On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3−/− mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustio

Palliative Care in Children With Advanced Heart Disease in a Tertiary Care Environment: A Mini Review

Palliative care for children continues to evolve. More recently, this has also been true in the field of pediatric cardiology, particularly for children with advanced heart disease. In these children, similarly to children with cancer, treatment successes are offset by the risks of long-term morbidities, including premature death. This mini review aims to provide an overview of current knowledge on children suffering from advanced heart disease, their medical care during various phases of illness (including the palliative and end-of-life phase), symptom burden, experiences of parents, prognostic understanding of parents and physicians, and current status of the involvement of pediatric palliative care. In conclusion, the suffering of these children at the end of their young lives is pronounced and many parents feel prepared neither for medical problems nor for the child's death. An effective and mutually trusting partnership between pediatric cardiology and pediatric palliative care would appear to be a prerequisite for the timely involvement of palliative care in further supporting these children and their families

Estimating the in vivo killing efficacy of cytotoxic T lymphocytes across different peptide-MHC complex densities

Cytotoxic T lymphocytes (CTLs) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. Recently developed experimental methods allow the estimation of the CTL's efficacy in detecting and clearing infected host cells. One method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. Surprisingly, killing efficacies measured by this method are often much higher than estimates obtained by other methods based on, for instance, the dynamics of escape mutations. In this study, we investigated what fraction of this variation can be explained by differences in peptide loads employed in in vivo killing assays. We addressed this question in mice immunized with lymphocytic choriomeningitis virus (LCMV). We conducted in vivo killing assays varying the loads of the immunodominant epitope GP33 on target cells. Using a mathematical model, we determined the efficacy of effector and memory CTL, as well as CTL in chronically infected mice. We found that the killing efficacy is substantially reduced at lower peptide loads. For physiological peptide loads, our analysis predicts more than a factor 10 lower CTL efficacies than at maximum peptide loads. Assuming that the efficacy scales linearly with the frequency of CTL, a clear hierarchy emerges among the groups across all peptide antigen concentrations. The group of mice with chronic LCMV infections shows a consistently higher killing efficacy per CTL than the acutely infected mouse group, which in turn has a consistently larger efficacy than the memory mouse group. We conclude that CTL killing efficacy dependence on surface epitope frequencies can only partially explain the variation in in vivo killing efficacy estimates across experimental methods and viral systems, which vary about four orders of magnitude. In contrast, peptide load differences can explain at most two orders of magnitude

Katalog druków śląskich XV-XVIII wieku ze zbiorów Zakładu Narodowego im. Ossolińskich - recenzja

Recenzja książki : Katalog druków śląskich XV-XVIII wieku ze zbiorów Zakładu Narodowego im. Ossolińskich. Oprac. Małgorzata Minkowska, Wrocław: Wydawnictwo Ossolineum, 2020, ss. 287, il., Osso Wczoraj i Dziś; ISBN 978-83-66267-12-

Do Predictors Exist for a Successful Withdrawal of Preoperative Prostaglandin E1 from Neonates with d-Transposition of the Great Arteries and Intact Ventricular Septum?

Prostaglandin E1 (PGE1) is given to neonates with d-transposition of the great arteries (d-TGA) to reduce cyanosis by reopening and maintaining the patency of the ductus arteriosus. To avoid side effects, this medication can be stopped for hemodynamically stable patients after balloon atrial septostomy (BAS). A consecutive series of neonates with d-TGA and an intact ventricular septum (IVS) presenting from 2000 through 2005 was analyzed retrospectively to search for side effects of PGE1 and to identify predictors for a safe preoperative withdrawal. The medication was stopped for hemodynamically stable patients with transcutaneous oxygen saturations higher than 80% after BAS and reinitiated for patients with an oxygen saturation lower than 65%. Patients successfully weaned were compared with those who had failed weaning in terms of atrial septal defect (ASD) size, ductus arteriosus size, and the transcutaneous oxygen saturation. Prostaglandin E1 was initiated for all 43 neonates with d-TGA. The median maintenance dose of PGE1 was 0.00625μg/kg/min (range, 0.00313-0.050μg/kg/min) for a median duration of 6days (range, 1-12days). For 16 patients, PGE1 was preoperatively withdrawn but then had to be reinitiated for 7 of the 16 patients. No predictors for a successful weaning of PGE1 were found based on ASD size, ductus arteriosus size, or oxygen saturation. The adverse effects of PGE1 were apnea in 10 patients and fever in 19 patients. Neither seizures nor necrotizing enterocolitis was documented. Prostaglandin E1 was successfully withdrawn for a minority of hemodynamically stable patients with d-TGA. No predictors for a successful weaning could be identified. Because apnea and fever are common side effects, withdrawal of PGE1 after BAS may improve patient safety and comfort. In this patient group, if PGE1 withdrawal was not well tolerated, it could be safely reinitiated. There were no serious side effects of PGE

No evidence for competition between cytotoxic T-lymphocyte responses in HIV-1 infection

Strong competition between cytotoxic T-lymphocytes (CTLs) specific for different epitopes in human immunodeficiency virus (HIV) infection would have important implications for the design of an HIV vaccine. To investigate evidence for this type of competition, we analysed CTL response data from 97 patients with chronic HIV infection who were frequently sampled for up to 96 weeks. For each sample, CTL responses directed against a range of known epitopes in gag, pol and nef were measured using an enzyme-linked immunospot assay. The Lotka–Volterra model of competition was used to predict patterns that would be expected from these data if competitive interactions materially affect CTL numbers. In this application, the model predicts that when hosts make responses to a larger number of epitopes, they would have diminished responses to each epitope and that if one epitope-specific response becomes dramatically smaller, others would increase in size to compensate; conversely if one response grows, others would shrink. Analysis of the experimental data reveals results that are wholly inconsistent with these predictions. In hosts who respond to more epitopes, the average epitope-specific response tends to be larger, not smaller. Furthermore, responses to different epitopes almost always increase in unison or decrease in unison. Our findings are therefore inconsistent with the hypothesis that there is competition between CTL responses directed against different epitopes in HIV infection. This suggests that vaccines that elicit broad responses would be favourable because they would direct a larger total response against the virus, in addition to being more robust to the effects of CTL escape

Immediate Cytotoxicity But Not Degranulation Distinguishes Effector and Memory Subsets of CD8+ T Cells

CD8+ T cells play a central role in the resolution and containment of viral infections. A key effector function of CD8+ T cells is their cytolytic activity toward infected cells. Here, we studied the regulation of cytolytic activity in naive, effector, and central versus effector memory CD8+ T cells specific for the same glycoprotein-derived epitope of lymphocytic choriomeningitis virus. Our results show that the kinetics of degranulation, assessed by a novel flow cytometric based assay, were identical in effector and both subsets of memory CD8+ T cells, but absent in naive CD8+ T cells. However, immediate cytolytic activity was most pronounced in effector T cells, low in effector memory T cells, and absent in central memory T cells, correlating with the respective levels of cytolytic effector molecules present in lytic granules. These results indicate that an inherent program of degranulation is a feature of antigen-experienced cells as opposed to naive CD8+ T cells and that the ability of CD8+ T cells to induce target cell apoptosis/death is dependent on granule protein content rather than on the act of degranulation itself. Furthermore, these results provide a potential mechanism by which central memory CD8+ T cell–mediated death of antigen-presenting cells within the lymph node is avoided

Outcome of Biventricular Repair in Infants With Multiple Left Heart Obstructive Lesions

The decision to perform biventricular repair for infants with multiple obstructive or hypoplastic left heart lesions (LHL) and borderline left ventricle (LV) may be controversial. This study sought to assess the mortality and morbidity of patients with LHL after biventricular repair and to determine the growth of the left-sided cardiac structures. Retrospective analysis of 39 consecutive infants with LHL who underwent biventricular repair was performed. The median age at surgery was 7days (range 1-225days), and the median follow-up period was 34months (range 1-177months). Between diagnosis and the end of the follow-up period, the size of the aortic annulus (z-score −4.1±2.8 vs. −0.1±2.7) and the LV (LV end-diastolic diameter z-score −1.7±2.8 vs. 0.21±1.7) normalized. During the follow-up period, 23 patients required 39 reinterventions (62%) consisting of redo surgery for 21 patients (57%) and catheter-guided reinterventions for 8 patients (22%). At the end of the follow-up period, 25 of 34 patients were doing subjectively well; 10 children (29%) received cardiac medication; 12 (35%) presented with failure to thrive (weight ≤ P3) and 5 (15%) with pulmonary hypertension. The overall mortality rate was 13%. Biventricular repair for patients with multiple LHL results in sufficient growth of the left-sided cardiac structures. Nevertheless, residual or newly developing obstructive lesions and pulmonary hypertension are frequent, causing significant morbidity that requires reinterventio