Alessandro Poggi | IRCCS AOU San Martino-IST Genova (original) (raw)

Papers by Alessandro Poggi

Research paper thumbnail of Glycogen Synthase Kinase 3

Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defe... more Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defense mechanisms are restrained. Here, we show that redox-modulating drugs including the retinoid N-(4-hydroxyphenyl)retinamide (4HPR), the synthetic triterpenoid bardoxolone (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester), arsenic trioxide (As 2 O 3 ), and phenylethyl isothiocyanate (PEITC), while affecting tumor cell viability, induce sustained Ser9 phosphorylation of the multifunctional kinase glycogen synthase kinase 3β (GSK3β). The antioxidant N-acetylcysteine decreased GSK3β phosphorylation and poly(ADP-ribose) polymerase cleavage induced by 4HPR, As 2 O 3 , and PEITC, implicating oxidative stress in these effects. GSK3β phosphorylation was associated with upregulation of antioxidant enzymes, in particular heme oxygenase-1 (HO-1), and transient elevation of intracellular glutathione (GSH) in cells surviving acute stress, before occurrence of irreversible damage and death. Genetic inactivation of GSK3β or transfection with the non-phosphorylatable GSK3β-S9A mutant inhibited HO-1 induction under redox stress, while tumor cells resistant to 4HPR exhibited increased GSK3β phosphorylation, HO-1 expression, and GSH levels. The above-listed findings are consistent with a role for sustained GSK3β phosphorylation in a signaling network activating antioxidant effector mechanisms during oxidoreductive stress. These data underlie the importance of combination regimens of antitumor redox drugs with inhibitors of survival signaling to improve control of tumor development and progression and overcome chemoresistance.

Research paper thumbnail of Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

European Journal of Pharmacology, 2008

Research paper thumbnail of Interaction between Human NK Cells and Bone Marrow Stromal Cells Induces NK Cell Triggering: Role of NKp30 and NKG2D Receptors1

sible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from ... more sible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from NK cell-mediated injury. Thus, NK cells, activated upon binding with BMSC, may regulate BMSC survival. The Journal of Immunology, 2005, 175: 6352-6360.

Research paper thumbnail of Platelet lysate enhances the inhibitory effect on T cell proliferation mediated by human articular chondrocytes and Synoviocytes in joint disorders

Research paper thumbnail of Triggering of Apoptosis and Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A

Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, 2005

ABSTRACT

Research paper thumbnail of Platelet lysate enhances the inhibitory effect on T cell proliferation mediated by human articular chondrocytes and synoviocytes in joint disorders

Research paper thumbnail of Defective Expression and Function of the Leukocyte Associated Ig-like Receptor 1 in B Lymphocytes from Systemic Lupus Erythematosus Patients

PLoS ONE, 2012

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoanti... more Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies and dysregulation of B cell function. The leukocyte associated Immunoglobulin (Ig)-like receptor (LAIR)1 is a transmembrane molecule belonging to Ig superfamily which binds to different types of collagen. Herein, we have determined the expression and function of LAIR1 on B lymphocyte from SLE patients. LAIR1 expression in peripheral blood B lymphocytes from 54 SLE, 24 mixed connective tissue disease (MCTD), 20 systemic sclerosis (SSc) patients, 14 rheumatoid arthritis (RA) and 40 sex and age matched healthy donors (HD) have been analyzed by immunofluorescence. The effect of LAIR1 ligation by specific monoclonal antibodies, collagen or collagen producing mesenchymal stromal cells from reactive lymph nodes or bone marrow on Ig production by pokeweed mitogen and B cell receptor (BCR)-mediated NF-kB activation was assessed by ELISA and TransAM assay. The percentage of CD20 + B lymphocytes lacking or showing reduced expression of LAIR1 was markedly increased in SLE and MCTD but not in SSc or RA patients compared to HD. The downregulation of LAIR1 expression was not dependent on corticosteroid therapy. Interestingly, LAIR1 engagement by collagen or collagen-producing mesenchymal stromal cells in SLE patients with low LAIR1 expression on B cells delivered a lower inhibiting signal on Ig production. In addition, NF-kB p65 subunit activation upon BCR and LAIR1 co-engagement was less inhibited in SLE patients than in HD. Our findings indicate defective LAIR1 expression and function in SLE B lymphocytes, possible contributing to an altered control of B lymphocytes behavior.

Research paper thumbnail of Correction: Defective Expression and Function of the Leukocyte Associated Ig-like Receptor 1 in B Lymphocytes from Systemic Lupus Erythematosus Patients

PLoS ONE, 2012

ABSTRACT [This corrects the article on p. e31903 in vol. 7.].

Research paper thumbnail of Role of gammadelta T lymphocytes in tumor defense

Frontiers in Bioscience, 2004

Research paper thumbnail of Stress immunity in lymphomas: mesenchymal cells as a target of therapy

Frontiers in Bioscience, 2014

The role of lymphocytes in eliminating lymphoma cells is based on the interaction between activat... more The role of lymphocytes in eliminating lymphoma cells is based on the interaction between activating receptors on lymphocytes and target surface ligands on lymphoma cells. Stress-related immunity can be triggered both in Hodgkin's (HL) and non-Hodgkin lymphomas (NHL), through the activation of the NKG2D receptor on CD8+ T and gammadelta T lymphocytes, by NKG2D-ligands (NKG2D-L), as the MHC class-I related molecules MIC-A/B and the UL16-binding proteins 1-4 (ULBPs), expressed on lymphoma cells. Furthermore, NKG2D-L can be shed and interact with NKG2D on effector lymphocytes affecting the recognition of lymphoma cells. Proteolytic cleavage of MIC-A is known to depend on the thiol isomerase ERp5 and the disintegrins and metalloproteinases ADAM10 and ADAM17, which also cleave ULPBs. Mesenchymal stromal cells (MSC) are relevant in regulating effector T lymphocytes-mediated lymphoma surveillance. Indeed, MSC can be seen as targets of potential new therapeutic schemes acting on lymphoma microenvironment, to redirect the stress immune response and avoid escape strategies, by inducing stress molecules, inhibiting sheddase activity, shifting cytokine production to Th1 pattern and blocking Treg differentiation.

Research paper thumbnail of HIV-1 Tat Triggers TGF-β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

Clinical and Developmental Immunology, 2006

Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion... more Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-b elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-b triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-b-induced activation of AP-1. TGF-b enhances starvation-induced NK cell apoptosis, reduces the transcription of the antiapoptotic protein Bcl-2 and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-b-mediated effects are prevented by PTX-B or PT9K/129G, through a PI-3K-dependent mechanism. Finally, PTX-B and PT9K/129G upregulate Bcl-x L , the isoform of Bcl-x that protects cells from starvation-induced apoptosis. Of note, in NK cells from patients with HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x L was consistently lower than that of healthy donors; interestingly, TGF-b and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-b production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

Research paper thumbnail of Antigen Presenting Cells and Stromal Cells Trigger Human Natural Killer Lymphocytes to Autoreactivity: Evidence for the Involvement of Natural Cytotoxicity Receptors (NCR) and NKG2D

Clinical and Developmental Immunology, 2006

Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of... more Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of inhibitory receptor superfamily (IRS) members by HLA-I. Nevertheless, NK cells kill self cells expressing low levels or lacking HLA-I, as it may occur during viral infections (missing-self hypothesis). Herein, we show that human NK cells can be activated upon binding with self antigen presenting cells or stromal cells despite the expression of HLA-I. Indeed, NK cells can kill and produce proinflammatory and regulating cytokines as IFN-g, TNF-a and IL10 during interaction with autologous dendritic cells or bone marrow stromal cells or skin fibroblasts. The killing of antigen presenting and stromal cells is dependent on LFA1/ICAM1 interaction. Further, the natural cytotoxicity receptors (NCR) NKp30 and NKp46 are responsible for the delivery of lethal hit to DC, whereas NKG2D activating receptor, the ligand of the MHC-related molecule MIC-A and the UL16 binding protein, is involved in stromal cell killing. These findings indicate that different activating receptors are involved in cell to self cell interaction. Finally, NK cells can revert the veto effect of stromal cells on mixed lymphocyte reaction further supporting the idea that NK cells may alter the interaction between T lymphocytes and microenvironment leading to autoreactivity.

Research paper thumbnail of Recruitment of host’s progenitor cells to sites of human amniotic fluid stem cells implantation

Biomaterials, 2011

The amniotic fluid is a new source of multipotent stem cells with a therapeutic potential for hum... more The amniotic fluid is a new source of multipotent stem cells with a therapeutic potential for human diseases. Cultured at low cell density, human amniotic fluid stem cells (hAFSCs) were still able to generate colony-forming unit-fibroblast (CFU-F) after 60 doublings, thus confirming their staminal nature. Moreover, after extensive in vitro cell expansion hAFSCs maintained a stable karyotype. The expression of genes, such as SSEA-4, SOX2 and OCT3/4 was confirmed at early and later culture stage. Also, hAFSCs showed bright expression of mesenchymal lineage markers and immunoregulatory properties. hAFSCs, seeded onto hydroxyapatite scaffolds and subcutaneously implanted in nude mice, played a pivotal role in mounting a response resulting in the recruitment of host's progenitor cells forming tissues of mesodermal origin such as fat, muscle, fibrous tissue and immature bone. Implanted hAFSCs migrated from the scaffold to the skin overlying implant site but not to other organs. Given their in vivo: (i) recruitment of host progenitor cells, (ii) homing towards injured sites and (iii) multipotentiality in tissue repair, hAFSCs are a very appealing reserve of stem cells potentially useful for clinical application in regenerative medicine.

Research paper thumbnail of A novel snRNA-like transcript affects amyloidogenesis and cell cycle progression through perturbation of Fe65L1 (APBB2) alternative splicing

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013

Research paper thumbnail of Editorial Hot Topic: Innate Immunity and Cytokines: How to Regulate Host Response Against Pathogens Avoiding Autoreactivity (Guest Editors: MR Zocchi and A. Poggi)

Research paper thumbnail of CD69-mediated pathway of lymphocyte activation: Anti-CD69 monoclonal antibodies trigger the cytolytic activity of different lymphoid effector cells with the exception of cytolytic T lymphocytes expressing T cell receptor α/β

Journal of Experimental Medicine

The effect of anti-CD69 monodonal antibodies (mAbs) on the induction of the cytolytic activity in... more The effect of anti-CD69 monodonal antibodies (mAbs) on the induction of the cytolytic activity in different types of lymphoid effector cells has been investigated. Three anti-CD69 mAbs, including the reference mAb MLR3 and two new mAbs (c227 and 31C4), have been used. All cloned CD3-CD16 + natural killer (NK) cells belonging to different subsets (as defined by the surface expression of GL183 and/or EB6 antigens) were efficiently triggered by anti-CD69 mAbs and lysed P815 mastocytoma ceUs in a redirected killing assay. Triggering of the cytolytic activity could also be induced in CD3-CD16-NK clones, which fail to respond to other stimuli (including anti-CD16, anti-CD2 mAbs, or phytohemagglutinin). A similar triggering effect was detected in T call receptor (TCR) 3,/~ + clones belonging to different subsets. On the other hand, anti-CD69 mAbs could not induce triggering of the cytolytic activity in TCR cr + cytolytic dones. Since all thymocytes are known to express CD69 antigen after cell activation, we analyzed a series of phenotypically different cytolytic thymocyte populations and clones for their responsiveness to anti-CD69 mAb in a redirected killing assay. Again, anti-CD69 mAb triggered TCR 3,/~ + but not TCR ce/~ + thymocytes. Anti-CD69 mAb efficiently triggered the cytolytic activity of "early" thymocytes lines or clones (CD3-4-8-7 +), which lack all other known pathways of cell activation. Thus, it appears that CD69 molecules may initiate a pathway of activation of cytolytic functions common to a number of activated effector lymphocytes with the remarkable exception of TCR ot/B + cytolytic cells.

Research paper thumbnail of Poggi, A. et al. Regulation of T cell survival by soluble HLA-I: Involvement of CD8 and activating killer Ig-like receptors. Eur. J. Immunol. 35, 2670-2678

European Journal of Immunology

We show that human Vd1 or Vd2 T lymphocytes secrete FasL and undergo apoptosis upon incubation wi... more We show that human Vd1 or Vd2 T lymphocytes secrete FasL and undergo apoptosis upon incubation with soluble HLA (sHLA)-I or after cross-linking of CD8, with a kinetics different from that observed following ligation of TCR. sHLA-I-induced apoptosis was blocked by anti-CD8 mAb; on the other hand, sHLA-I was not effective in CD8clones, while an HLA-I mutated in the a3 domain, responsible for CD8 binding, was not functional on CD8 + clones. Purified sHLA-Cw3 or -Cw4 alleles, isolated from the Cw3or Cw4-transfected 721.221 lymphoblastoid cell line, triggered cd T cell apoptosis, interacting with the specific receptors CD158j/KIR2DS2 or CD158 h/KIR2DS1, respectively, also known as activating isoforms of killer Ig-like receptors (KIR). Again, this effect was dependent on FasL secretion and it was blocked by specific mAb to KIR2DS2 or KIR2DS1. The engagement of CD8 or activating KIR also triggered the production of TNF-a. Noteworthy, sHLA-I molecules synergize with antigen-mediated activation of Vd2 T cells: Indeed, Vd2 T lymphocytes produced TNF-a when stimulated with isopentenyl pyrophosphate, and this effect was enhanced by sHLA-I. These findings suggest that sHLA-I can regulate cd T cell survival and that activating KIR may amplify antigen-specific Vd2 T cell responses.

Research paper thumbnail of Evaluation of cytotoxic cell-target cell conjugates. Comparison between flow cytometric analysis and 51Cr binding assay

Haematologica

Two methods for evaluating the conjugate formation between either bulk cultured or cloned NK cell... more Two methods for evaluating the conjugate formation between either bulk cultured or cloned NK cells and fresh tumor target cells or tumor cell lines were compared. Flow cytometric analysis and 51Cr binding assay yielded comparable results using NK clones as effector cells; however, flow cytometry provides less accuracy using large granular lymphocytes or unfractionated lymphocytes.

Research paper thumbnail of HIV-I Tat: a polypeptide for all seasons

Research paper thumbnail of Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells

Journal of Leukocyte Biology

We show that interleukin-18 is constitutively produced by dendritic cells; synthesis and secretio... more We show that interleukin-18 is constitutively produced by dendritic cells; synthesis and secretion are poorly affected by maturative stimuli.

Research paper thumbnail of Glycogen Synthase Kinase 3

Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defe... more Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defense mechanisms are restrained. Here, we show that redox-modulating drugs including the retinoid N-(4-hydroxyphenyl)retinamide (4HPR), the synthetic triterpenoid bardoxolone (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester), arsenic trioxide (As 2 O 3 ), and phenylethyl isothiocyanate (PEITC), while affecting tumor cell viability, induce sustained Ser9 phosphorylation of the multifunctional kinase glycogen synthase kinase 3β (GSK3β). The antioxidant N-acetylcysteine decreased GSK3β phosphorylation and poly(ADP-ribose) polymerase cleavage induced by 4HPR, As 2 O 3 , and PEITC, implicating oxidative stress in these effects. GSK3β phosphorylation was associated with upregulation of antioxidant enzymes, in particular heme oxygenase-1 (HO-1), and transient elevation of intracellular glutathione (GSH) in cells surviving acute stress, before occurrence of irreversible damage and death. Genetic inactivation of GSK3β or transfection with the non-phosphorylatable GSK3β-S9A mutant inhibited HO-1 induction under redox stress, while tumor cells resistant to 4HPR exhibited increased GSK3β phosphorylation, HO-1 expression, and GSH levels. The above-listed findings are consistent with a role for sustained GSK3β phosphorylation in a signaling network activating antioxidant effector mechanisms during oxidoreductive stress. These data underlie the importance of combination regimens of antitumor redox drugs with inhibitors of survival signaling to improve control of tumor development and progression and overcome chemoresistance.

Research paper thumbnail of Sensitivity of different resistant tumour cell lines to the two novel compounds (2Z,4E)-2-methylsulfanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate and (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

European Journal of Pharmacology, 2008

Research paper thumbnail of Interaction between Human NK Cells and Bone Marrow Stromal Cells Induces NK Cell Triggering: Role of NKp30 and NKG2D Receptors1

sible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from ... more sible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from NK cell-mediated injury. Thus, NK cells, activated upon binding with BMSC, may regulate BMSC survival. The Journal of Immunology, 2005, 175: 6352-6360.

Research paper thumbnail of Platelet lysate enhances the inhibitory effect on T cell proliferation mediated by human articular chondrocytes and Synoviocytes in joint disorders

Research paper thumbnail of Triggering of Apoptosis and Pro-Inflammatory Cytokines in NK Cells: Regulation by Cyclosporin A

Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents, 2005

ABSTRACT

Research paper thumbnail of Platelet lysate enhances the inhibitory effect on T cell proliferation mediated by human articular chondrocytes and synoviocytes in joint disorders

Research paper thumbnail of Defective Expression and Function of the Leukocyte Associated Ig-like Receptor 1 in B Lymphocytes from Systemic Lupus Erythematosus Patients

PLoS ONE, 2012

Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoanti... more Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies and dysregulation of B cell function. The leukocyte associated Immunoglobulin (Ig)-like receptor (LAIR)1 is a transmembrane molecule belonging to Ig superfamily which binds to different types of collagen. Herein, we have determined the expression and function of LAIR1 on B lymphocyte from SLE patients. LAIR1 expression in peripheral blood B lymphocytes from 54 SLE, 24 mixed connective tissue disease (MCTD), 20 systemic sclerosis (SSc) patients, 14 rheumatoid arthritis (RA) and 40 sex and age matched healthy donors (HD) have been analyzed by immunofluorescence. The effect of LAIR1 ligation by specific monoclonal antibodies, collagen or collagen producing mesenchymal stromal cells from reactive lymph nodes or bone marrow on Ig production by pokeweed mitogen and B cell receptor (BCR)-mediated NF-kB activation was assessed by ELISA and TransAM assay. The percentage of CD20 + B lymphocytes lacking or showing reduced expression of LAIR1 was markedly increased in SLE and MCTD but not in SSc or RA patients compared to HD. The downregulation of LAIR1 expression was not dependent on corticosteroid therapy. Interestingly, LAIR1 engagement by collagen or collagen-producing mesenchymal stromal cells in SLE patients with low LAIR1 expression on B cells delivered a lower inhibiting signal on Ig production. In addition, NF-kB p65 subunit activation upon BCR and LAIR1 co-engagement was less inhibited in SLE patients than in HD. Our findings indicate defective LAIR1 expression and function in SLE B lymphocytes, possible contributing to an altered control of B lymphocytes behavior.

Research paper thumbnail of Correction: Defective Expression and Function of the Leukocyte Associated Ig-like Receptor 1 in B Lymphocytes from Systemic Lupus Erythematosus Patients

PLoS ONE, 2012

ABSTRACT [This corrects the article on p. e31903 in vol. 7.].

Research paper thumbnail of Role of gammadelta T lymphocytes in tumor defense

Frontiers in Bioscience, 2004

Research paper thumbnail of Stress immunity in lymphomas: mesenchymal cells as a target of therapy

Frontiers in Bioscience, 2014

The role of lymphocytes in eliminating lymphoma cells is based on the interaction between activat... more The role of lymphocytes in eliminating lymphoma cells is based on the interaction between activating receptors on lymphocytes and target surface ligands on lymphoma cells. Stress-related immunity can be triggered both in Hodgkin's (HL) and non-Hodgkin lymphomas (NHL), through the activation of the NKG2D receptor on CD8+ T and gammadelta T lymphocytes, by NKG2D-ligands (NKG2D-L), as the MHC class-I related molecules MIC-A/B and the UL16-binding proteins 1-4 (ULBPs), expressed on lymphoma cells. Furthermore, NKG2D-L can be shed and interact with NKG2D on effector lymphocytes affecting the recognition of lymphoma cells. Proteolytic cleavage of MIC-A is known to depend on the thiol isomerase ERp5 and the disintegrins and metalloproteinases ADAM10 and ADAM17, which also cleave ULPBs. Mesenchymal stromal cells (MSC) are relevant in regulating effector T lymphocytes-mediated lymphoma surveillance. Indeed, MSC can be seen as targets of potential new therapeutic schemes acting on lymphoma microenvironment, to redirect the stress immune response and avoid escape strategies, by inducing stress molecules, inhibiting sheddase activity, shifting cytokine production to Th1 pattern and blocking Treg differentiation.

Research paper thumbnail of HIV-1 Tat Triggers TGF-β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

Clinical and Developmental Immunology, 2006

Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion... more Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-b elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-b triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-b-induced activation of AP-1. TGF-b enhances starvation-induced NK cell apoptosis, reduces the transcription of the antiapoptotic protein Bcl-2 and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-b-mediated effects are prevented by PTX-B or PT9K/129G, through a PI-3K-dependent mechanism. Finally, PTX-B and PT9K/129G upregulate Bcl-x L , the isoform of Bcl-x that protects cells from starvation-induced apoptosis. Of note, in NK cells from patients with HIV-1 infection, mRNA expression of Bcl-2 and Bcl-x L was consistently lower than that of healthy donors; interestingly, TGF-b and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-b production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

Research paper thumbnail of Antigen Presenting Cells and Stromal Cells Trigger Human Natural Killer Lymphocytes to Autoreactivity: Evidence for the Involvement of Natural Cytotoxicity Receptors (NCR) and NKG2D

Clinical and Developmental Immunology, 2006

Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of... more Human natural killer (NK) lymphocytes should not damage autologous cells due to the engagement of inhibitory receptor superfamily (IRS) members by HLA-I. Nevertheless, NK cells kill self cells expressing low levels or lacking HLA-I, as it may occur during viral infections (missing-self hypothesis). Herein, we show that human NK cells can be activated upon binding with self antigen presenting cells or stromal cells despite the expression of HLA-I. Indeed, NK cells can kill and produce proinflammatory and regulating cytokines as IFN-g, TNF-a and IL10 during interaction with autologous dendritic cells or bone marrow stromal cells or skin fibroblasts. The killing of antigen presenting and stromal cells is dependent on LFA1/ICAM1 interaction. Further, the natural cytotoxicity receptors (NCR) NKp30 and NKp46 are responsible for the delivery of lethal hit to DC, whereas NKG2D activating receptor, the ligand of the MHC-related molecule MIC-A and the UL16 binding protein, is involved in stromal cell killing. These findings indicate that different activating receptors are involved in cell to self cell interaction. Finally, NK cells can revert the veto effect of stromal cells on mixed lymphocyte reaction further supporting the idea that NK cells may alter the interaction between T lymphocytes and microenvironment leading to autoreactivity.

Research paper thumbnail of Recruitment of host’s progenitor cells to sites of human amniotic fluid stem cells implantation

Biomaterials, 2011

The amniotic fluid is a new source of multipotent stem cells with a therapeutic potential for hum... more The amniotic fluid is a new source of multipotent stem cells with a therapeutic potential for human diseases. Cultured at low cell density, human amniotic fluid stem cells (hAFSCs) were still able to generate colony-forming unit-fibroblast (CFU-F) after 60 doublings, thus confirming their staminal nature. Moreover, after extensive in vitro cell expansion hAFSCs maintained a stable karyotype. The expression of genes, such as SSEA-4, SOX2 and OCT3/4 was confirmed at early and later culture stage. Also, hAFSCs showed bright expression of mesenchymal lineage markers and immunoregulatory properties. hAFSCs, seeded onto hydroxyapatite scaffolds and subcutaneously implanted in nude mice, played a pivotal role in mounting a response resulting in the recruitment of host's progenitor cells forming tissues of mesodermal origin such as fat, muscle, fibrous tissue and immature bone. Implanted hAFSCs migrated from the scaffold to the skin overlying implant site but not to other organs. Given their in vivo: (i) recruitment of host progenitor cells, (ii) homing towards injured sites and (iii) multipotentiality in tissue repair, hAFSCs are a very appealing reserve of stem cells potentially useful for clinical application in regenerative medicine.

Research paper thumbnail of A novel snRNA-like transcript affects amyloidogenesis and cell cycle progression through perturbation of Fe65L1 (APBB2) alternative splicing

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2013

Research paper thumbnail of Editorial Hot Topic: Innate Immunity and Cytokines: How to Regulate Host Response Against Pathogens Avoiding Autoreactivity (Guest Editors: MR Zocchi and A. Poggi)

Research paper thumbnail of CD69-mediated pathway of lymphocyte activation: Anti-CD69 monoclonal antibodies trigger the cytolytic activity of different lymphoid effector cells with the exception of cytolytic T lymphocytes expressing T cell receptor α/β

Journal of Experimental Medicine

The effect of anti-CD69 monodonal antibodies (mAbs) on the induction of the cytolytic activity in... more The effect of anti-CD69 monodonal antibodies (mAbs) on the induction of the cytolytic activity in different types of lymphoid effector cells has been investigated. Three anti-CD69 mAbs, including the reference mAb MLR3 and two new mAbs (c227 and 31C4), have been used. All cloned CD3-CD16 + natural killer (NK) cells belonging to different subsets (as defined by the surface expression of GL183 and/or EB6 antigens) were efficiently triggered by anti-CD69 mAbs and lysed P815 mastocytoma ceUs in a redirected killing assay. Triggering of the cytolytic activity could also be induced in CD3-CD16-NK clones, which fail to respond to other stimuli (including anti-CD16, anti-CD2 mAbs, or phytohemagglutinin). A similar triggering effect was detected in T call receptor (TCR) 3,/~ + clones belonging to different subsets. On the other hand, anti-CD69 mAbs could not induce triggering of the cytolytic activity in TCR cr + cytolytic dones. Since all thymocytes are known to express CD69 antigen after cell activation, we analyzed a series of phenotypically different cytolytic thymocyte populations and clones for their responsiveness to anti-CD69 mAb in a redirected killing assay. Again, anti-CD69 mAb triggered TCR 3,/~ + but not TCR ce/~ + thymocytes. Anti-CD69 mAb efficiently triggered the cytolytic activity of "early" thymocytes lines or clones (CD3-4-8-7 +), which lack all other known pathways of cell activation. Thus, it appears that CD69 molecules may initiate a pathway of activation of cytolytic functions common to a number of activated effector lymphocytes with the remarkable exception of TCR ot/B + cytolytic cells.

Research paper thumbnail of Poggi, A. et al. Regulation of T cell survival by soluble HLA-I: Involvement of CD8 and activating killer Ig-like receptors. Eur. J. Immunol. 35, 2670-2678

European Journal of Immunology

We show that human Vd1 or Vd2 T lymphocytes secrete FasL and undergo apoptosis upon incubation wi... more We show that human Vd1 or Vd2 T lymphocytes secrete FasL and undergo apoptosis upon incubation with soluble HLA (sHLA)-I or after cross-linking of CD8, with a kinetics different from that observed following ligation of TCR. sHLA-I-induced apoptosis was blocked by anti-CD8 mAb; on the other hand, sHLA-I was not effective in CD8clones, while an HLA-I mutated in the a3 domain, responsible for CD8 binding, was not functional on CD8 + clones. Purified sHLA-Cw3 or -Cw4 alleles, isolated from the Cw3or Cw4-transfected 721.221 lymphoblastoid cell line, triggered cd T cell apoptosis, interacting with the specific receptors CD158j/KIR2DS2 or CD158 h/KIR2DS1, respectively, also known as activating isoforms of killer Ig-like receptors (KIR). Again, this effect was dependent on FasL secretion and it was blocked by specific mAb to KIR2DS2 or KIR2DS1. The engagement of CD8 or activating KIR also triggered the production of TNF-a. Noteworthy, sHLA-I molecules synergize with antigen-mediated activation of Vd2 T cells: Indeed, Vd2 T lymphocytes produced TNF-a when stimulated with isopentenyl pyrophosphate, and this effect was enhanced by sHLA-I. These findings suggest that sHLA-I can regulate cd T cell survival and that activating KIR may amplify antigen-specific Vd2 T cell responses.

Research paper thumbnail of Evaluation of cytotoxic cell-target cell conjugates. Comparison between flow cytometric analysis and 51Cr binding assay

Haematologica

Two methods for evaluating the conjugate formation between either bulk cultured or cloned NK cell... more Two methods for evaluating the conjugate formation between either bulk cultured or cloned NK cells and fresh tumor target cells or tumor cell lines were compared. Flow cytometric analysis and 51Cr binding assay yielded comparable results using NK clones as effector cells; however, flow cytometry provides less accuracy using large granular lymphocytes or unfractionated lymphocytes.

Research paper thumbnail of HIV-I Tat: a polypeptide for all seasons

Research paper thumbnail of Interleukin-18 synthesis and secretion by dendritic cells are modulated by interaction with antigen-specific T cells

Journal of Leukocyte Biology

We show that interleukin-18 is constitutively produced by dendritic cells; synthesis and secretio... more We show that interleukin-18 is constitutively produced by dendritic cells; synthesis and secretion are poorly affected by maturative stimuli.