100,573 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
Differential impact of L-arginine deprivation on the activation and effector functions of T cells and macrophages.
No full textThe metabolism of the amino acid L-arginine is emerging as a crucial mechanism for the regulation of immune responses. Here, we characterized the impact of L-arginine deprivation on T cell and macrophage (MPhi) effector functions: We show that whereas L-arginine is required unconditionally for T cell activation, MPhi can up-regulate activation markers and produce cytokines and chemokines in the absence of L-arginine. Furthermore, we show that L-arginine deprivation does not affect the capacity of activated MPhi to up-regulate L-arginine-metabolizing enzymes such as inducible NO synthase and arginase 1. Thus, our results show that to exert their effector functions, T cells and MPhi have different requirements for L-arginine
Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion.
No full textTumor-growth is often associated with the expansion of myeloid derived suppressor cells that lead to local or systemic arginine depletion via the enzyme arginase. It is generally assumed that this arginine deficiency induces a global shut-down of T cell activation with ensuing tumor immune escape. While the impact of arginine depletion on polyclonal T cell proliferation and cytokine secretion is well documented, its influence on chemotaxis, cytotoxicity and antigen specific activation of human T cells has not been demonstrated so far. We show here that chemotaxis and early calcium signaling of human T cells are unimpaired in the absence of arginine. We then analyzed CD8(+) T cell activation in a tumor peptide as well as a viral peptide antigen specific system: (i) CD8(+) T cells with specificity against the MART-1aa26-35*A27L tumor antigen expanded with in vitro generated dendritic cells, and (ii) clonal CMV pp65aa495-503 specific T cells and T cells retrovirally transduced with a CMV pp65aa495-503 specific T cell receptor were analyzed. Our data demonstrate that human CD8(+) T cell antigen specific cytotoxicity and perforin secretion are completely preserved in the absence of arginine, while antigen specific proliferation as well as IFN-γ and granzyme B secretion are severely compromised. These novel results highlight the complexity of antigen specific T cell activation and demonstrate that human T cells can preserve important activation-induced effector functions in the context of arginine deficiency
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Erratum: Correction to: Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer\u27s Disease (Molecular neurobiology (2015) 52 3 (1067-1076))
No full textThe original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004 should have been included on the paper
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
Correction to: Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus
No full textThe original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004 should have been included on the paper
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
Erratum: Correction to: Comparison of the Effect of Exercise on Late-Phase LTP of the Dentate Gyrus and CA1 of Alzheimer\u27s Disease Model (Molecular neurobiology (2016) 53 10 (6859-6868))
No full textThe original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004 should have been included on the paper
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
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