There is much evidence to support a role for natural killer (NK) cells in controlling the progres... more There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA damage response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and A...
Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in ... more Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in peripheral and central nervous system (CNS), consists in altered vascular permeability followed by leukocyte recruitment and activation in the inflamed tissue, release of inflammatory mediators including cytokines and chemokines, and finally in activation of microglia and astrocytes in the spinal cord and CNS. This phenomenon mediates and even worsen the inflammatory pain in many painful states and is responsible for central sensitization leading to pain chronicity. We describe the major neuroinflammatory mechanisms shared by cancer and non cancer pain. Particular attention is given to two different chronic inflammatory painful diseases such as the Complex Regional Pain Syndrome and the Rheumatoid Arthritis as prototypes of neuroinflammatory diseases (gliopathies). In addition, we describe the complexity of tumor microenvironment, their main cellular components (tumor cells, tumor infiltrating leukocytes and sensory neurons) and their reciprocal interactions that characterize different forms and intensity of cancer pain. We also hypothesize that one type of cancer pain, the breakthrough pain, can be attributable to receptor-mediated interaction of opioids with tumor cells and intratumoral leukocytes. Surprisingly, long-term opioid treatment shares the same neuroinflammatory potential responsible for the chronicity of both cancer and non cancer pain, thus resulting in paradoxical worsening rather than relieving pain. This paradox has up-set the world of pain therapy, with neuroinflammation now being a main target of emerging therapies.
Efficient elimination of transformed and virus-infected cells by natural killer (NK) cells mainly... more Efficient elimination of transformed and virus-infected cells by natural killer (NK) cells mainly depends on the recognition of “induced self” ligands by activating receptors, including NKG2D and DNAM1. The surface expression of these ligands in stressed or diseased cells results from the integration of transcriptional, post-transcriptional and post-translational mechanisms. Among post-translational mechanisms, recent findings indicate that ubiquitin and ubiquitin-like modifications, namely ubiquitination and SUMOylation, contribute to a very rapid negative regulation of NKG2D and DNAM1 ligand surface expression promoting either ligand degradation or ligand intracellular retention. On the other hand, accumulating evidences demonstrate that NKG2D receptor expression is down-regulated by ubiquitin-dependent endocytosis upon ligand stimulation. In this scenario, the overall consequence of the post-translational modifications of activating NK cell receptors and of their ligands on target cells is to impair effector cell-mediated recognition of damaged cells. Our review summarizes recent findings on the role of post-translational modifications in the modulation of target cell susceptibility to NK cell-mediated killing.
A multicolor flow cytometry panel was designed and optimized to define the following nine mouse T... more A multicolor flow cytometry panel was designed and optimized to define the following nine mouse T cell subsets: Treg (CD3+ CD4+ CD8− FoxP3+), CD4+ T naïve (CD3+ CD4+ CD8−FoxP3− CD44int/low CD62L+), CD4+ T central memory (CD3+ CD4+ CD8− FoxP3− CD44high CD62L+), CD4+ T effector memory (CD3+ CD4+ CD8− FoxP3− CD44high CD62L−), CD4+ T EMRA (CD3+ CD4+ CD8− FoxP3− CD44int/low CD62L−), CD8+ T naïve (CD3+ CD8+ CD4− CD44int/low CD62L+), CD8+ T central memory (CD3+ CD8+ CD4− CD44high CD62L+), CD8+ T effector memory (CD3+ CD8+ CD4− CD44high CD62L−), and CD8+ T EMRA (CD3+ CD8+ CD4− CD44int/low CD62L−). In each T cell subset, a dual staining for Ki‐67 expression and DNA content was employed to distinguish the following cell cycle phases: G0 (Ki67−, with 2n DNA), G1 (Ki67+, with 2n DNA), and S‐G2/M (Ki67+, with 2n < DNA ≤ 4n). This panel was established for the analysis of mouse (C57BL/6J) spleen.
There is much evidence to support a role for natural killer (NK) cells in controlling the progres... more There is much evidence to support a role for natural killer (NK) cells in controlling the progression of multiple myeloma (MM), a malignancy characterized by an abnormal plasma cell proliferation in the bone marrow (BM). Induction of DNA damage response has been recently shown capable of enhancing NKG2D ligand (NKG2DL) expression, but nothing is known about DNAM-1 ligand (DNAM-1L) regulation. In this study, we show that myeloma cells treated with low doses of therapeutic agents commonly used in the management of patients with MM, such as doxorubicin, melphalan, and bortezomib, up-regulate DNAM-1 and NKG2D ligands. Accordingly, therapeutic drug treatment of MM cells increases NK-cell degranulation, the NKG2D and DNAM-1 receptors being the major triggering molecules. Similar data were also obtained using ex vivo primary plasma cells derived from MM patients. Drug-induced DNAM-1 and NKG2D ligand expression was abolished after treatment with the ATM (ataxia telangiectasia mutated) and A...
Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in ... more Neuroinflammation, a peculiar form of inflammation that occurs in response to noxious stimuli in peripheral and central nervous system (CNS), consists in altered vascular permeability followed by leukocyte recruitment and activation in the inflamed tissue, release of inflammatory mediators including cytokines and chemokines, and finally in activation of microglia and astrocytes in the spinal cord and CNS. This phenomenon mediates and even worsen the inflammatory pain in many painful states and is responsible for central sensitization leading to pain chronicity. We describe the major neuroinflammatory mechanisms shared by cancer and non cancer pain. Particular attention is given to two different chronic inflammatory painful diseases such as the Complex Regional Pain Syndrome and the Rheumatoid Arthritis as prototypes of neuroinflammatory diseases (gliopathies). In addition, we describe the complexity of tumor microenvironment, their main cellular components (tumor cells, tumor infiltrating leukocytes and sensory neurons) and their reciprocal interactions that characterize different forms and intensity of cancer pain. We also hypothesize that one type of cancer pain, the breakthrough pain, can be attributable to receptor-mediated interaction of opioids with tumor cells and intratumoral leukocytes. Surprisingly, long-term opioid treatment shares the same neuroinflammatory potential responsible for the chronicity of both cancer and non cancer pain, thus resulting in paradoxical worsening rather than relieving pain. This paradox has up-set the world of pain therapy, with neuroinflammation now being a main target of emerging therapies.
Efficient elimination of transformed and virus-infected cells by natural killer (NK) cells mainly... more Efficient elimination of transformed and virus-infected cells by natural killer (NK) cells mainly depends on the recognition of “induced self” ligands by activating receptors, including NKG2D and DNAM1. The surface expression of these ligands in stressed or diseased cells results from the integration of transcriptional, post-transcriptional and post-translational mechanisms. Among post-translational mechanisms, recent findings indicate that ubiquitin and ubiquitin-like modifications, namely ubiquitination and SUMOylation, contribute to a very rapid negative regulation of NKG2D and DNAM1 ligand surface expression promoting either ligand degradation or ligand intracellular retention. On the other hand, accumulating evidences demonstrate that NKG2D receptor expression is down-regulated by ubiquitin-dependent endocytosis upon ligand stimulation. In this scenario, the overall consequence of the post-translational modifications of activating NK cell receptors and of their ligands on target cells is to impair effector cell-mediated recognition of damaged cells. Our review summarizes recent findings on the role of post-translational modifications in the modulation of target cell susceptibility to NK cell-mediated killing.
A multicolor flow cytometry panel was designed and optimized to define the following nine mouse T... more A multicolor flow cytometry panel was designed and optimized to define the following nine mouse T cell subsets: Treg (CD3+ CD4+ CD8− FoxP3+), CD4+ T naïve (CD3+ CD4+ CD8−FoxP3− CD44int/low CD62L+), CD4+ T central memory (CD3+ CD4+ CD8− FoxP3− CD44high CD62L+), CD4+ T effector memory (CD3+ CD4+ CD8− FoxP3− CD44high CD62L−), CD4+ T EMRA (CD3+ CD4+ CD8− FoxP3− CD44int/low CD62L−), CD8+ T naïve (CD3+ CD8+ CD4− CD44int/low CD62L+), CD8+ T central memory (CD3+ CD8+ CD4− CD44high CD62L+), CD8+ T effector memory (CD3+ CD8+ CD4− CD44high CD62L−), and CD8+ T EMRA (CD3+ CD8+ CD4− CD44int/low CD62L−). In each T cell subset, a dual staining for Ki‐67 expression and DNA content was employed to distinguish the following cell cycle phases: G0 (Ki67−, with 2n DNA), G1 (Ki67+, with 2n DNA), and S‐G2/M (Ki67+, with 2n < DNA ≤ 4n). This panel was established for the analysis of mouse (C57BL/6J) spleen.
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Papers by Angela Santoni