A Tabilio

Università degli Studi dell'Aquila, Aquila, Abruzzo, Italy

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Publications (254)1413.92 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: The impact of chronic lymphatic leukemia (CLL) tumor burden on the autologous immune system has already been demonstrated. This study attempted to elucidate the molecular mechanisms underlying T-cell immunologic deficiencies in CLL. Freshly isolated CD3(+) T cells from patients with a diagnosis of CLL and healthy donors were analyzed by gene expression profiling. Activated T cells from 20 patients with CLL were tested in vitro for cytotoxicity against mutated and unmutated autologous B cells and DAUDI, K562 and P815 cell lines. To investigate T-cell mediated cytotoxicity in vivo, we co-transplanted OKT3-activated T lymphocytes and autologous B-cell CLL (B-CLL) cells into NOD/SCID mice. Gene expression profiles of peripheral blood T cells from B-CLL patients showed 25 down-regulated, and 31 up-regulated, genes that were mainly involved in cell differentiation, proliferation, survival, apoptosis, cytoskeleton formation, vesicle trafficking and T-cell activation. After culture, the T-cell count remained unchanged, CD8 cells expanded more than CD4 and a cytotoxicity index >30% was present in 5/20 patients. Cytotoxicity against B autologous leukemic cells did not correlate with B-cell mutational status. Only activated T cells exerting cytotoxicity against autologous leukemic B cells prevented CLL in a human-mouse chimera. This study indicates that patients with CLL are affected by a partial immunologic defect that might be somewhat susceptible to repair. This study identifies the molecular pathways underlying T-cell deficiencies in CLL and shows that cytotoxic T-cell functions against autologous B-CLL can be rebuilt at least in part in vitro and in vivo.
    No preview · Article · Dec 2009 · Cytotherapy
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    [Show abstract] [Hide abstract] ABSTRACT: Although CD4(+)/CD25(+) T regulatory cells (T(regs)) are a potentially powerful tool in bone marrow transplantation, a prerequisite for clinical use is a cell-separation strategy complying with good manufacturing practice guidelines. We isolated T(regs) from standard leukapheresis products using double-negative selection (anti-CD8 and anti-CD19 monoclonal antibodies) followed by positive selection (anti-CD25 monoclonal antibody). The final cell fraction (CD4(+)/CD25(+)) showed a mean purity of 93.6% +/- 1.1. Recovery efficiency was 81.52% +/- 7.4. The CD4(+)/CD25(+bright) cells were 28.4% +/- 6.8. The CD4(+)/CD25(+) fraction contained a mean of 51.9% +/- 15.1 FoxP3 cells and a mean of 18.9% +/- 11.5 CD127 cells. Increased FoxP3 and depleted CD127 mRNAs in CD4(+)CD25(+)FoxP3(+) cells were in line with flow cytometric results. In Vbeta spectratyping the complexity scores of CD4(+)/CD25(+) cells and CD4(+)/CD25(-) cells were not significantly different, indicating that T(regs) had a broad T cell receptor repertoire. The inhibition assay showed that CD4(+)/CD25(+) cells inhibited CD4(+)/CD25(-) cells in a dose-dependent manner (mean inhibition percentages: 72.4 +/- 8.9 [ratio of T responder (T(resp)) to T(regs), 1:2]; 60.8% +/- 20.5 (ratio of T(resp) to T(regs), 1:1); 25.6 +/- 19.6 (ratio of T(resp) to T(regs), 1:0.1)). Our study shows that negative/positive T(reg) selection, performed using the CliniMACS device and reagents, enriches significantly CD4(+)CD25(+)FoxP3(+) cells endowed with immunosuppressive capacities. The CD4(+)CD25(+)FoxP3(+) population is a source of natural T(reg) cells that are depleted of CD8(+) and CD4(+)/CD25(-) reacting clones which are potentially responsible for triggering graft-versus-host disease (GvHD). Cells isolated by means of this approach might be used in allogeneic haematopoietic cell transplantation to facilitate engraftment and reduce the incidence and severity of GvHD without abrogating the potential graft-versus-tumour effect.
    Preview · Article · Apr 2009 · Clinical & Experimental Immunology
  • M Bodo · T Baroni · A Tabilio
    [Show abstract] [Hide abstract] ABSTRACT: During human embryogenesis, differentiation of haematopoietic stem cells (HSCs) and their progeny is regulated spatially and temporally. In the adult, hemopoiesis is restricted to bone marrow (BM) which contains HSCs residing within the so-called 'niches'. These are microenvironments consisting of extracellular matrix (ECM) macromolecules (mainly glycosaminoglycans, proteoglycans, fibronectin and collagens) and stromal cells that act in concert to keep HSCs in quiescence or to promote their growth and differentiation, since BM stromal cells secrete specific growth factors acting on responsive stem cells. Haematopoietic precursors also secrete numerous regulatory molecules as fibroblast growth factors (FGF), interleukin 1 (IL1), and transforming growth factor-beta1 (TGFbeta1), regulating in an autocrine and/or paracrine manner the various stages of normal hematopoiesis. Although the majority of stem cells are quiescent and do nor respond to external signals, a few active stem cells responde to paracrine produced growth factors and differentiate into the more committed CD34+ haematopoietic stem cell or into a mesenchymal stem cell, which generate even more specified tissue. This review focuses on the role of both ECM molecules and growth factors that form a dynamic, interactive system crucial for lineage commitment and amplification. In this perspective, we recently described the pivotal role of ECM, FGF and TGFbeta on the GM-490 phenotype, which is a cell line established from the bone marrow of a patient with acute lymphoblastic leukemia. Our findings indicated the GM-490 cell line possess characteristics of both haematopoietic and mesenchymal precursors.
    No preview · Article · Jan 2009 · Journal of stem cells
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    [Show abstract] [Hide abstract] ABSTRACT: Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by progressive anemia, massive splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis and in about 50% of cases the presence of JAK2V617F mutation. Curative therapy in PMF is currently possible only with allogeneic haematopoietic stem cell transplantation which is, unfortunately, associated with relatively high risks of mortality and morbidity which undermine its broad applications. Non-transplant treatment modalities are used for palliative purposes. Recently, anti-angiogenic drugs such as thalidomide have been used to treat these patients on the basis of the prominent bone marrow angiogenesis. Here, we report the case of a patient suffering from JAK2V617F-positive PMF with marked bone marrow neo-angiogenesis. The patient was treated with thalidomide but after 20days developed life-threatening toxic epidermal necrolysis (TEN). To the best of our knowledge this is the first case of TEN in a patient with PMF under thalidomide therapy.
    Full-text · Article · Jan 2009 · International Journal of Hematology
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    [Show abstract] [Hide abstract] ABSTRACT: Mesenchymal stem cells (MSCs) are a promising cell line for the treatment of ischemic heart disease. To evaluate the success of their transplantation into living animals, noninvasive imaging techniques that are able to track the distribution and fate of those cells would be useful. The aim of this study was to investigate the feasibility of infecting rat MSCs with adenoviruses and retroviruses carrying the herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene; to compare the level of transgene expression induced by the 2 viral vectors; to evaluate the effects of viral transduction on cell phenotype, viability, proliferation rates, and differentiation capabilities; and to test the possibility of noninvasively imaging transduced MSCs using 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (18F-FHBG) and small-animal PET after their transplantation into living rats. We infected rat bone marrow MSCs with adenoviruses carrying the HSV1 mutant tk (Ad-HSV1-sr39tk) PET reporter gene (PRG) or with a retroviral construct expressing the wild-type HSV1-tk PRG. The efficacy and intensity of HSV1-sr39tk and HSV1-tk gene expression were determined by a direct comparison of [8-3H]-penciclovir ([8-3H]-PCV) cell uptake in both infected MSC populations and noninfected control MSCs. Small-animal PET studies were performed on living rats after an intramuscular injection of infected MSCs. The MSCs either have been incubated in advance with 18F-FHBG or they were administered and 18F-FHBG was thereafter intravenously administered [corrected] Both adenoviral and retroviral vectors can be used to introduce the tk PRG in MSCs. Neither adenovirus nor retrovirus infections significantly modify MSC phenotype, viability, proliferation, and differentiation capabilities. No significant 3H-PCV uptake was observed in noninfected MSCs. By contrast, after both adenoviral and retroviral infections, the infected MSC populations exhibited a similar, significantly higher, 3H-PCV accumulation. Small-animal PET images showed intense activity within the transplanted regions irrespective of the infected MSC population used. Our results demonstrate the feasibility of infecting MSCs with adenoviruses and retroviruses expressing the HSV1-tk PRG and suggest that infected MSCs can be noninvasively imaged with 18F-FHBG and small-animal PET after their transplantation into living animals.
    Full-text · Article · Dec 2008 · Journal of Nuclear Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Retroviral vectors are used in human gene therapy trials to stably introduce therapeutic genes in the genome of patients' cells. Their applicability, however, is frustrated by the limited viability of transformed cells and/or by risks linked to selection of oncogene-mutated clones. The reasons for these drawbacks are not yet completely understood. In this study, we show that LXSN-NeoR gene/interleukin-7-engineered mesenchymal stromal cells exhibited a marked enhancement of reactive oxygen species production compared with untransfected cells. This effect resulted to be independent on the product of the gene carried by the retroviral vehicle as it was reproducible in cells transfected with the empty vector alone. Stable transfection of mesenchymal stromal cells with the different retroviral vectors pBabe-puro and PINCO-puro and the lentiviral vector pSico PGK-puro caused similar redox imbalance, unveiling a phenomenon of more general impact. The enhanced production of reactive oxygen species over the basal level was attributable to mitochondrial dysfunction and brought back to altered activity of the NADH-CoQ oxidoreductase (complex I) of the respiratory chain. The oxidative stress in transfected mesenchymal stem cells was completely reversed by treatment with a cAMP analog, thus pointing to alteration in the protein kinase A-dependent signaling pathway of the host cell. Transfection of mesenchymal stromal cells with a PINCO-parental vector harboring the green fluorescent protein gene as selection marker in place of the puromycin-resistance gene resulted in no alteration of the redox phenotype. These novel findings provide insights and caveats to the applicability of cell- or gene-based therapies and indicate possible intervention to improve them.Disclosure of potential conflicts of interest is found at the end of this article.
    Full-text · Article · Oct 2008 · Stem Cells
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    [Show abstract] [Hide abstract] ABSTRACT: Notch signaling is involved in tumorigenesis, but its role in B-chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor-kappa B (NF-kappaB) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (XIAP) expression. In contrast, Notch-signaling inhibition by the gamma-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-kappaB activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.
    Full-text · Article · Oct 2008 · Blood
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    [Show abstract] [Hide abstract] ABSTRACT: Bone Marrow Transplantation is a high quality, peer-reviewed journal covering all aspects of clinical and basic haemopoietic stem cell transplantation.
    Preview · Article · Oct 2008 · Bone marrow transplantation
  • No preview · Conference Paper · Sep 2008
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    [Show abstract] [Hide abstract] ABSTRACT: The discovery of the Janus kinase 2 Val617Phe mutation has brought new insights into the development of myeloproliferative disorders; however, the pathogenesis of essential thrombocythemia and its related thrombotic complications has not been completely understood. Although the Janus kinase 2 Val617Phe mutation confirms the initially suspected clonal character of the disease, factors influencing clonal transformation and expansion in the bone marrow have not been fully detected. Furthermore, patients affected by essential thrombocythemia who are carriers of the Janus kinase 2 Val617Phe mutation show a higher incidence of venous thromboembolism both before, and at the time of diagnosis, compared with noncarriers, and recent evidence of splanchnic and cerebral vein thrombosis in carriers of the Janus kinase 2 Val617Phe mutation has been reported. The intake of oral contraceptives is a strong and independent risk factor for venous thromboembolism. In addition, in-vitro tests showed both an altered primary haemostatic plug formation and enhanced platelet aggregation in patients taking such drugs. Little is known, though, about the influence of steroid hormones on both megakaryopoiesis and platelet function in patients with the Janus kinase 2 Val617Phe mutation. Herewith, we report the case of a 30-year-old woman who took a third generation oral contraceptive for 5 months and developed an essential thrombocythemia with spleno-portal axis and superior mesenteric vein thrombosis. She was found to carry the kinase gene Janus kinase 2 mutation.
    Full-text · Article · Aug 2008 · Blood Coagulation and Fibrinolysis
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    Preview · Article · Jul 2008 · Biochimica et Biophysica Acta (BBA) - Bioenergetics
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    Full-text · Article · Jun 2008 · Journal of the American Academy of Dermatology
  • [Show abstract] [Hide abstract] ABSTRACT: We report a noteworthy case of Eubacterium plautii infection after kidney transplantation. Our 33-yr-old transplant recipient received standard care; his post-transplant course was uneventful. However, on day 44 he underwent an emergency laparotomy for perforation of the ileum. He was initially treated with ceftazidime, fluconazole and metronidazole, but his fever persisted, so he was switched to meropenem and vancocin. We could not find any cause for his infection. On day 70, his temperature normalized. On day 75, he developed severe leukopenia (280 cell/mL). His cytomegalovirus-DNA test result was negative, so all immunosuppressants, except for prednisone, were stopped; instead, antibiotic prophylaxis was started, using caspofungin, trimethoprim-sulfamethoxazole and ciprofloxacin. On day 83, he underwent percutaneous drainage of massive left pleural effusion. We repeatedly cultured the pleural liquid, but it was not till three wk later that we were finally able to identify the causative organism. We hypothesize that the microorganism - which normally resides on the surface of the intestinal lumen - entered the bloodstream via bacterial translocation, eventually colonizing the pleurae. This translocation was favored by our patient poor clinical condition, his immunosuppressive treatment and his heavy antibiotherapy. Our experience highlights the need for wiser use of antibiotics in transplant recipients.
    No preview · Article · Apr 2008 · Clinical Transplantation
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    [Show abstract] [Hide abstract] ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Preview · Article · Apr 2008 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    [Show abstract] [Hide abstract] ABSTRACT: Despite much investigation into T regulatory cells (Tregs), little is known about the mechanism controlling their recruitment and function. Because multipotent mesenchymal stromal cells (MSCs) exert an immune regulatory function and suppress T-cell proliferation, this in vitro study investigated their role in Treg recruitment and function. Human MSCs and different T cell populations (CD3(+), CD3(+)/CD45RA(+), CD3(+)/CD45RO(+), CD4(+)/CD25(+), CD4(+)/CD25(+)/CD45RO(+), CD4(+)/CD25(+)/CD45RA(+)) from healthy donors were cocultured for up to 15 days. Harvested lymphocytes were analyzed by flow cytometry and FoxP3 and CD127 expressions were measured by real-time polymerase chain reaction. Their regulatory activity was assessed. We demonstrate MSC recruit Tregs from a fraction of CD3(+) and from immunoselected CD3(+)/CD45RA(+) and CD3(+)/CD45RO(+) fractions. After culture with MSCs both immunoselected fractions registered increases in the CD4(+)/CD25(bright)/FoxP3 subset and CD127 expression was downregulated. When purified Treg populations (CD4/CD25(+), CD4/CD25(+)/CD45RA(+), and CD4/CD25(+)/CD45RO(+)) are used in MSC cocultures, they maintain FoxP3 expression and CD127 expression is downregulated. Treg suppressive capacity was maintained in Treg populations that were layered on MSC for up to 15 days while control Tregs lost all suppressive activity after 5 days culture. In conclusion, our study demonstrates that MSCs recruit, regulate, and maintain T-regulatory phenotype and function over time.
    Preview · Article · Apr 2008 · Experimental Hematology
  • [Show abstract] [Hide abstract] ABSTRACT: Vasculogenesis is a physiologic process typical of fetal development in which new blood vessels develop from undifferentiated precursors (or angioblasts). In tumors, near angiogenesis, vasculogenesis contributes to the formation of the microvascular plexus that is important for diffusion. Here, we show that hematopoietic stem and progenitor cells (HSPC) of multiple myeloma (MM) patients are able to differentiate into cells with endothelial phenotype on exposure to angiogenic cytokines. Circulating HSPCs were purified with an anti-CD133 antibody from patients with newly diagnosed MM before autologous transplantation and exposed to vascular endothelial growth factor (VEGF), fibroblast growth factor-2 and insulin-like growth factor in a 3-week culture. HSPCs gradually lost CD133 expression and acquired VEGF receptor-2, factor VIII-related antigen, and vascular endothelial-cadherin expression. The expression pattern overlapped with paired MM endothelial cells (MMEC). During culture, cells adhered to fibronectin, spread, and acquired an endothelial cell shape. Differentiated HSPCs also became capillarogenic in the Matrigel assay with maximal activity at the third week of culture. Bone marrow biopsies revealed HSPCs inside the neovessel wall in patients with MM but not in those with monoclonal gammopathy of undetermined significance. In patients with MM, but not in those with monoclonal gammopathy of undetermined significance, HSPCs contribute to the neovessel wall building together with MMECs. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. Tentatively, we hypothesize that in HSPC cultures a multipotent cell population expressing low VEGF receptor-2 levels corresponds to the endothelial progenitor cell precursor and seems to be the MMEC precursor.
    No preview · Article · Apr 2008 · Clinical Cancer Research
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    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to characterize the local distribution and organization of the plasma membrane NADPH-oxidase (NOX) in human haematopoietic stem cell (HSC) by means of the fluorescence scanning near-field optical microscopy approach. The presence of NOX in haematopoietic stem cells is thought to have a functional role as O(2) sensor and/or as low-level reactive oxygen species (ROS) producer to be used as redox messenger for controlling cell growth and differentiation. Given the harmful potential of ROS, a fine-tuning of NOX activity is needed. The high resolution imaging of haematopoietic stem cell membrane obtained in this study combined with the immunodetection of NOX indicates for this the occurrence of a cluster-organized structure. These membrane 'rafts'-like micro-compartments may constitute localized protein aggregates whereby the assembly/activation of the NOX components are functionally integrated with upstream factors constituting signal-transduction platforms.
    Full-text · Article · Apr 2008 · Journal of Microscopy
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    Preview · Article · Mar 2008 · Nephrology Dialysis Transplantation
  • [Show abstract] [Hide abstract] ABSTRACT: Although adoptive transfer of donor lymphocytes protects from infections and relapse after allogeneic hematopoietic stem cell transplantation in both mice and in men, it is associated with a high risk of graft versus host disease (GvHD) which rises with HLA mismatching and the number of T lymphocytes that are infused. Elimination/reduction of alloreactive donor T lymphocytes is an appealing approach and several strategies have been proposed. Here we describe generation of anti-3rd party T lymphocytes under conditions of IL-2 deprivation and their effects in a pre-clinical murine model. Our results clearly indicated that anti-3rd party T lymphocytes generated on a large scale by means of IL-2 deprivation maintain a broad T cell repertoire, do not proliferate in a mixed lymphocyte reaction and do not cause GvHD in NOD-SCID mice. These anti-3rd party lymphocytes contain a large adaptive T regulatory cell subset which might contribute to in vitro and in vivo immune modulation.
    No preview · Article · Feb 2008 · Blood Cells Molecules and Diseases
  • No preview · Conference Paper · Jan 2008

Publication Stats

7k Citations
1,413.92 Total Impact Points


  • 2006-2009
    • Università degli Studi dell'Aquila
      • Department of Internal Medicine and Public Health
      Aquila, Abruzzo, Italy
  • 1983-2009
    • Università degli Studi di Perugia
      • • Department of Clinical and Experimental Medicine
      • • Department of Internal Medicine
      Perugia, Umbria, Italy
  • 2007
    • Università degli Studi G. d'Annunzio Chieti e Pescara
      Chieta, Abruzzo, Italy
  • 1996-2006
    • Università degli studi di Parma
      • Department of Clinical and Experimental Medicine
      Parma, Emilia-Romagna, Italy
  • 1990-2005
    • Sapienza University of Rome
      • Department of Cellular Biotechnology and Hematology BCE
      Roma, Latium, Italy
  • 2003
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 2001
    • Polyclinic of Modena
      Modène, Emilia-Romagna, Italy
  • 1999
    • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano
      Milano, Lombardy, Italy
  • 1994
    • Weizmann Institute of Science
      Rhovot, Central District, Israel
  • 1991
    • Mediterranean Institute of Hematology
      Roma, Latium, Italy
  • 1989
    • Università degli Studi di Torino
      Torino, Piedmont, Italy
  • 1983-1984
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 1980
    • Southern Illinois University School of Medicine
      Springfield, Illinois, United States