Hyaluronic acid-decorated liposomes as innovative targeted delivery system for lung fibrotic cells

Collagen Tissue Disease-associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1\u3b2, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-\u3b2 mRNA. However, upon analyzing TGF-\u3b2 release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients

Calcineurin Inhibitor-Based Immunosuppression and COVID-19: Results from a Multidisciplinary Cohort of Patients in Northern Italy

The role of immunosuppression in SARS-CoV-2-related disease (COVID-19) is a matter of debate. We here describe the course and the outcome of COVID-19 in a cohort of patients undergoing treatment with calcineurin inhibitors. In this monocentric cohort study, data were collected from the COVID-19 outbreak in Italy up to April 28th 2020. Patients were followed at our hospital for solid organ transplantation or systemic rheumatic disorders (RMDs) and were on calcineurin inhibitor (CNI)-based therapy. Selected patients were referred from the North of Italy. The aim of our study was to evaluate the clinical course of COVID-19 in this setting. We evaluated 385 consecutive patients (220 males, 57%; median age 61 years, IQR 48-69); 331 (86%) received solid organ transplantation and 54 (14%) had a RMD. CNIs were the only immunosuppressant administered in 47 patients (12%). We identified 14 (4%) COVID-19 patients, all transplanted, mainly presenting with fever (86%) and diarrhea (71%). Twelve patients were hospitalized and two of them died, both with severe comorbidities. No patients developed acute respiratory distress syndrome or infectious complications. The surviving 10 patients are now fully recovered. The clinical course of COVID-19 patients on CNIs is generally mild, and the risk of superinfection seems low

Deficit of social cognition in subjects with surgically treated frontal lobe lesions and in subjects affected by schizophrenia

The ability of humans to predict and explain other people’s behaviour by attributing independent mental states such as desires and beliefs to them, is considered to be due to our ability to construct a “Theory of Mind”. Recently, several neuroimaging studies have implicated the medial frontal lobes as playing a critical role in a dedicated “mentalizing” or “Theory of Mind” network in the human brain. In this study we compare the performance of patients with right and left medial prefrontal lobe lesions in theory of mind and in social cognition tasks, with the performance of people with schizophrenia. We report a similar social cognitive profile between patients with prefrontal lobe lesions and schizophrenic subjects in terms of understanding of false beliefs, in understanding social situations and in using tactical strategies. These findings are relevant for the functional anatomy of “Theory of Mind”

Effect of induction therapy on peripheral blood lymphocytes after lung transplantation: A multicenter international study

International audienceIntroduction: Lymphocytes, which are targeted by immunosuppressive therapies, may be influenced by induction and recipient characteristics. The objective of this study was to evaluate the influence of induction therapy on lymphocyte kinetics after lung transplantation (LTx) according to the recipient characteristics and allograft outcomes. Methods: We retrospectively collected total lymphocyte counts from peripheral blood, which was monitored before and after transplantation (days 7, 14, 30, 90, 180, 365 and 730) in patients from 3 different lung transplant centers in Europe who encountered different induction strategies (no induction, anti-thymocyte globulins and basiliximab). Results: A total of 164 recipients were included: 50 patients who did not receive induction therapy and 114 patients who received induction therapy (57 with anti-thymocyte globulins and 57 with basiliximab). The pre-transplant lymphocyte levels and induction therapy were associated with higher lymphocyte differences between pre-transplantation and day 7 (p < .001). The lymphocyte reconstitution was correlated with the pre-transplant weight (+10 cells/mu L/kg, 95%CI [+5; +15], p < 0.001), pre-transplant lymphocyte level (-248 cells/mu L, 95%CI [-368; -127] between low and high level recipients, p < 0.001), induction therapy with anti-thymocyte globulins (-636 cells/mu L, 95%CI [-797; -475], p < 0.001), and induction with basiliximab (-641 cells/mu L, 95%CI [-801; -481], p < 0.001) compared with no induction. Age was associated with a delayed reconstitution at day 30 (-9 cells/mu L/year, 95%CI [-17; -1], p = 0.04) and day 90 (-8 cells/mu L/year, 95%CI [-16; -1], p = 0.04). One-year mortality was associated with a lower lymphocyte count (-325 cells/mu L, 95%CI [-522; -128), p = 0.001) and a best predictive threshold of 1000 cells/mu L at day 90. Conclusion: The blood lymphocyte count after LTx is associated with the pre-transplant lymphocyte level, age, weight and induction therapy and predicts one-year mortality

Virulence of Mycobacterium tuberculosis affects inteleukin-8, monocyte chemoattractant protein-1 and interleukin-10 production by human mononuclear phagocytes

Microbial virulence and cytokine-mediated immune responses to Mycobacterium tuberculosis infection are important determinants of the pathogenesis of human tuberculosis. To determine the interrelationship between mycobacterial virulence and cytokine induction, human monocytes and monocyte-derived macrophages were infected with attenuated (H37Ra) and virulent (H37Rv and CH306) strains of M. tuberculosis and the amount of proinflammatory [interleukin (IL)-8 and monocyte chemoattractant protein (MCP)- 1] and inhibitory (IL- 10) cytokines was measured in the culture supernatants by enzyme-linked immunosorbent assay (ELISA). Infection with live bacilli induced de novo synthesis of IL-8, MCP-1 and IL-10, since cytokine release was abolished when cells were preincubated with the protein synthesis inhibitor cycloheximide. A differential production of antiinflammatory and inhibitory cytokines was observed. The amount of IL-8 and MCP-1 release was inversely related to strain virulence, the attenuated H37Ra strain being more prone than virulent strains to induce secretion of chemokines. In contrast, virulent strains induced greater amounts of the inhibitory cytokine IL-10. Efficient upregulation of IL-10 synthesis, but not of chemokines, required infection of cells with live bacilli, since heat killing of organisms or challenge with soluble mycobacterial products completely abrogated the effect. Moreover, cells infected with virulent strains produced IL-10 even at a very low bacillus-to-cell ratio and secreted IL-10 continuously during the 96 h that followed infection. The results suggest that the degree of virulence affects host cell responses to M. tuberculosis infection. Continued production of IL-10 may be one of the means by which M. tuberculosis downregulates acute local inflammatory reactions, favoring the development of tuberculosis

A 10-year survey of Mycobacterium tuberculosis isolates in Pavia and their drug resistance: a comparison with other Italian reports

A retrospective review was made of the bacteriological and medical records of patients with culture-confirmed pulmonary tuberculosis who attended the IRCCS San Matteo Polyclinic of Pavia, between 1990 and 2000. Altogether, 279 patients were included in the survey: 220 new cases and 59 prior treatment cases. Resistance to at least one drug, and resistance to both isoniazid and rifampicin (MDR) were more common among previously treated patients than among new cases (86.4% vs. 34.1%, and 44% vs. 5.9%, respectively). While the frequency of resistance to any drug showed no variation in the period examined, a trend toward a progressive decrease in the frequency of primary MDR-TB was observed (from 11.9% in 1990-1992 to 1.3% in 1998-2000). The level of resistance observed in our study suggests that all isolates of Mycobacterium tuberculosis should be tested for drug susceptibility, especially when obtained from patients who report a previous episode of the disease

T-lymphocyte subsets in lung transplant recipients: Association between nadir CD4 T-cell count and viral infections after transplantation

BACKGROUND: Little is known about the kinetics of T-cell subsets in lung transplant recipients (LTR) and their association with the occurrence of opportunistic infections (OI). OBJECTIVES: To analyze the kinetics of T-lymphocyte subsets in LTR and the association between nadir CD4 T-cell count and viral infections after transplantation. STUDY DESIGN: Serial measurements of peripheral blood CD4 and CD8 T-cell counts obtained during the first year post-transplantation from 83 consecutive LTR and their correlation with both viral OI and community-acquired infections post-transplantation were retrospectively analyzed. RESULTS: LTR with a nadir CD4 T-cell count 200 cells/μl (p200 cells/μl (p=0.0012 and p=0.0058, respectively). A nadir CD4 T-cell count <200 cells/μl within the first three months post-transplantation predicted a higher frequency of viral infectious episodes in BAL samples within the subsequent six month period (p=0.0066). CONCLUSIONS: Stratification of patients according to nadir CD4 T-cell count may represent a new and simple approach for early identification of patients at risk for subsequent virus infections

Clinical utility of CD4+ function assessment (ViraCor-IBT ImmuKnow test) in lung recipients

Abstract The ImmuKnow assay measures cell-mediated immunity, quantifying ATP production from peripheral blood CD4 + T-cells in solid-organ transplant patients who undergo immunosuppressive therapy. We aimed to measure functional immunity in lung transplant recipients and correlate Immuknow values with immunosuppression levels, presence of chronic lung allograft dysfunction (CLAD) and infections. We evaluated 61 lung recipients who underwent follow-up for lung transplantation between 2010 and 2014. Rejection and infection were retrospectively analyzed. The association between over-immunosuppression and a number of predictors was assessed by means of univariate and multivariate logistic regression models. 71 out of 127 samples (56%) showed an over-immunosuppression with an ImmuKnow assay mean level of 112.92 ng/ml (SD ± 58.2), vs. 406.14 ng/ml (SD ± 167.7) of the rest of our cohort. In the over-immunosuppression group we found 51 episodes of infection (71%) (OR 2.754, 95% CI 1.40–5.39; P-value 0.003). In the other group, only 25 samples (44%) were taken during an infectious episode. The mean absolute ATP level was significantly different between patients with or without infection (202.38 ± 139.06 ng/ml vs. 315.51 ± 221.60 ng/ml; P < 0.001). RAS (Restrictive allograft syndrome) was associated to low ImmuKnow level (P < 0.001). These results were confirmed by the multivariate analysis. The ImmuKnow assay levels were significantly lower in infected lung transplant recipients compared with non-infected recipients and in RAS patients