scholarly journals 685 A highly selective and potent HPK1 inhibitor enhances immune cell activation and induces robust tumor growth inhibition in a murine syngeneic tumor model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A724-A724
Author(s):  
David Ciccone ◽  
Vad Lazari ◽  
Ian Linney ◽  
Michael Briggs ◽  
Samantha Carreiro ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Tumor Model ◽  
Tumor Growth Inhibition ◽  
Immune Cell Activation ◽  
Syngeneic Tumor ◽  
Human T Cells

BackgroundHPK1, a member of the MAP4K family of protein serine/threonine kinases, is involved in regulating signal transduction cascades in cells of hematopoietic origin. Recent data from HPK1 knockout animals and kinase-inactive knock-in animals underscores the role of HPK1 in negatively regulating immune cell activation. This negative-feedback role of HPK1 combined with its restricted expression in cells of hematopoietic origin, make it a compelling drug target for enhancing anti-tumor immunity.MethodsA structure-based drug design approach was used to identify potent and selective inhibitors of HPK1. Biochemical assays, as well as primary human and mouse immune cell-based activation assays, were utilized for multiple iterations of structure-activity relationship (SAR) studies. In vivo efficacy, target engagement and pharmacodynamic data were generated using murine syngeneic tumor models.ResultsA highly potent, HPK1 inhibitor was identified, that showed high selectivity against T cell-specific kinases and kinases in the MAP4K family. In vitro, HPK1 small molecule inhibition resulted in enhanced IL-2 production in primary mouse and human T cells, enhanced IL-6 and IgG production in primary human B cells, and enhanced mouse dendritic cell activation and antigen presentation capacity. Furthermore, HPK1 inhibition alleviated the immuno-suppressive effects of PGE2 on naïve human T cells and restored the proliferative capacity of exhausted human T cells. In vivo, HPK1 inhibitionHPK1 inhibition abrogated T cell receptor-stimulated phospho-SLP-76, enhanced cytokine production, and mediated robust tumor growth inhibition in a murine syngeneic tumor model.ConclusionsPharmacological blockade of HPK1 kinase activity represents a novel and potentially valuable immunomodulatory approach for anti-tumor immunity.

scholarly journals The Role of T Cells and Macrophages in Asthma Pathogenesis: A New Perspective on Mutual Crosstalk

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Xueyi Zhu ◽  
Jie Cui ◽  
La Yi ◽  
Jingjing Qin ◽  
Wuniqiemu Tulake ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Innate And Adaptive Immunity ◽  
Immune Cell Activation ◽  
Inflammatory Signals ◽  
Macrophage Dysfunction ◽  
New Perspective

Asthma is associated with innate and adaptive immunity mediated by immune cells. T cell or macrophage dysfunction plays a particularly significant role in asthma pathogenesis. Furthermore, crosstalk between them continuously transmits proinflammatory or anti-inflammatory signals, causing the immune cell activation or repression in the immune response. Consequently, the imbalanced immune microenvironment is the major cause of the exacerbation of asthma. Here, we discuss the role of T cells, macrophages, and their interactions in asthma pathogenesis.

scholarly journals Neuronal guidance proteins in cardiovascular inflammation

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Marius Keller ◽  
Valbona Mirakaj ◽  
Michael Koeppen ◽  
Peter Rosenberger
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Therapeutic Approaches ◽  
Immune Cell Activation ◽  
Cytokines And Chemokines ◽  
The Future ◽  
Cardiovascular Pathologies ◽  
Neuronal Guidance

AbstractCardiovascular pathologies are often induced by inflammation. The associated changes in the inflammatory response influence vascular endothelial biology; they complicate the extent of ischaemia and reperfusion injury, direct the migration of immune competent cells and activate platelets. The initiation and progression of inflammation is regulated by the classical paradigm through the system of cytokines and chemokines. Therapeutic approaches have previously used this knowledge to control the extent of cardiovascular changes with varying degrees of success. Neuronal guidance proteins (NGPs) have emerged in recent years and have been shown to be significantly involved in the control of tissue inflammation and the mechanisms of immune cell activation. Therefore, proteins of this class might be used in the future as targets to control the extent of inflammation in the cardiovascular system. In this review, we describe the role of NGPs during cardiovascular inflammation and highlight potential therapeutic options that could be explored in the future.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

Abstract MP41: A Role Of Isolevuglandins In Systemic Lupus Erythematosus Associated Autoimmunity And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
David M Patrick ◽  
Nestor de la Visitacion ◽  
Michelle J Ormseth ◽  
Charles Stein ◽  
Sean S Davies ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immune Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Immune Cell ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Immune Cell Activation ◽  
Systemic Immune Activation

Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions that disproportionately affect women. SLE has heterogeneous manifestations and treatment is limited to the use of non-specific global immunosuppression. Importantly, there is an increased prevalence of hypertension in women with SLE compared to healthy controls. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation. Previous studies have shown an essential role of IsoLGs in immune cell activation and the development of hypertension in animal models. We hypothesize that isoLGs are important for the development of hypertension and systemic immune activation in SLE. We first examined isoLG adduct accumulation within monocytes of human subjects with SLE compared to healthy controls. By flow cytometry, we found marked accumulation of isoLG adducts within CD14 + monocytes (34.2% ± 12.4% vs 3.81% ± 2.1% of CD14 + , N = 10-11, P <0.05). We confirmed this increase in isoLG adducts by mass spectrometry. To determine a causative role of isoLG adducts in immune activation and hypertension in SLE, we employed the B6.SLE123 and NZBWF1 mouse models of SLE. Animals were treated with the isoLG scavenger 2-hydroxybenzylamine (2-HOBA) or vehicle beginning at 7 weeks and were sacrificed at 32 weeks of age. C57BL/6 and NZW were used as controls. Importantly, treatment with 2-HOBA attenuated blood pressure in both mouse models (systolic BP 136.2 ± 5.6 mmHg for B6.SLE123 vs 120.9 ± 4.46 mmHg for B6.SLE123 +2HOBA; 164.7 ± 24.4 mmHg for NZBWF1 vs 136.9 ± 14.9 mmHg for NZBWF1 +2HOBA, N = 6-8, P < 0.05). Moreover, treatment with 2-HOBA reduced albuminuria and renal injury in the B6.SLE123 model (albumin/creatinine ratio 33.8 ± 2.0 x 10 -2 μg/mg for B6.SLE123 vs 5.5 ± 0.9 x 10 -2 μg/mg for B6.SLE123 +2HOBA, N = 7-9, P < 0.05). Finally, immune cell accumulation in primary and secondary lymphoid organs is significantly attenuated by 2-HOBA. These studies suggest a critical role of isoLG adduct accumulation in both systemic immune activation and hypertension in SLE.

scholarly journals Investigating the role of chromosomal instability in immune cell activation

2019 ◽  
Vol 30 ◽  
pp. vii25-vii26
Author(s):  
M. Sokac ◽  
L. Dyrskjøt Andersen ◽  
M. Roelsgaard Jakobsen ◽  
N. Birkbak
Keyword(s):  
Chromosomal Instability ◽  
Cell Activation ◽  
Immune Cell ◽  
Immune Cell Activation

scholarly journals Identification of distinct immune activation profiles in adult humans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Renaud Cezar ◽  
Audrey Winter ◽  
Delphine Desigaud ◽  
Manuela Pastore ◽  
Lucy Kundura ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Liver Steatosis ◽  
Treg Cells ◽  
Microbial Translocation ◽  
Color Flow

AbstractLatent infectious agents, microbial translocation, some metabolites and immune cell subpopulations, as well as senescence modulate the level and quality of activation of our immune system. Here, we tested whether various in vivo immune activation profiles may be distinguished in a general population. We measured 43 markers of immune activation by 8-color flow cytometry and ELISA in 150 adults, and performed a double hierarchical clustering of biomarkers and volunteers. We identified five different immune activation profiles. Profile 1 had a high proportion of naïve T cells. By contrast, Profiles 2 and 3 had an elevated percentage of terminally differentiated and of senescent CD4+ T cells and CD8+ T cells, respectively. The fourth profile was characterized by NK cell activation, and the last profile, Profile 5, by a high proportion of monocytes. In search for etiologic factors that could determine these profiles, we observed a high frequency of naïve Treg cells in Profile 1, contrasting with a tendency to a low percentage of Treg cells in Profiles 2 and 3. Moreover, Profile 5 tended to have a high level of 16s ribosomal DNA, a direct marker of microbial translocation. These data are compatible with a model in which specific causes, as the frequency of Treg or the level of microbial translocation, shape specific profiles of immune activation. It will be of interest to analyze whether some of these profiles drive preferentially some morbidities known to be fueled by immune activation, as insulin resistance, atherothrombosis or liver steatosis.

scholarly journals Sex differences in obesity-induced hypertension and vascular dysfunction: a protective role for estrogen in adipose tissue inflammation?

2016 ◽  
Vol 311 (4) ◽  
pp. R714-R720 ◽  
Author(s):  
Lia E. Taylor ◽  
Jennifer C. Sullivan
Keyword(s):  
Energy Homeostasis ◽  
Cell Activation ◽  
Immune Cell ◽  
Vascular Dysfunction ◽  
Protective Role ◽  
Experimental Models ◽  
Immune Cell Activation ◽  
The Subject ◽  
Associated Risk Factors

Obesity is a potent predictor of cardiovascular disease and associated risk factors, including hypertension. Systemic inflammation has been suggested by a number of studies to be an important link between excess adiposity and hypertension, yet the majority of the studies have been conducted exclusively in males. This is problematic since women represent ∼53% of hypertensive cases and are more likely than men to be obese. There is a growing body of literature supporting a central role for immune cell activation in numerous experimental models of hypertension, and both the sex of the subject and the sex of the T cell have been shown to impact blood pressure (BP) responses to hypertensive stimuli. Moreover, sex steroid hormones play an important role in energy homeostasis, as well as in the regulation of immune responses; estrogen, in particular, has a well-known impact on both cardiovascular and metabolic disorders. Therefore, the purpose of this review is to examine whether sex or sex hormones regulate the role of the immune system in the development of hypertension and related vascular dysfunction in response to metabolic changes and stimuli, including a high-fat diet.

scholarly journals Bacterial Pathogens Induce Abscess Formation by CD4+ T-Cell Activation via the CD28–B7-2 Costimulatory Pathway

2000 ◽  
Vol 68 (12) ◽  
pp. 6650-6655 ◽  
Author(s):  
Arthur O. Tzianabos ◽  
Anil Chandraker ◽  
Wiltrud Kalka-Moll ◽  
Francesca Stingele ◽  
Victor M. Dong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Cell Activation ◽  
Bacterial Pathogens ◽  
Abscess Formation

ABSTRACT Abscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naı̈ve rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, including Staphylococcus aureus,Bacteroides fragilis, and a combination ofEnterococcus faecium and Bacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28–B7-2 pathway.

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