Abstract
The objective of the present study was to identify biological signatures of severe coronavirus disease 2019 (COVID-19) predictive of admission in the intensive care unit (ICU). Over 170 ...immunological markers were investigated in a ‘discovery’ cohort (n = 98 patients) of the Lausanne University Hospital (LUH-1). Here we report that 13 out of 49 cytokines were significantly associated with ICU admission in the three cohorts (
P
< 0.05 to
P
< 0.001), while cellular immunological markers lacked power in discriminating between ICU and non-ICU patients. The cytokine results were confirmed in two ‘validation’ cohorts,
i.e
. the French COVID-19 Study (FCS; n = 62) and a second LUH-2 cohort (n = 47). The combination of hepatocyte growth factor (HGF) and C-X-C motif chemokine ligand 13 (CXCL13) was the best predictor of ICU admission (positive and negative predictive values ranging from 81.8% to 93.1% and 85.2% to 94.4% in the 3 cohorts) and occurrence of death during patient follow-up (8.8 fold higher likelihood of death when both cytokines were increased). Of note, HGF is a pleiotropic cytokine with anti-inflammatory properties playing a fundamental role in lung tissue repair, and CXCL13, a pro-inflammatory chemokine associated with pulmonary fibrosis and regulating the maturation of B cell response. Up-regulation of HGF reflects the most powerful counter-regulatory mechanism of the host immune response to antagonize the pro-inflammatory cytokines including CXCL13 and to prevent lung fibrosis in COVID-19 patients.
IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects ...including severe pulmonary edema. Here, we show that IL-2-induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rβγ, including CD8⁺ T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31⁺ pulmonary endothelial cells via binding to functional αβγ IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2-mediated pulmonary edema was abrogated by a blocking antibody to IL-2Rα (CD25), genetic disruption of CD25, or the use of IL-2Rβγ—directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Rαβγ⁺ pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rβγ⁺ effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2-based tumor immunotherapy.
Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. ...However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir.
clinicaltrials.gov NTC02092116.
The partial efficacy reported in the RV144 HIV vaccine trial in 2009 has driven the HIV vaccine field to define correlates of risk associated with HIV-1 acquisition and connect these functionally to ...preventing HIV infection. Immunological correlates, mainly including CD4(+) T cell responses to the HIV envelope and Fc-mediated antibody effector function, have been connected to reduced acquisition. These immunological correlates place immunological and genetic pressure on the virus. Indeed, antibodies directed at conserved regions of the V1V2 loop and antibodies that mediate antibody-dependent cellular cytotoxicity to HIV envelope in the absence of inhibiting serum immunoglobulin A antibodies correlated with decreased HIV risk. More recently, researchers have expanded their search with nonhuman primate studies using vaccine regimens that differ from that used in RV144; these studies indicate that non-neutralizing antibodies are associated with protection from experimental lentivirus challenge as well. These immunological correlates have provided the basis for the design of a next generation of vaccine regimens to improve upon the qualitative and quantitative degree of magnitude of these immune responses on HIV acquisition.
Decision making under risk entails the anticipation of prospective outcomes, typically leading to the greater sensitivity to losses than gains known as loss aversion. Previous studies on the neural ...bases of choice-outcome anticipation and loss aversion provided inconsistent results, showing either bidirectional mesolimbic responses of activation for gains and deactivation for losses, or a specific amygdala involvement in processing losses. Here we focused on loss aversion with the aim to address interindividual differences in the neural bases of choice-outcome anticipation. Fifty-six healthy human participants accepted or rejected 104 mixed gambles offering equal (50%) chances of gaining or losing different amounts of money while their brain activity was measured with functional magnetic resonance imaging (fMRI). We report both bidirectional and gain/loss-specific responses while evaluating risky gambles, with amygdala and posterior insula specifically tracking the magnitude of potential losses. At the individual level, loss aversion was reflected both in limbic fMRI responses and in gray matter volume in a structural amygdala-thalamus-striatum network, in which the volume of the "output" centromedial amygdala nuclei mediating avoidance behavior was negatively correlated with monetary performance. We conclude that outcome anticipation and ensuing loss aversion involve multiple neural systems, showing functional and structural individual variability directly related to the actual financial outcomes of choices. By supporting the simultaneous involvement of both appetitive and aversive processing in economic decision making, these results contribute to the interpretation of existing inconsistencies on the neural bases of anticipating choice outcomes.
The detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies in the serum of an individual indicates previous infection or vaccination. However, it provides ...limited insight into the protective nature of this immune response. Neutralizing antibodies recognizing the viral spike protein are more revealing, yet their measurement traditionally requires virus- and cell-based systems that are costly, time-consuming, inflexible, and potentially biohazardous. Here, we present a cell-free quantitative neutralization assay based on the competitive inhibition of trimeric SARS-CoV-2 spike protein binding to the angiotensin-converting enzyme 2 (ACE2) receptor. This high-throughput method matches the performance of the gold standard live virus infection assay, as verified with a panel of 206 seropositive donors with varying degrees of infection severity and virus-specific immunoglobulin G titers, achieving 96.7% sensitivity and 100% specificity. Furthermore, it allows for the parallel assessment of neutralizing activities against multiple SARS-CoV-2 spike protein variants of concern. We used our assay to profile serum samples from 59 patients hospitalized with coronavirus disease 2019 (COVID-19). We found that although most sera had high activity against the 2019-nCoV parental spike protein and, to a lesser extent, the α (B.1.1.7) variant, only 58% of serum samples could efficiently neutralize a spike protein derivative containing mutations present in the β (B.1.351) variant. Thus, we have developed an assay that can evaluate effective neutralizing antibody responses to SARS-CoV-2 spike protein variants of concern after natural infection and that can be applied to characterize vaccine-induced antibody responses or to assess the potency of monoclonal antibodies.
IL-2 plays a pivotal role in regulating the adaptive immune system by controlling the survival and proliferation of regulatory T (Treg) cells, which are required for the maintenance of immune ...tolerance. Moreover, IL-2 is implicated in the differentiation and homeostasis of effector T-cell subsets, including TH 1, TH 2, TH 17, and memory CD8+ T cells. The IL-2 receptor is composed of 3 distinct subunits, namely the α (CD25), β (CD122), and γ (γc) chains. Of crucial importance for the delivery of IL-2 signals to Treg cells is the expression of CD25, which, along with CD122 and γc, confers high affinity binding to IL-2. Notably, recent findings suggest a novel role for CD25, whereby CD25 molecules on Treg cells and possibly other cells are capable of influencing T-cell homeostasis by means of IL-2 deprivation. This review explores these findings and integrates them into our current understanding of T-cell homeostasis.
The field of vaccinology began in ignorance of how protection was instilled in vaccine recipients. Today, a greater knowledge of immunology allows us to better understand what is being stimulated by ...various vaccines that leads to their protective effects: that is, their correlates of protection. Here we describe what is known about the correlates of protection for existing vaccines against a range of different viral diseases and discuss the correlates of protection against disease during natural infection with HIV-1. We will also discuss why it is important to design phase 3 clinical trials of HIV vaccines to determine the correlates of protection for each individual vaccine.
The present study was conducted to investigate whether a different implant neck design could affect survival rate and peri-implant tissue health in a cohort of disease-free partially edentulous ...patients in the molar-premolar region. The investigation was conducted on 122 dental implants inserted in 97 patients divided into two groups: Group A (rough wide-neck implants) vs. Group B (rough reduced-neck implants). All patients were monitored through clinical and radiological checkups. Survival rate, probing depth, and marginal bone loss were assessed at 12- and 24-month follow-ups. Patients assigned to Group A received 59 implants, while patients assigned to Group B 63. Dental implants were placed by following a delayed loading protocol, and cemented metal-ceramic crowns were delivered to the patients. The survival rates for both Group A and B were acceptable and similar at the two-year follow-up (96.61% vs. 95.82%). Probing depth and marginal bone loss tended to increase over time (
: t
= 12 vs. t
= 24 months) in both groups of patients. Probing depth (
= 0.015) and bone loss (
= 0.001) were significantly lower in Group A (3.01 vs. 3.23 mm and .92 vs. 1.06 mm; Group A vs. Group B). Within the limitations of the present study, patients with rough wide-neck implants showed less marginal bone loss and minor probing depth, as compared to rough reduced-neck implants placed in the molar-premolar region. These results might be further replicated through longer-term trials, as well as comparisons between more collar configurations (e.g., straight vs. reduced vs. wide collars).
Mn-WO
3
/TiO
2
catalysts were investigated for Selective Catalytic Reduction (SCR) of NO with NH
3
. The catalysts were synthesized by wetness impregnation method with different Mn loadings (1.5-3-12 ...wt%) on 8wt%WO
3
/TiO
2
. All three catalysts were compared with 8wt%WO
3
/TiO
2
and bare MnO
x
oxide, used as references. The 1.5wt%Mn-8wt%WO
3
/TiO
2
exhibited the highest performance in NO conversion and N
2
selectivity. A commercial catalyst, based on titania supported vanadia and tungsta, (V
2
O
5
-WO
3
/TiO
2
), widely used for its high efficiency, was also investigated in the present work. The morphological, structural, redox and electronic properties of the catalysts and their thermal stability were studied by several techniques (N
2
adsorption/desorption, X-ray diffraction, H
2
temperature-programmed reduction, NH
3
temperature programmed desorption, X-ray photoelectron spectroscopy).
The aim of this paper is to study the effect of different Mn loadings on 8wt%WO
3
/TiO
2
with the ambition to obtain highly active and selective catalysts in a large window of temperature. The replacement of toxic vanadium used in the classic V
2
O
5
-WO
3
/TiO
2
catalyst with MnO
x
in the best performing catalyst, 1.5wt%Mn-8wt%WO
3
/TiO
2,
represents an important achievement to improve the environmental sustainability.
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