234 research outputs found
L-arginine deprivation impairs Leishmania major-specific T-cell responses.
No full textThe amino acid L-arginine plays a crucial role in the regulation of immune responses. We have recently shown that uncontrolled replication of Leishmania parasites at the site of pathology correlates with high levels of arginase activity in nonhealing leishmaniasis and that this elevated arginase activity causes local depletion of L-arginine. To further our understanding of the impact of L-arginine deprivation in experimental leishmaniasis, here we characterize in detail the effects of L-arginine deprivation on antigen-specific T cells and MPhi. The results of our study show that decrease of L-arginine levels in the extracellular milieu affects the biological activities of Leishmania major-specific T cells, both at the level of the magnitude and the quality of their responses. L. major-specific CD4(+) T cells rendered hyporesponsive by L-arginine deprivation can be partially rescued by addition of exogenous L-arginine to produce IL-4 and IL-10, but not to produce IFN-gamma. Furthermore, our results show that L-arginine deprivation also greatly impacts parasite growth in activated macrophages. In summary, our results suggest that L-arginine levels affect both Th cell responses and parasite replication
Hyperaktivierung humaner T-Zellen durch neutrophile Granulozyten unter Arginaseinhibition
No full textIm TME wirken unterschiedlichste Mechanismen immunsuppressiv und hemmen vor allem T-Zellen in ihren antitumoralen Funktionen und Eigenschaften. Diese umfassen die Induktion und Rekrutierung von MDSCs, die Expression von hemmenden Rezeptoren, die Reduktion von Nährstoffen und Sauerstoff und somit veränderte metabolische Bedingungen für T-Zellen, die Sekretion von hemmenden Zytokinen oder ROS und die Arginase-vermittelte Depletion von der für die T-Zellaktivierung essenziellen Aminosäure Arginin. Diese vielfältigen immunsuppressiven Mechanismen machen deutlich, dass Tumor(immun)therapie vielfältig sein muss, um die Funktion von T-Zellen auf unterschiedlichste Weise zu unterstützen und zu verbessern. Ein bei konsekutiver Hemmung der Arginase-induzierten Arginin-Depletion gewonnener Überstand humaner PMN (PMN-ÜS) wirkt dagegen auf aktivierte T-Zellen sehr stark stimulierend, wie unserer Arbeitsgruppe erstmals gezeigt hatte.
In der hier vorliegenden Arbeit wurden verschiedene zentrale Aspekte dieser so hyperaktivierten T-Zellen detailliert untersucht. Diese T-Zellen zeigten eine deutliche Differenzierung hin zu effizienten antitumoralen T-Zellphänotypen wie TCM und naiven CD28+CD57- T-Zellen. Dies zeigte sich nicht nur in T-Zellen gesunder Spender, sondern auch in anergen und seneszenten T-Zellen aus dem Knochenmark und peripheren Blut von Patienten mit Multiplen Myelom, die bei Aktivierung in PMN-ÜS stark proliferieren können. Die Hyperaktivierung humaner T-Zellen war assoziiert mit einem gesteigerten Metabolismus, sowohl von Glykolyse als auch von oxidativer Phosphorylierung, vermehrter Glukose-Aufnahme sowie einem Kinase-Profil, welches mit einer gesteigerten Protein-Translation assoziiert ist. Auch konnte eine verstärkte Degranulation, ein Grundpfeiler effektiver Zytotoxizität, in den T-Zellen induziert werden. Hyperaktivierte T-Zellen zeigten eine bessere Viabilität in Langzeitkultivierungen und auch nach wiederholter peptidspezifischer Restimulation eine höhere antitumorale Zytotoxizität. Durch die PMN-induzierte Hyperaktivierung erlangen T-Zellen also Eigenschaften, die sie vermutlich deutlich effektiver in ihren antitumoralen Funktionen auch in vivo machen.
Ein Großteil der neu entwickelten Tumortherapien basiert auf der Aktivierung des T-Zell-Kompartiments im Immunsystem. Für ICI, CAR-T-Zellen, TCR-T-Zellen, Tumorimpfungen oder bispezifische Antikörper liefern die, molekular noch nicht identifizierten, durch PMN sezernierten T-Zell stimulierenden Faktoren unter Arginaseinhibition genau die Art der vielfältigen T-Zellaktivierung, die in der zukünftigen Tumorimmuntherapie eine immer größere Rolle spielen wird.174 Seiten ; Illustrationen, Diagramm
Prognostic Risk Factors in Randomized Clinical Trials of Face-to-Face and Internet-Based Psychotherapy for Depression: A Systematic Review and Meta-Regression Analysis.
No full textIMPORTANCE
Variables such as severe symptoms, comorbidity, and sociodemographic characteristics (eg, low educational attainment or unemployment) are associated with a poorer prognosis in adults treated for depressive symptoms. The exclusion of patients with a poor prognosis from RCTs is negatively associated with the generalizability of research findings.
OBJECTIVE
To compare the prognostic risk factors (PRFs) in patient samples of RCTs of face-to-face therapy (FTF) and internet-based therapy (IBT) for depression.
DATA SOURCES
PsycINFO, Cochrane CENTRAL, and reference lists of published meta-analyses were searched from January 1, 2000, to December 31, 2021.
STUDY SELECTION
RCTs that compared FTF (individual or group therapy) and IBT (guided or self-guided interventions) against a control (waitlist or treatment as usual) in adults with symptoms of depression were included.
DATA EXTRACTION AND SYNTHESIS
Data were extracted by 2 independent observers. The Cochrane revised risk-of-bias tool was used to assess the risk of bias. The study was preregistered with OSF Registries and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.
MAIN OUTCOMES AND MEASURES
The primary outcome was the standardized mean difference (Hedges g effect size) in depressive symptoms at treatment termination (assessed with standard patient self-report questionnaires), with a positive standardized mean difference indicating larger improvements in the intervention compared with those in the control group. Meta-regression analyses were adjusted for the type of control group. Three preregistered and 2 exploratory sensitivity analyses were conducted. A prognostic risk index (PROG) was created that calculated the sum of 12 predefined individual indicators, with scores ranging from 0 to 12 and higher scores indicating that a sample comprised patients with poorer prognoses.
RESULTS
This systematic review and meta-regression analysis identified 105 eligible RCTs that comprised 18 363 patients. In total, 48 studies (46%) examined FTF, and 57 studies (54%) examined IBT. The PROG was significantly higher in the RCTs of FTF than in the RCTs of IBT (FTF: mean [SD], 3.55 [1.75]; median [IQR], 3.5 [2.0-4.5]; IBT: mean [SD], 2.27 [1.66]; median [IQR], 2.0 [1.0-3.5]; z = -3.68, P < .001; Hedges g = 0.75; 95% CI, 0.36-1.15). A random-effects meta-regression analysis found no association of the PROG with the effect size. Sensitivity analyses with outliers excluded and accounting for risk of bias or small-study effects yielded mixed results on the association between the PROG and effect size.
CONCLUSIONS AND RELEVANCE
The findings of this systematic review and meta-regression analysis suggest that samples of RCTs of FTF vs IBT differ with regard to PRFs. These findings have implications for the generalizability of the current evidence on IBT for depression. More RCTs of internet-based interventions with clinically representative samples are needed, and the reporting of PRFs must be improved
Intensity of Treatment as Usual and Its Impact on the Effects of Face-to-Face and Internet-Based Psychotherapy for Depression: A Preregistered Meta-Analysis of Randomized Controlled Trials.
No full textINTRODUCTION
Treatment as usual (TAU) is the most frequently used control group in randomized trials of psychotherapy for depression. Concerns have been raised that the heterogeneity of treatments in TAU leads to biased estimates of psychotherapy efficacy and to an unclear difference between TAU and control groups like waiting list (WL).
OBJECTIVE
We investigated the impact of control group intensity (i.e., amount and degree to which elements of common depression treatments are provided) on the effects of face-to-face and internet-based psychotherapy for depression.
METHODS
We conducted a preregistered meta-analysis (www.osf.io/4mzyd). We included trials comparing psychotherapy with TAU or WL in patients with symptoms of unipolar depression. Six indicators were used to assess control group intensity.
PRIMARY OUTCOME
Standardized mean difference (SMD) of psychotherapy and control in depressive symptoms at treatment termination.
RESULTS
We included 89 trials randomizing 14,474 patients to 113 psychotherapy conditions and 89 control groups (TAU in 42 trials, WL in 47 trials). Control group intensity predicted trial results in preregistered (one-sided ps < 0.042) and exploratory analyses. Psychotherapy effects were significantly smaller (one-sided p = 0.002) in trials with higher intensity TAU (SMD = 0.324, CI 0.209 to 0.439) than in trials with lower intensity TAU (SMD = 0.628, CI 0.455 to 0.801). Psychotherapy effects against lower intensity TAU did not differ from effects against WL (two-sided p = 0.663).
CONCLUSIONS
Our results suggest that variation in TAU intensity impacts the outcome of trials. More scrutiny in the design of control groups for clinical trials is recommended
Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in Ethiopia.
No full textBACKGROUND: Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs. CONCLUSION: Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions
Human contact in internet-based interventions for depression: A pre-registered replication and meta-analysis of randomized trials
No full textIntroduction: Internet-based self-help interventions have shown to be effective in the treatment of depression. Several meta-analyses indicated that human contact has a crucial impact on adherence and outcome. While most research focused on the role of guidance during interventions, a review by Andersson and Johansson (2012) suggested that contact before the intervention too may play an important role. Objective: We investigated the impact of the degree of contact in internet-based interventions (IBIs) for depression on outcome in adults suffering from elevated symptoms of depression. Methods: We conducted a preregistered meta-analysis (www.osf.io/4mzyd) and included trials comparing IBIs for depression against control conditions (treatment as usual [TAU] or waiting list [WL]) in patients with symptoms of unipolar depression searching the databases PsycINFO and Cochrane's Central Register of Controlled Trials (CENTRAL) limited to entries from EMBASE and PubMed. Following Andersson and Johansson (2012), contact before an intervention was defined as having had a diagnostic interview before the IBI, and contact during intervention was defined as having received guidance during the IBI. IBIs were grouped as providing (0) no contact, (1) contact before the IBI, (2) contact during the IBI, or (3) contact both before and during the IBI. The primary outcome was standardized mean difference (SMD) of the IBI and control in depressive symptoms at treatment termination. Secondary outcomes were study dropout and adherence to the IBI. Results: We included 56 eligible trials that randomized 13,335 patients to 75 internet-based intervention conditions and control groups (TAU in 23 trials, WL in 33 trials). In total, 44 trials (78.57 %) were judged to show some concerns or a high risk of bias. Overall heterogeneity was high regarding the primary outcome (I2s < 66 %) and even higher for secondary outcomes (I2s < 91 %). Degree of contact was a robust predictor of outcome and adherence in all pre-registered and exploratory analyses. We found the effect of the IBI to increase with higher degree of contact. However, in pair-wise contrasts, only IBIs offering both contact before and during the intervention (SMD = 0.573, 95 % CI: 0.437, 0.709) significantly outperformed interventions offering no contact (SMD = 0.224, 95 % CI: 0.090, 0.340). Conclusions: The results suggest that contact before and during an intervention increases the effects of IBIs. The combination of contact before and during the intervention seems to a pivotal role regarding adherence as well as treatment outcome for patients suffering from depression
Arginase activity - a marker of disease status in patients with visceral leishmaniasis in ethiopia.
No full textThe underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood. Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells
Depletion of L-arginine induces autophagy as a cytoprotective response to endoplasmic reticulum stress in human T lymphocytes
No full textPMCID: PMC3494587L-arginine (L-Arg) deficiency results in decreased T-cell proliferation and impaired T-cell function. Here we have found that L-Arg depletion inhibited expression of different membrane antigens, including CD247 (CD3ζ), and led to an ER stress response, as well as cell cycle arrest at G(0)/G(1) in both human Jurkat and peripheral blood mitogen-activated T cells, without undergoing apoptosis. By genetic and biochemical approaches, we found that L-Arg depletion also induced autophagy. Deprivation of L-Arg induced EIF2S1 (eIF2α), MAPK8 (JNK), BCL2 (Bcl-2) phosphorylation, and displacement of BECN1 (Beclin 1) binding to BCL2, leading to autophagosome formation. Silencing of ERN1 (IRE1α) prevented the induction of autophagy as well as MAPK8 activation, BCL2 phosphorylation and XBP1 splicing, whereas led T lymphocytes to apoptosis under L-Arg starvation, suggesting that the ERN1-MAPK8 pathway plays a major role in the activation of autophagy following L-Arg depletion. Autophagy was required for survival of T lymphocytes in the absence of L-Arg, and resulted in a reversible process. Replenishment of L-Arg made T lymphocytes to regain the normal cell cycle profile and proliferate, whereas autophagy was inhibited. Inhibition of autophagy by ERN1, BECN1 and ATG7 silencing, or by pharmacological inhibitors, promoted cell death of T lymphocytes incubated in the absence of L-Arg. Our data indicate for the first time that depletion of L-Arg in T lymphocytes leads to a reversible response that preserves T lymphocytes through ER stress and autophagy, while remaining arrested at G(0)/G(1). Our data also show that the L-Arg depletion-induced ER stress response could lead to apoptosis when autophagy is blocked.This work was supported by the Spanish Ministerio de Ciencia e Innovación (SAF2008-02251, SAF2011-30518, and RD06/0020/1037 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), European Community’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986), Junta de Castilla y León (CSI052A11-2, GR15-Experimental Therapeutics and Translational Oncology Program, Biomedicine Project 2009), and Acciones Integradas Spain-Germany (HA2007-0080).Peer Reviewe
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