Acute exercise enhances the expansion of cytotoxic T-cells specific to leukemia and melanoma antigens: implications for adoptive transfer immunotherapy?

INTRODUCTION: The ex vivo expansion of tumor-associated-antigen (TAA)-specific cytotoxic T-cells from healthy donors for adoptive transfer in cancer patients has been used successfully to prevent relapse after hematopoietic stem cell transplantation (HSCT). However, this therapy is limited by the difficulty in priming and expanding sufficient numbers of functional TAA-specific T-cells, as T-cells recognizing TAA are usually low in frequency and avidity in healthy donors. Furthermore, monocyte-derived dendritic cells (Mo-DC) are used for TAA-presentation, but their manufacture is limited by low blood monocyte numbers. Therefore, large and impractical numbers of blood cells are required to successfully expand TAA-specific T-cells. Acute exercise is well-known to transiently activate and increase the numbers of T-cells and monocytes in peripheral blood. We therefore hypothesized that the immune-enhancing effects of exercise could be harnessed to enhance the ex vivo expansion of TAA-specific T-cells for adoptive transfer immunotherapy. AIMS: To examine the effects of acute exercise on (1) the number and function of TAA-specific T-cells expanded ex vivo, and 2) the generation and function of mo-DC. METHODS: 12 healthy adults (mean ± SD: Age 27±2.6yrs) completed an acute bout of stair-running exercise (time: 104±17sec). Mo-DC generated from pre and post exercise blood samples were pulsed with the melanoma-associated-antigens MAGE-A4 and PRAME, the common tumor-antigen survivin, and the leukemia-associated-antigen WT-1. Autologous DC were used to expand TAA-specific T-cells obtained before and after exercise over 14-days. T-cells were enumerated and phenotyped by flow cytometry and function was assessed by ELISPOT and antigen-specific cytotoxicity. RESULTS: A greater number of mo-DC were generated from post-exercise blood samples (pre: 2.0±1.0 X106cells, post: 5.2±2.6 X106cells). This was due to the 1.7 fold increase in blood monocytes post-exercise, as the number of mo-DC generated per input CD14+cell did not differ (pre: 0.40±0.25, post: 0.59±0.36). Total T-cell expansion was increased post-exercise (fold-increase: pre: 2.48±0.75, post: 2.90±0.74). ELISPOT revealed that the majority of donors had enrichment in TAA-specific T-cells post-exercise, as T-cell lines expanded from post-exercise samples exhibited an increased interferon-gamma response to TAA compared to T-cell lines expanded from pre-exercise samples. Exercise had no effect on T-cell phenotype or antigen-specific cytotoxicity in the expanded cells. CONCLUSION: These data indicate that a single bout of exercise enhances mo-DC generation and the expansion of TAA-specific T-cells ex vivo. Exercise may therefore serve as an adjuvant to enhance the expansion of TAA-specific T-cells in healthy donors and improve the efficacy of adoptive transfer therapy in cancer patients

CMV-specific T-cells Mobilized with Exercise have Broad Epitope Specificity and a High-Differentiated Effector Memory Phenotype.

Introduction: Dynamic exercise evokes a rapid redeployment of cytotoxic T-cell subsets with high surface expression of b2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, the main aim of this study was to examine latent CMV infection as a potential confounder to age-related differences in blood CD8+ T-cell responses to exercise. The second aim of this study was to examine the impact of acute exercise on the mobilization of CMV-specific T-cells in the peripheral blood compartment. Methods: Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-minutes at ~80% peak cycling power. Isolated blood lymphocytes phenotypes were assessed by flow cytometry and Enzyme-linked immunospot (ELISPOT) analysis was used to determine the frequency and function of T-cells secreting IFN-g in response to CMV antigens. Maximum likelihood linear mixed models (LMM) were used to determine main effects of exercise (pre, post and 1h post-exercise), age (young or old) and CMV status (positive or negative) on total numbers of blood lymphocytes and their subsets. Results: Those with CMV redeployed ~2 times more CD8+ T-cells and ~6-times more KLRG1+/CD28- and CD45RA+/CCR7- CD8+ subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8+ T-cells, CD45RA+/CCR7+ and (KLRG1-/CD28+) CD8+ subsets. Redeployed CD8+ T-cell numbers were similar between infected young and old. CMVpp65 specific CD8+ cells in HLA/A2* subjects increased ~2.7 fold after exercise, a response that was driven by the KLRG1+/CD28-/CD8+ subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4 fold increases in CMVpp65 and CMV IE-1 IFN-g secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. Conclusion: We conclude that latent CMV infection overrides age-related impairments in CD8+ T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high-differentiated effector memory phenotype. We anticipate that these findings may have clinical implications, with acute exercise serving as a simple strategy to increase numbers of available antigen-specific cells in blood that can be harvested for expansion and adoptive T-cell transfer in HSCT recipients

Obesity Related Alterations in Plasma Cytokines and Metabolic Hormones in Chimpanzees

Obesity is characterized by chronic low-grade inflammation and serves as a major risk factor for hypertension, coronary artery disease, dyslipidemias, and type-2 diabetes. The purpose of this study was to examine changes in metabolic hormones, inflammatory cytokines, and immune function, in lean, overweight, and obese chimpanzees in a controlled environment. We observed increased plasma circulating levels of proinflammatory TH-1 cytokines, Interferon gamma, interleukin-6, interleukin-12p40, tumor necrosis factor, soluble CD40 ligand, and Interleukin-1β and anti-inflammatory TH-2 cytokines, Interleukin-4, Interleukin-RA, Interleukin-10, and Interleukin-13 in overweight and obese chimpanzees. We also observed increased levels of metabolic hormones glucagon-like-peptide-1, glucagon, connecting peptide, insulin, pancreatic peptide YY3–36, and leptin in the plasma of overweight and obese chimpanzees. Chemokine, eotaxin, fractalkine, and monocyte chemoattractant protein-1 were higher in lean compared to obese chimpanzees, while chemokine ligand 8 increased in plasma of obese chimpanzees. We also observed an obesity-related effect on immune function as demonstrated by lower mitogen induced proliferation, and natural killer activity and higher production of IFN-γ by PBMC in Elispot assay, These findings suggest that lean, overweight, and obese chimpanzees share circulating inflammatory cytokines and metabolic hormone levels with humans and that chimpanzees can serve as a useful animal model for human studies

UK B.1.1.7 variant exhibits increased respiratory replication and shedding in nonhuman primates.

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, African green monkeys were infected intranasally with either a contemporary D614G or the UK B.1.1.7 variant. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tract tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases. ONE-SENTENCE SUMMARY: UK B.1.1.7 infection of African green monkeys exhibits increased respiratory replication and shedding but no disease enhancement

A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques

The deployment of a vaccine that limits transmission and disease likely will be required to end the coronavirus disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S [chimpanzee adenovirus-severe acute respiratory syndrome-coronavirus-2-S]) in the upper and lower respiratory tracts of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged 1 month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induces neutralizing antibodies and T cell responses and limits or prevents infection in the upper and lower respiratory tracts after SARS-CoV-2 challenge. As ChAd-SARS-CoV-2-S confers protection in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans

Privatization and State Capacity in Postcommunist Society

Economists have used cross-national regression analysis to argue that postcommunist economic failure is the result of inadequate adherence liberal economic policies. Sociologists have relied on case study data to show that postcommunist economic failure is the outcome of too close adherence to liberal policy recommendations, which has led to an erosion of state effectiveness, and thus produced poor economic performance. The present paper advances a version of this statist theory based on a quantitative analysis of mass privatization programs in the postcommunist world. We argue that rapid large-scale privatization creates severe supply and demand shocks for enterprises, thereby inducing firm failure. The resulting erosion of tax revenues leads to a fiscal crisis for the state, and severely weakens its capacity and bureaucratic character. This, in turn, reacts back on the enterprise sector, as the state can no longer support the institutions necessary for the effective functioning of a modern economy, thus resulting in deindustrialization. Using cross-national regression techniques we find that the implementation of mass privatization programs negatively impacts measures of economic growth, state capacity and the security of property rights.http://deepblue.lib.umich.edu/bitstream/2027.42/40192/3/wp806.pd

SARS-Like coronavirus WIV1-CoV does not replicate in Egyptian fruit bats (Rousettus aegyptiacus)

Severe acute respiratory syndrome (SARS)-like WIV1-coronavirus (CoV) was first isolated from Rhinolophus sinicus bats and can use the human angiotensin converting enzyme 2 (ACE2) receptor. In the current study, we investigate the ability of WIV1-CoV to infect Rousettus aegyptiacus bats. No clinical signs were observed throughout the experiment. Furthermore, only four oropharyngeal swabs and two respiratory tissues, isolated on day 3 post inoculation, were found positive for viral RNA. Two out of twelve bats showed a modest increase in coronavirus specific antibodies post challenge. In conclusion, WIV1-CoV was unable to cause a robust infection in Rousettus aegyptiacus bats

Immunological correlates of protection afforded by PHV02 live, attenuated recombinant vesicular stomatitis virus vector vaccine against Nipah virus disease

IntroductionImmune correlates of protection afforded by PHV02, a recombinant vesicular stomatitis (rVSV) vector vaccine against Nipah virus (NiV) disease, were investigated in the African green monkey (AGM) model. Neutralizing antibody to NiV has been proposed as the principal mediator of protection against future NiV infection.MethodsTwo approaches were used to determine the correlation between neutralizing antibody levels and outcomes following a severe (1,000 median lethal doses) intranasal/intratracheal (IN/IT) challenge with NiV (Bangladesh): (1) reduction in vaccine dose given 28 days before challenge and (2) challenge during the early phase of the antibody response to the vaccine.ResultsReduction in vaccine dose to very low levels led to primary vaccine failure rather than a sub-protective level of antibody. All AGMs vaccinated with the nominal clinical dose (2 × 107 pfu) at 21, 14, or 7 days before challenge survived. AGMs vaccinated at 21 days before challenge had neutralizing antibodies (geometric mean titer, 71.3). AGMs vaccinated at 7 or 14 days before challenge had either undetectable or low neutralizing antibody titers pre-challenge but had a rapid rise in titers after challenge that abrogated the NiV infection. A simple logistic regression model of the combined studies was used, in which the sole explanatory variable was pre-challenge neutralizing antibody titers. For a pre-challenge titer of 1:5, the predicted survival probability is 100%. The majority of animals with pre-challenge neutralizing titer of ≥1:20 were protected against pulmonary infiltrates on thoracic radiograms, and a majority of those with titers ≥1:40 were protected against clinical signs of illness and against a ≥fourfold antibody increase following challenge (indicating sterile immunity). Controls receiving rVSV-Ebola vaccine rapidly succumbed to NiV challenge, eliminating the innate immunity stimulated by the rVSV vector as a contributor to survival in monkeys challenged as early as 7 days after vaccination.Discussion and conclusionIt was concluded that PHV02 vaccine elicited a rapid onset of protection and that any detectable level of neutralizing antibody was a functional immune correlate of survival

Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures

<p>Abstract</p> <p>Background</p> <p>Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.</p> <p>Methods</p> <p>We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.</p> <p>Results</p> <p>Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.</p> <p>Conclusions</p> <p>Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.</p

Cost-effectiveness of decompression according to Gill versus instrumented spondylodesis in the treatment of sciatica due to low grade spondylolytic spondylolisthesis: A prospective randomised controlled trial [NTR1300]

Background. Nerve root decompression with instrumented spondylodesis is the most frequently performed surgical procedure in the treatment of patients with symptomatic low-grade spondylolytic spondylolisthesis. Nerve root decompression without instrumented fusion, i.e. Gill's procedure, is an alternative and less invasive approach. A comparative cost-effectiveness study has not been performed yet. We present the design of a randomised controlled trial on cost-effectiveness of decompression according to Gill versus instrumented spondylodesis. Methods/design. All patients (age between 18 and 70 years) with sciatica or neurogenic claudication lasting more than 3 months due to spondylolytic spondylolisthesis grade I or II, are eligible for inclusion. Patients will be randomly allocated to nerve root decompression according to Gill, either unilateral or bilateral, or pedicle screw fixation with interbody fusion. The main primary outcome measure is the functional assessment of the patient measured with the Roland Disability Questionnaire for Sciatica at 12 weeks and 2 years. Other primary outcome measures are perceived recovery and intensity of leg pain and low back pain. The secondary outcome measures include, incidence of re-operations, complications, serum creatine phosphokinase, quality of life, medical consumption, costs, absenteeism, work perception, depression and anxiety, and treatment preference. The study is a randomised prospective multicenter trial in which two surgical techniques are compared in a parallel group design. Patients and research nurse will not be blinded during the follow-up period of 2 years. Discussion. Currently, nerve root decompression with instrumented fusion is the golden standard in the surgical treatment of low-grade spondylolytic spondylolisthesis, although scientific proof justifying instrumented spondylodesis over simple decompression is lacking. This trial is designed to elucidate the controversy in best surgical treatment of symptomatic patients with low-