictions), experiences (e.g., COVID-19 Worries), and age predicted each outcome subgroup.LimitationsNotable limitations of the study are its cross-sectional nature and focus on the first six months of the pandemic.ConclusionsConcomitantly assessing variation in changes of symptoms and service access during the first phase of the pandemic revealed differential outcome profiles in ASD/NDD youth. Subgroups were characterized by distinct prediction patterns across a set of pre- and pandemic-related experiences/contexts. Results may inform recovery efforts and preparedness in future crises; they also underscore the critical value of international data-sharing and collaborations to address the needs of those most vulnerable in times of crisis

Serum uric acid, influence of sacubitril/valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON-HF

Aims: To determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure with preserved ejection fraction (HFpEF), and whether sacubitril/valsartan reduces SUA and SUA‐related therapies. Methods and Results: We analyzed 4795 participants from PARAGON‐HF. We related baseline hyperuricemia (using assay definitions) to the primary outcome (CV death and total HF hospitalization). Between baseline and 4 months, we assessed the association between changes in SUA and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ‐OSS) and other cardiac biomarkers. We simultaneously adjusted for baseline and time‐updated SUA to determine whether lowering SUA was associated with clinical benefit. Average age was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricemia was associated with increased risk for the primary outcome (rate ratio 1.61, 95%CI 1.37, 1.90). The treatment effect of sacubitril/valsartan for the primary endpoint was not significantly modified by hyperuricemia (p‐interaction = 0.14). Sacubitril/valsartan reduced SUA −0.38 mg/dL (95%CI: −0.45, −0.31) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (−0.51 vs. ‐0.32 mg/dL) (p‐interaction = 0.031). Sacubitril/valsartan reduced the odds of initiating SUA‐related treatments by 32% during follow‐up (p < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ‐OSS and directly associated with high‐sensitivity Troponin T (p < 0.05). Time‐updated SUA was a stronger predictor of adverse outcomes than baseline SUA. Conclusions: SUA independently predicted adverse outcomes in HFpEF. Sacubitril/valsartan reduced SUA and related therapy initiation compared to valsartan. Reducing SUA was associated with improved outcomes

A life course examination of the physical environmental determinants of physical activity behaviour: A “Determinants of Diet and Physical Activity” (DEDIPAC) umbrella systematic literature review.

Background: Participation in regular physical activity is associated with a multitude of health benefits across the life course. However, many people fail to meet PA recommendations. Despite a plethora of studies, the evidence regarding the environmental (physical) determinants of physical activity remains inconclusive. Objective: To identify the physical environmental determinants that influence PA across the life course. Methods: An online systematic literature search was conducted using MEDLINE, ISI Web of Science, Scopus and SPORTDiscus. The search was limited to studies published in English (January 2004 to April 2016). Only systematic literature reviews (SLRs) and meta-analyses (MAs) of observational studies, that investigated the association between physical determinants and physical activity outcomes, were eligible for inclusion. The extracted data were assessed on the importance of determinants, strength of evidence and methodological quality. Results: The literature search identified 28 SLRs and 3 MAs on 67 physical environmental characteristics potentially related to physical activity that were eligible for inclusion. Among preschool children, a positive association was reported between availability of backyard space and outdoor toys/equipment in the home and overall physical activity. The availability of physical activity programs and equipment within schools, and neighbourhood features such as pedestrian and cyclist safety structure were positively associated with physical activity in children and adolescents. Negative street characteristics, for example, lack of sidewalks and streetlights, were negatively associated with physical activity in adults. Inconsistent associations were reported for the majority of reviewed determinants in adults. Conclusion: This umbrella SLR provided a comprehensive overview of the physical environment determinants of physical activity across the life course and has highlighted, particularly amongst youth, a number of key determinants that may be associated with overall physical activity. Given the limited evidence drawn mostly from cross-sectional studies, longitudinal studies are needed to further explore these associations

Dapagliflozin in patients recently hospitalized with heart failure and mildly reduced or preserved ejection fraction

Background: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. Objectives: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. Methods: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. Results: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. Conclusions: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)