What is the Contribution of Host-Derived CMV Immunity after Allogeneic Transplantation following Non-Myeloablative Conditioning?

in Haematologica (2012), 97(Supplement 1), 720

Thymic recovery after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning is limited to patients younger than 60 years of age

in Haematologica (2011), 96(2)

Thymosin Beta 4 has tumor suppressive effects and its decreased expression results in poor prognosis and decreased survival in multiple myeloma

in Haematologica (2010), 95(1), 163-167

Prolonged ex vivo culture of human bone marrow mesenchymal stem cells influences their supportive activity toward NOD/SCID -repopulating cells and committed progenitor cells of B lymphoid and myeloid lineages

in Haematologica (2010), 95(1), 47-56

Background Bone marrow (BM) mesenchymal stem cells (MSC) support proliferation and differentiation of hematopoietic progenitor cells (HPC) in vitro. Since they represent a rare subset of BM cells, MSC ... [more ▼]

Background Bone marrow (BM) mesenchymal stem cells (MSC) support proliferation and differentiation of hematopoietic progenitor cells (HPC) in vitro. Since they represent a rare subset of BM cells, MSC preparations for clinical purposes involves a preparative step of ex vivo multiplication. The aim of our study was to analyze the influence of culture duration on MSC supportive activity. DESIGN AND METHODS: MSC were expanded for up to 10 passages. MSC and CD34(+) cells were seeded in cytokine-free co-cultures after which the phenotype, clonogenic capacity and in vivo repopulating activity of harvested hematopoietic cells were assessed. RESULTS: Early passage MSC supported HPC expansion and differentiation toward both B lymphoid and myeloid lineages. Late passage MSC did not support HPC and myeloid cell outgrowth but maintained B cell supportive ability. In vitro maintenance of NOD/SCID mouse repopulating cells cultured for one week in contact with MSC was effective until the fourth MSC passage and declined afterwards. CD34(+) cells achieved higher levels of engraftment in NOD/SCID mice when co-injected with early passage MSC; however MSC expanded beyond 9 passages were ineffective in promoting CD34(+) cell engraftment. Non-contact cultures indicated that MSC supportive activity involved diffusible factors. Among these, interleukin (IL)-6 and IL-8 contributed to the supportive activity of early passage MSC but not of late passage MSC. MSC phenotype as well as fat, bone and cartilage differentiation capacity did not change during MSC culture. Conclusions Extended MSC culture alters their supportive ability toward HPC without concomitant changes in phenotype and differentiation capacity. [less ▲]

The prevention of spontaneous apoptosis of follicular lymphoma B cells by a follicular dendritic cell line: involvement of caspase-3, caspase-8 and c-FLIP.

in Haematologica (2008), 93(8), 1169-77

BACKGROUND: Follicular lymphoma, the neoplastic counterpart of germinal center B cells, typically recapitulates a follicular architecture. Several observations point to the crucial role of the cellular ... [more ▼]

BACKGROUND: Follicular lymphoma, the neoplastic counterpart of germinal center B cells, typically recapitulates a follicular architecture. Several observations point to the crucial role of the cellular microenvironment in the development and/or progression of follicular lymphoma cells in vivo. The aim of our study was to characterize the spontaneous apoptosis of follicular lymphoma cells in vitro, and the modulation of this apoptosis by follicular dendritic cells. DESIGN AND METHODS: We used a cell line derived from follicular dendritic cells to model the functional interactions of these cells and lymphoma cells in co-culture. Follicular lymphoma cells were isolated from tissue biopsies. Apoptosis was quantified by flow cytometry and apoptotic pathways were investigated by western blotting. RESULTS: The spontaneous apoptosis of follicular lymphoma cells in vitro involves the activation of caspases-3 and -8 but not of caspase-9, occurs despite persistent high levels of BCL-2 and MCL-1, and is associated with down-regulation of c-FLIP(L). Spontaneous apoptosis of follicular lymphoma cells is partially prevented by co-culture with the follicular dendritic cells, which prevents activation of caspase-8, caspase-3 and induces an upregulation of c-FLIP(L). Using neutralizing antibodies, we demonstrated that interactions involving CD54 (ICAM-1), CD106 (VCAM-1) and CD40 are implicated in this biological process. CONCLUSIONS: Follicular dendritic cells constitute a useful tool to study the functional interactions between follicular lymphoma cells and follicular dendritic cells in vitro. Understanding the molecular mechanisms involved in these protective interactions may lead to the identification of therapeutic agents that might suppress the survival and growth of follicular lymphoma cells. [less ▲]

Duplication of the MYB oncogene in T-cell acute lymphoblastic leukemia

in Haematologica (2007, June), 92(Suppl. 1), 164

Modulation of homing properties of primitive progenitor cells generated by ex vivo expansion.

in Haematologica (2005), 90(4), 445-51

BACKGROUND AND OBJECTIVES: The maintenance of adequate interactions with the bone marrow (BM) microenvironment is critical to ensure efficient homing of ex vivo-expanded hematopoietic cells. This study ... [more ▼]

BACKGROUND AND OBJECTIVES: The maintenance of adequate interactions with the bone marrow (BM) microenvironment is critical to ensure efficient homing of ex vivo-expanded hematopoietic cells. This study was intended to assess adhesion and migration properties of long-term culture-initiating cells (LTC-IC) harvested after self-renewal division in ex vivo culture and to determine their susceptibility to growth-inhibitory signals mediated by adhesion to BM stromal ligands. DESIGN AND METHODS: We used cell tracking to isolate primitive LTC-IC that had accomplished 1 or 2 divisions ex vivo. Adhesion, migration and growth inhibition of divided LTC-IC were determined in the presence of purified BM ligands, and compared to the properties of uncultured LTC-IC. RESULTS: As compared to undivided LTC-IC, adhesion and migration mediated by very late antigen (VLA)-4 integrin across both vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (Fn) were downregulated in post-mitotic LTC-IC. Conversely, binding and motility via VLA-5 across Fn were stimulated. No changes occurred in LTC-IC interactions with intercellular adhesion molecule-1 (ICAM-1) or with E- or P-selectin. Proliferation of uncultured LTC-IC was inhibited by VLA-4-mediated binding to VCAM-1 and the CS-1 domain of Fn, as well as binding to P-selectin. Growth of ex vivo-generated LTC-IC became unresponsive to these 3 ligands but was suppressed through VLA-5 engagement by the cell binding domain of Fn. INTERPRETATION AND CONCLUSIONS: The generation of LTC-IC in expansion culture is associated with functional alterations of adhesion receptors, modulating not only binding and migration in the BM but also responsiveness to adhesion-mediated growth inhibitory signals. Such changes may limit homing and engraftment of expanded primitive stem/progenitor cells. [less ▲]

Efficacy of recombinant human erythropoietin therapy started one month after autologous peripheral blood stem cell transplantation.

in Haematologica (2005), 90(9), 1269-70

On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment ... [more ▼]

On day 30 after autologous peripheral blood stem cell transplantation (PBSCT), 20 patients were randomized to receive either erythropoietin at a dose of 500 U/kg/week s.c. (Epo group) or no treatment (control group). After 3 weeks, hemoglobin (p<0.0001) and serum transferrin receptor (p<0.0001) concentrations were higher in the Epo group. Hb response (+2 g/dL) was achieved in 100% vs 28% (p<0.0001) and Hb correction (> or =13 g/dL) in 70% vs 10% (p=0.0238) of the patients, respectively. This is the first randomized study showing an efficacy of erythropoietin therapy on Hb levels after autologous PBSCT. [less ▲]

Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin's lymphoma for patients <= 50 years old in first complete remission: results of the EORTC ALL-3 trial

in Haematologica (2004), 89(7), 809-817

Background and Objectives. In the EORTC ALL-3 trial, the efficacy of allogeneic transplantation was compared with that of autologous marrow transplantation and maintenance chemotherapy in patients less ... [more ▼]

Background and Objectives. In the EORTC ALL-3 trial, the efficacy of allogeneic transplantation was compared with that of autologous marrow transplantation and maintenance chemotherapy in patients less than or equal to 50 years who reached CR. Design and Methods. Among 340 patients who entered the study, 279 were less than or equal to 50 years old. Out of these, 220 reached CR, 184 patients started consolidation and were HLA typed; 68 had a donor and 116 had no sibling donor. The median follow-up was 9.5 years; 93 patients relapsed, 26 died in CR, and overall 116 patients died. Allogeneic transplantation was performed in 47 (68%) patients with a donor while autologous transplantation or maintenance chemotherapy was given to 84 (72%) patients without a sibling donor. Results. The 6-year disease-free survival rate was similar in the groups with and without donor [38.2% (SE=5.9%) vs. 36.8% (SE=4.6%), hazard ratio 1.01, 95% CI 0.67-1.53]. Comparing the donor group with the no donor group, the former had a lower relapse incidence (38.2% vs. 56.3%, p=0.001), but a higher cumulative incidence of death in CR (23.5% vs. 6.9%, p=0.0004). The 6-year survival rates were similar [41.2% (SE=6.0%) vs. 38.8% (SE=4.6%)]. Interpretation and Conclusions. This trial did not show that allogeneic transplantation, when a sibling donor is available, produces a better outcome than the policy of offering autotransplantation or chemotherapy in the absence of a donor. [less ▲]

Platelet expression of non-functional P2X1delL ion channels in mice reduces arterial thrombosis

in Haematologica (2004)