G. Borsellino - Academia.edu (original) (raw)

Papers by G. Borsellino

Blood, 2000

Human gammadelta T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but ... more Human gammadelta T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their precise function remains unknown. In adults the major circulating gammadelta T-cell subset expresses the Vgamma9Vdelta2 T-cell receptor and responds to protease-resistant phosphorylated derivatives found in many pathogens. In this study we show that activation of Vdelta2(+) cells with the nonpeptidic antigen isopentenyl pyrophosphate (IPP) rapidly induces (within 4-12 hours) the C-C chemokines MIP-1alpha, MIP-1beta, and lymphotactin but not MCP-1. The most robust response was obtained for MIP-1beta. IPP induction of MIP-1alpha and MIP-1beta was not affected by costimulation with interleukin-4 (IL-4), IL-10, TGF-beta, or interferon-gamma (INF-gamma). However, IL-12 significantly enhanced IPP-induced expression and release of MIP-1alpha that was down-regulated by TGF-beta whereas the induction of MIP-1beta by IPP+IL-12 was refractory to cotreatment with TGFbeta indicating that these ...

Blood, 2008

The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models... more The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models to prevent inflammatory immune and autoimmune diseases. Translation into therapeutic applications, however, is hindered by the lack of suitable techniques and markers. CD25, commonly used to isolate Treg cells from mice, has only limited value in humans as it is also present on proinflammatory CD4+ effector cells. Here we show that clean populations of human Foxp3+ Treg cells can be obtained with antibodies directed against CD49d. The marker is present on proinflammatory peripheral blood mononuclear cells but is absent on immune-suppressive Treg cells. Depletion with α-CD49d removes contaminating interferon-γ (IFN-γ)– and interleukin-17 (IL-17)–secreting cells from Treg preparations of CD4+CD25high cells. More importantly, in combination with α-CD127 it allows the isolation of “untouched” Foxp3+ Treg (ie, cells that have not been targeted by an antibody during purification). The removal...

The Journal of Immunology

The presence of NK receptors (NKR) on populations of T cells has been proposed to play a regulato... more The presence of NK receptors (NKR) on populations of T cells has been proposed to play a regulatory role in T cell function, fine tuning the response to Ag, and influencing the nature of the immune response through rapid secretion of large amounts of cytokines. In this study, we assessed the nature and distribution of NKR on human peripheral blood gamma delta T cells and established clones to study cytokine release. In circulating gamma delta T cells, approximately 80% expressed CD94, approximately 25% expressed NKR-P1A, and approximately 20% expressed p58, values substantially higher than those found on alpha beta T cells from the same donors. When cloned for specific NKR expression, most cells in culture were NKR-P1A+ whereas p58 expression was variable, suggesting that the NKR-P1A phenotype can be acquired in culture whereas expression of p58 is more stable. Some clones were triple positive for CD94, NKR-P1A, and p58. V delta 2+ cells generally expressed a wider range of NKR than...

The Journal of Immunology

γδ T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contri... more γδ T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contributing to demyelinization and fibrosis in the central nervous system. In this study, we show that, in MS patients with active disease, the percentage of circulating Vδ2+ γδ T cells coexpressing NKRP1A is significantly increased compared with healthy donors. Vδ2+ and Vδ1+ T cells were sorted from MS patients and healthy volunteers and cloned. At variance with Vδ1+ clones, all Vδ2+ clones expressed NKRP1A, which was strongly up-regulated upon culture with IL-12; this effect was neutralized by specific anti-IL-12 Abs. No up-regulation of NKRP1A by IL-12 was noted on Vδ1+ clones. RNase protection assay showed that IL-12R β2 subunit transcript was significantly less represented in Vδ1+ than Vδ2+ clones. This finding may explain the different effect exerted by IL-12 on these clones. In transendothelial migration assays, Vδ2+ NKRP1A+ clones migrated more effectively than Vδ1+ clones, and this m...

Blood, 2000

Human γδ T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their pr... more Human γδ T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their precise function remains unknown. In adults the major circulating γδ T-cell subset expresses the Vγ9Vδ2 T-cell receptor and responds to protease-resistant phosphorylated derivatives found in many pathogens. In this study we show that activation of Vδ2+ cells with the nonpeptidic antigen isopentenyl pyrophosphate (IPP) rapidly induces (within 4-12 hours) the C-C chemokines MIP-1, MIP-1β, and lymphotactin but not MCP-1. The most robust response was obtained for MIP-1β. IPP induction of MIP-1 and MIP-1β was not affected by costimulation with interleukin-4 (IL-4), IL-10, TGF-β, or interferon-γ (INF-γ). However, IL-12 significantly enhanced IPP-induced expression and release of MIP-1 that was down-regulated by TGF-β whereas the induction of MIP-1β by IPP+IL-12 was refractory to cotreatment with TGFβ indicating that these chemokines are differentially regulated by these cytokines. Vδ2+ T cell...

Immunology, 2017

Article type : Original Article Programmed death 1 is highly expressed on CD8+CD57+ T cells in pa... more Article type : Original Article Programmed death 1 is highly expressed on CD8+CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to EBV

Cell Death & Disease, 2015

Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeosta... more Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases’ cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that ...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 8, 2015

Purpose We evaluated leukemia-associated immunophenotypes (LAIP) and their correlation with fms-l... more Purpose We evaluated leukemia-associated immunophenotypes (LAIP) and their correlation with fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) gene mutational status in order to contribute a better identification of patients at highest risk of relapse in AML. Bone marrow samples from 132 patients with acute myeloid leukemia (AML) were analyzed by 9-color multiparametric flow cytometry (MPFC). We confirmed the presence of the mutation in diagnostic samples and in sorted cells by conventional RT-PCR and by patient-specific RQ-PCR. Within the CD34+ve cell fraction we identified a discrete population expressing high levels of the IL-3 receptor alpha-chain (CD123) and MIC-2 (CD99) in combination with the IL-2 receptor alpha-chain (CD25). The presence of this population positively correlated with the internal tandem duplications (ITD) mutation in the FLT3 gene (r = 0.71). Receiver operating characteristics (ROC) showed that, within the CD34+ve cell fraction a percentage of CD123/C...

From Basic Immunology to Immune-Mediated Demyelination, 1999

Immune-mediated damage is probably the most relevant event among those that contribute to the pat... more Immune-mediated damage is probably the most relevant event among those that contribute to the pathogenesis of multiple sclerosis (MS). The search for autoantigens inducing T cell responses in MS as well as in other immune-mediated, organ-specific diseases was initated as soon as efficient techniques for the isolation and expansion of antigen-specific T cell lines became available [1].

Proceedings of the National Academy of Sciences, 2005

Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological p... more Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological processes. Because of its varied clinical presentation, natural history, and response to therapeutic interventions, MS can be considered to be a group of diseases that have not been yet characterized, thus resulting in difficult evaluation of prognosis. In the last few years, the role of autoAbs in MS has been reevaluated, and, therefore, their identification as specific biomarkers became a relevant target. In this paper, we demonstrate that an aberrant N -glucosylation is a fundamental determinant of autoAb recognition in MS. Thus, we developed CSF114(Glc), an antigenic probe accurately measuring IgM autoAbs in the sera of a patient population, as disease biomarker. The relevance of CSF114(Glc) is demonstrated by its clinical application and correlation with disease activity and prognosis. In fact, CSF114(Glc), a structure-based designed glycopeptide, is able to recognize, by ELISA, the ...

PLoS ONE, 2011

FoxP3 + Treg cells are believed to play a role in the occurrence of autoimmunity and in the deter... more FoxP3 + Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.

Journal of Neuroimmunology, 2000

Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible ... more Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS.

Journal of Neuroimmunology, 1998

Journal of Neuroimmunology, 2000

In this report we review current information on the phenotypic and functional properties of γδ T ... more In this report we review current information on the phenotypic and functional properties of γδ T cells in demyelinating disorders. The results support the conclusion that although γδ T cells show evidence of activation in patients with either multiple sclerosis (MS) or Guillain Barrè syndrome (GBS), differences exist in the phenotypic and functional properties of these cells between the two

Blood, 2000

Human gammadelta T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but ... more Human gammadelta T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their precise function remains unknown. In adults the major circulating gammadelta T-cell subset expresses the Vgamma9Vdelta2 T-cell receptor and responds to protease-resistant phosphorylated derivatives found in many pathogens. In this study we show that activation of Vdelta2(+) cells with the nonpeptidic antigen isopentenyl pyrophosphate (IPP) rapidly induces (within 4-12 hours) the C-C chemokines MIP-1alpha, MIP-1beta, and lymphotactin but not MCP-1. The most robust response was obtained for MIP-1beta. IPP induction of MIP-1alpha and MIP-1beta was not affected by costimulation with interleukin-4 (IL-4), IL-10, TGF-beta, or interferon-gamma (INF-gamma). However, IL-12 significantly enhanced IPP-induced expression and release of MIP-1alpha that was down-regulated by TGF-beta whereas the induction of MIP-1beta by IPP+IL-12 was refractory to cotreatment with TGFbeta indicating that these ...

Blood, 2008

The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models... more The adoptive transfer of regulatory Foxp3+ T (Treg) cells has been shown in various animal models to prevent inflammatory immune and autoimmune diseases. Translation into therapeutic applications, however, is hindered by the lack of suitable techniques and markers. CD25, commonly used to isolate Treg cells from mice, has only limited value in humans as it is also present on proinflammatory CD4+ effector cells. Here we show that clean populations of human Foxp3+ Treg cells can be obtained with antibodies directed against CD49d. The marker is present on proinflammatory peripheral blood mononuclear cells but is absent on immune-suppressive Treg cells. Depletion with α-CD49d removes contaminating interferon-γ (IFN-γ)– and interleukin-17 (IL-17)–secreting cells from Treg preparations of CD4+CD25high cells. More importantly, in combination with α-CD127 it allows the isolation of “untouched” Foxp3+ Treg (ie, cells that have not been targeted by an antibody during purification). The removal...

The Journal of Immunology

The presence of NK receptors (NKR) on populations of T cells has been proposed to play a regulato... more The presence of NK receptors (NKR) on populations of T cells has been proposed to play a regulatory role in T cell function, fine tuning the response to Ag, and influencing the nature of the immune response through rapid secretion of large amounts of cytokines. In this study, we assessed the nature and distribution of NKR on human peripheral blood gamma delta T cells and established clones to study cytokine release. In circulating gamma delta T cells, approximately 80% expressed CD94, approximately 25% expressed NKR-P1A, and approximately 20% expressed p58, values substantially higher than those found on alpha beta T cells from the same donors. When cloned for specific NKR expression, most cells in culture were NKR-P1A+ whereas p58 expression was variable, suggesting that the NKR-P1A phenotype can be acquired in culture whereas expression of p58 is more stable. Some clones were triple positive for CD94, NKR-P1A, and p58. V delta 2+ cells generally expressed a wider range of NKR than...

The Journal of Immunology

γδ T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contri... more γδ T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contributing to demyelinization and fibrosis in the central nervous system. In this study, we show that, in MS patients with active disease, the percentage of circulating Vδ2+ γδ T cells coexpressing NKRP1A is significantly increased compared with healthy donors. Vδ2+ and Vδ1+ T cells were sorted from MS patients and healthy volunteers and cloned. At variance with Vδ1+ clones, all Vδ2+ clones expressed NKRP1A, which was strongly up-regulated upon culture with IL-12; this effect was neutralized by specific anti-IL-12 Abs. No up-regulation of NKRP1A by IL-12 was noted on Vδ1+ clones. RNase protection assay showed that IL-12R β2 subunit transcript was significantly less represented in Vδ1+ than Vδ2+ clones. This finding may explain the different effect exerted by IL-12 on these clones. In transendothelial migration assays, Vδ2+ NKRP1A+ clones migrated more effectively than Vδ1+ clones, and this m...

Blood, 2000

Human γδ T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their pr... more Human γδ T lymphocytes respond to viral, bacterial, protozoal, and tumoral antigens, but their precise function remains unknown. In adults the major circulating γδ T-cell subset expresses the Vγ9Vδ2 T-cell receptor and responds to protease-resistant phosphorylated derivatives found in many pathogens. In this study we show that activation of Vδ2+ cells with the nonpeptidic antigen isopentenyl pyrophosphate (IPP) rapidly induces (within 4-12 hours) the C-C chemokines MIP-1, MIP-1β, and lymphotactin but not MCP-1. The most robust response was obtained for MIP-1β. IPP induction of MIP-1 and MIP-1β was not affected by costimulation with interleukin-4 (IL-4), IL-10, TGF-β, or interferon-γ (INF-γ). However, IL-12 significantly enhanced IPP-induced expression and release of MIP-1 that was down-regulated by TGF-β whereas the induction of MIP-1β by IPP+IL-12 was refractory to cotreatment with TGFβ indicating that these chemokines are differentially regulated by these cytokines. Vδ2+ T cell...

Immunology, 2017

Article type : Original Article Programmed death 1 is highly expressed on CD8+CD57+ T cells in pa... more Article type : Original Article Programmed death 1 is highly expressed on CD8+CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to EBV

Cell Death & Disease, 2015

Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeosta... more Functionally distinct T-helper (Th) subsets orchestrate immune responses. Maintenance of homeostasis through the tight control of inflammatory Th cells is crucial to avoid autoimmune inflammation. Activation-Induced Cell Death (AICD) regulates homeostasis of T cells, and it has never been investigated in human Th cells. We generated stable clones of inflammatory Th subsets involved in autoimmune diseases, such as Th1, Th17 and Th1/17 cells, from healthy donors (HD) and multiple sclerosis (MS) patients and we measured AICD. We find that human Th1 cells are sensitive, whereas Th17 and Th1/17 are resistant, to AICD. In particular, Th1 cells express high level of FAS-ligand (FASL), which interacts with FAS and leads to caspases’ cleavage and ultimately to cell death. In contrast, low FASL expression in Th17 and Th1/17 cells blunts caspase 8 activation and thus reduces cell death. Interestingly, Th cells obtained from healthy individuals and MS patients behave similarly, suggesting that ...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 8, 2015

Purpose We evaluated leukemia-associated immunophenotypes (LAIP) and their correlation with fms-l... more Purpose We evaluated leukemia-associated immunophenotypes (LAIP) and their correlation with fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) gene mutational status in order to contribute a better identification of patients at highest risk of relapse in AML. Bone marrow samples from 132 patients with acute myeloid leukemia (AML) were analyzed by 9-color multiparametric flow cytometry (MPFC). We confirmed the presence of the mutation in diagnostic samples and in sorted cells by conventional RT-PCR and by patient-specific RQ-PCR. Within the CD34+ve cell fraction we identified a discrete population expressing high levels of the IL-3 receptor alpha-chain (CD123) and MIC-2 (CD99) in combination with the IL-2 receptor alpha-chain (CD25). The presence of this population positively correlated with the internal tandem duplications (ITD) mutation in the FLT3 gene (r = 0.71). Receiver operating characteristics (ROC) showed that, within the CD34+ve cell fraction a percentage of CD123/C...

From Basic Immunology to Immune-Mediated Demyelination, 1999

Immune-mediated damage is probably the most relevant event among those that contribute to the pat... more Immune-mediated damage is probably the most relevant event among those that contribute to the pathogenesis of multiple sclerosis (MS). The search for autoantigens inducing T cell responses in MS as well as in other immune-mediated, organ-specific diseases was initated as soon as efficient techniques for the isolation and expansion of antigen-specific T cell lines became available [1].

Proceedings of the National Academy of Sciences, 2005

Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological p... more Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological processes. Because of its varied clinical presentation, natural history, and response to therapeutic interventions, MS can be considered to be a group of diseases that have not been yet characterized, thus resulting in difficult evaluation of prognosis. In the last few years, the role of autoAbs in MS has been reevaluated, and, therefore, their identification as specific biomarkers became a relevant target. In this paper, we demonstrate that an aberrant N -glucosylation is a fundamental determinant of autoAb recognition in MS. Thus, we developed CSF114(Glc), an antigenic probe accurately measuring IgM autoAbs in the sera of a patient population, as disease biomarker. The relevance of CSF114(Glc) is demonstrated by its clinical application and correlation with disease activity and prognosis. In fact, CSF114(Glc), a structure-based designed glycopeptide, is able to recognize, by ELISA, the ...

PLoS ONE, 2011

FoxP3 + Treg cells are believed to play a role in the occurrence of autoimmunity and in the deter... more FoxP3 + Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.

Journal of Neuroimmunology, 2000

Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible ... more Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS.

Journal of Neuroimmunology, 1998

Journal of Neuroimmunology, 2000

In this report we review current information on the phenotypic and functional properties of γδ T ... more In this report we review current information on the phenotypic and functional properties of γδ T cells in demyelinating disorders. The results support the conclusion that although γδ T cells show evidence of activation in patients with either multiple sclerosis (MS) or Guillain Barrè syndrome (GBS), differences exist in the phenotypic and functional properties of these cells between the two