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ABSTRACT: BACKGROUND: Immunomagnetic cell selection (ICS) cells is increasingly used in allogeneic hematopoietic transplantation in order to reduce the T cells quantity. The aim of this study was to evaluate an protocol based on Ficoll method before ICS. STUDY DESIGN AND METHODS: The automated procedure was compared with the standard method. In the group 1 the cell processing involves the extraction of the buffy-coat by Ficoll before incubation with antibodies. This procedure was performed with the Sepax S-100 device. The efficacy of this automated procedure was compared with the group 2. In this group, the cell washing and the incubation were performed through the standard method. The CD34+ cells collected by apheresis (HPC-A) were selected with ICS. RESULTS: The results obtained after Ficoll procedure, showed a total nucleated cells (TNCs) and CD34+ cells recovery of 85.73% (75.90-90.63; SD 4.25) and 79.31% (51.77-112.31; SD 18.40), respectively. The TNC and CD34+ cells recovery after the pre-incubation washing performed through the standard method, was 75.54% (38.36-97.76; SD 22.5) and 61.51% (30.87-81.79; SD 19.3), respectively. The CD34+ cells recovery after ICS was 79% (51.77-100; SD 18.40) and 44% (15.57-88.24; SD 25.91) in the group 1 and the group 2, respectively. This difference was statistically significant (p=0.001). CONCLUSION: The efficacy of the ICS which resulted to be higher in the group 1 compared to the group 2. Overall, our data suggest that the Ficoll procedure before incubation is suitable for the clinical routine in the ICS for haploidentical transplantation in patients affected by thalassemia.
Transfusion and Apheresis Science 02/2013; · 1.25 Impact Factor
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ABSTRACT: The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class-based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation.
Cold Spring Harbor perspectives in medicine. 05/2012; 2(5):a011825.
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ABSTRACT: Immunomagnetic cell selection (ICS) of CD34(+) cells is being used increasingly in allogeneic transplantation in order to reduce T-cell quantity. The aim of this study was to evaluate an automated washing protocol before immunomagnetic selection.
The automated method was compared with a conventional washing procedure. In the study group the cell processing using the automated procedure, both before and after antibody incubation, was performed with a Sepax S-100 device. The efficacy of the automated procedure was compared with the control group, where washing were performed using a standard method.
The results obtained after pre-incubation washing performed using the automated system showed a total nucleated cell (NC) and CD34(+) cell recovery of 84.87% (71.80-105, SD 8.62; range, standard deviation) and 83.45% (47-109, SD 16.12), respectively. The NC and CD34(+) cell recovery after the pre-incubation washing cycle was performed using the standard method was 75.54% (38.36-97.76, SD 22.5) and 61.51% (30.87-81.79, SD 19.3), respectively. The CD34(+) cell recovery after ICS was 51.27% (13.77-98.82, SD 24.97) and 48.89% (15.57-88.24, SD 25.91) for group 1 and group 2, respectively. The average purity in group 1 was 86.46% (67.4-96.10, SD 13.07) and in group 2 84.97% (58.1-97.8, SD 15.58).
The efficacy of the ICS led to an optimal purity without affecting cell recovery, which was higher in group 1. Overall, our data suggest that the automated method is suitable for washing hematopoietic progenitor cell apheresis (HPC-A) concentrates before immunomagnetic cell selection in daily clinical routines.
Cytotherapy 04/2012; 14(7):811-7. · 3.63 Impact Factor
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Blood 01/2012; 119(4):1091-2. · 9.90 Impact Factor
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Pietro Sodani,
Antonella Isgrò,
Javid Gaziev,
Katia Paciaroni,
Marco Marziali,
Maria Domenica Simone,
Andrea Roveda,
Gioa De Angelis,
Cristiano Gallucci,
Fabio Torelli,
Giancarlo Isacchi,
Francesco Zinno,
Fabiola Landi,
Gaspare Adorno,
Alessandro Lanti,
Manuela Testi,
Marco Andreani, Guido Lucarelli
Pediatric reports 06/2011; 3 Suppl 2:e13.
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ABSTRACT: Previous studies have shown that a stable presence of both donor and recipient haematopoietic derived cells after allogeneic haematopoietic stem cell transplantation (HSCT) occurs in approximately ten percent of the patients affected by β-Thalassemia. Once achieved this condition, defined as persistent mixed chimerism (PMC), the patients do not require additional red blood cells (RBCs) support and, regardless of the presence in some cases of an extremely low percentage of donor-derived nucleated cells, they are clinically cured by an incomplete, but functional graft. Most of the published papers have, however, investigated the impact of donor engraftment in the nucleated cells rather than in the mature erythrocytes. We have recently published a paper showing that in four long-term transplanted patients affected by hemoglobinopathies, characterized by the presence of few donor engrafted nucleated cells-both in the peripheral blood and in the bone marrow-the majority of the erythrocytes were of donor origin. Moreover we showed that the proportion of donor-derived erythroid precursors, determined by analyzing singularly picked-up burst-forming unit erythroid colonies, was equivalent to that observed in the mature nucleated cells rather than in the red blood cells. These results suggest that in patients characterized by the presence of PMC after HSCT a selective advantage of the donor erythroid precursors maturation might successfully contrast the problems bound to the recipient ineffective erythropoiesis. When genetically modified HSCT will be a possible option for treating Thalassemia Major, the co-existence of the repaired cells with those still expressing the genetic defect will be an expected scenario, not in an allogeneic, but in an autologous environment.
Chimerism (Print). 01/2011; 2(1):21-22.
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ABSTRACT: Hematopoietic stem cell transplantation (HSCT) offers potentially curative therapy for patients with thalassemia major and sickle cell disease (SCD). Current myeloablative treatment protocols allow the cure of 78% to 90% of patients with thalassemia and 72% to 96% with SCD, depending on disease status at the time of transplantation. The major limitation to successful transplantation is the lack of a suitable HLA-matched family donor. Unrelated donor HSCT is now extensively used to treat thalassemia, with results similar to those obtained following transplantation using HLA-matched sibling donors. Patients who lack a matched related or unrelated donor can now benefit from successful transplantation using haploidentical donors.
Hematology/oncology clinics of North America 12/2010; 24(6):1145-63. · 2.05 Impact Factor
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ABSTRACT: Hematopoietic stem cell transplantation (HSCT) represents the only cure for patients with thalassemia. At present HSCT in younger patients from an HLA- matched sibling donor offers 80% to 87% probability of cure according to risk classes. However, results HSCT in adult patients continue to be inferior due to advanced of disease. High-resolution tissue typing techniques have enabled transplant centres to offer allogeneic HSCT from unrelated donors to patients with thalassemia who could not benefit from matched sibling donor transplantation with results comparable to those obtained using sibling donors. Advances in transplantation biology have made it possible to perform haploidentical HSCT in patients with thalassemia who lack a related or unrelated matched donor. Although limited number of patients, results of unrelated cord blood transplantation for thalassemia are encouraging. Patients with graft failure could now benefit from second transplantation using the same donor with a high disease-free survival rate. Most ex-thalassemics continue to have disease and treatment-related complications acquired before transplantation which require adequate treatment following BMT.
Current Stem Cell Research & Therapy 12/2010; 6(2):162-9.
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Antonella Isgrò,
Marco Marziali,
Pietro Sodani,
Javid Gaziev,
Buket Erer,
Paola Polchi,
Katia Paciaroni,
Andrea Roveda,
Gioia De Angelis,
Cristiano Gallucci, [......],
Maria Domenica Simone,
Francesco Zinno,
Giancarlo Isacchi,
Gaspare Adorno,
Alessandro Lanti,
Wilma Leti,
Fernando Aiuti,
Daniela Fraboni,
Marco Andreani, Guido Lucarelli
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ABSTRACT: To analyze immunohematologic reconstitution, particularly of natural killer (NK) cells, we evaluated 13 β-thalassemia patients after 20 and 60 days and 1 year posttransplantation with T cell-depleted HLA-haploidentical stem cells. We assessed lymphocyte and bone marrow (BM) progenitor cell phenotype and differentiation capacity, spontaneous BM cytokine production, stromal cells, and stromal cell interleukin (IL)-7 production. A reduced clonogenic capability manifested at day +20. Patients had significantly lower CD4(+) T cells versus controls, mainly in the CD45RA(+)CD62L(+) subset. NKs were among the first lymphocytes to repopulate the peripheral blood. At day +60, an increase in primitive BM progenitor cells paralleled small increases in CD4(+), naïve CD4(+), and thymic naïve Th cells. A significant increase in CD4(+) and CD8(+) markers paralleled an increase in CD3⁻CD16(+) NKs, especially with full engraftment. In patients with stable mixed chimerism we observed very low levels of CD3(+) donor chimerism early after transplant that increased over time, but a stable population of high donor NK cells, suggesting a role of these cells on donor engraftment. Stromal cells secreted less IL-7 and displayed "macrophage-like" morphology. Patients initially manifested impaired stem/progenitor cell growth and differentiation capacity in parallel with altered T cell homeostasis and a reduced T cell naïve compartment. We hypothesize that T cell compartment damage partly arises from altered new T cell production from the hematopoietic stem/progenitor cells under stromal cytokine influence. NNK subset analysis might be useful for determining transplant outcome.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2010; 16(11):1557-66. · 3.15 Impact Factor
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Marco Andreani,
Manuela Testi,
Javid Gaziev,
Rossella Condello,
Andrea Bontadini,
Pier Luigi Tazzari,
Francesca Ricci,
Lidia De Felice,
Francesca Agostini,
Daniela Fraboni,
Giuliana Ferrari,
Mariarosa Battarra,
Maria Troiano,
Pietro Sodani, Guido Lucarelli
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ABSTRACT: Persistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit - erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow.
The donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit - erythroid colonies singly picked out after 14 days of incubation.
The proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit - erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. Conclusions Our results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.
Haematologica 10/2010; 96(1):128-33. · 6.42 Impact Factor
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Emanuela Anna Roselli,
Riccardo Mezzadra,
Marta Claudia Frittoli,
Giulietta Maruggi,
Erika Biral,
Fulvio Mavilio,
Fabrizio Mastropietro,
Antonio Amato,
Giovanni Tonon,
Chiara Refaldi,
Maria Domenica Cappellini,
Marco Andreani, Guido Lucarelli,
Maria Grazia Roncarolo,
Sarah Marktel,
Giuliana Ferrari
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ABSTRACT: Beta-thalassemia is a common monogenic disorder due to mutations in the beta-globin gene and gene therapy, based on autologous transplantation of genetically corrected haematopoietic stem cells (HSCs), holds the promise to treat patients lacking a compatible bone marrow (BM) donor. We recently showed correction of murine beta-thalassemia by gene transfer in HSCs with the GLOBE lentiviral vector (LV), expressing a transcriptionally regulated human beta-globin gene. Here, we report successful correction of thalassemia major in human cells, by studying a large cohort of pediatric patients of diverse ethnic origin, carriers of different mutations and all candidates to BM transplantation. Extensive characterization of BM-derived CD34(+) cells before and following gene transfer shows the achievement of high frequency of transduction, restoration of haemoglobin A synthesis, rescue from apoptosis and correction of ineffective erythropoiesis. The procedure does not significantly affect the differentiating potential and the relative proportion of haematopoietic progenitors. Analysis of vector integrations shows preferential targeting of transcriptionally active regions, without bias for cancer-related genes. Overall, these results provide a solid rationale for a future clinical translation.
EMBO Molecular Medicine 08/2010; 2(8):315-28. · 10.33 Impact Factor
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ABSTRACT: Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. A risk classes-based approach to transplantation in thalassemia has led to disease-free survival probability of 87, 85, and 80% in classes 1, 2, and 3 patients, respectively. Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging.
Annals of the New York Academy of Sciences 08/2010; 1202:149-54. · 3.15 Impact Factor
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Javid Gaziev,
Laurent Nguyen,
Christian Puozzo,
Alessia Francesca Mozzi,
Marialuisa Casella,
Michela Perrone Donnorso,
Paolo Gravina,
Pietro Sodani,
Marco Marziali,
Antonella Isgrò,
Maria Domenica Simone,
Marco Andreani,
Amanda Formosa,
Manuela Testi,
Giorgio Federici,
Sergio Bernardini, Guido Lucarelli
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ABSTRACT: We prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 microMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.
Blood 03/2010; 115(22):4597-604. · 9.90 Impact Factor
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ABSTRACT: The thalassemias are a group of hemoglobin disorders characterized by a reduced synthesis of one or more of the globin chains
(α, β, γ, δβ, γδβ, δ and εγδβ) and are the commonest monogenic disorders to cause a major public health problem in the world
[1]. It is estimated that there are 270 million carriers of hemoglobin disorders, of whom 80 million are carriers of β thalassemia.
The clinical manifestations of β-thalassemia are extremely diverse, ranging from the transfusion-dependent state of thalassemia
major to slightly less severe transfusion-dependent state of thalassemia intermedia or to the asymptomatic state of thalassemia
trait. The most severe form of this disease is characterized by the complete absence of β-globin production and results from
the inheritance of two β0 thalassemia allels, homozygous or compound heterozygous states. These combinations usually result in β-thalassemia major
and the patients present themselves within 6 months of life with severe anemia, and if not treated with regular blood transfusions,
die within the first 2 years. The anemia is due to a combination of ineffective erythropoiesis, excessive peripheral red blood
cell hemolysis, and progressive splenomegaly.
02/2010: pages 491-504;
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ABSTRACT: Despite improvements in the management of thalassemia major and sickle cell disease, treatment complications are frequent and life expectancy remains diminished for these patients. Hematopoietic stem cell transplantation (HSCT) is the only curative option currently available. Existing results for HSCT in patients with hemoglobinopathy are excellent and still improving. New conditioning regimens are being used to reduce treatment-related toxicity and new donor pools accessed to increase the number of patients who can undergo HSCT.
Pediatric Clinics of North America 02/2010; 57(1):181-205. · 2.24 Impact Factor
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Javid Gaziev,
Pierpaolo Paba,
Roberto Miano,
Stefano Germani,
Pietro Sodani,
Pierluigi Bove,
Carlo Federico Perno,
Marco Marziali,
Cristiano Gallucci,
Antonella Isgrò,
Katia Paciaroni,
Andrea Roveda,
Maria Domenica Simone,
Gioia De Angelis,
Cecilia Alfieri, Guido Lucarelli
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ABSTRACT: Little is known about late-onset hemorrhagic cystitis (HC) in children, its relationship to BK virus, and treatment with cidofovir (CDV) following hematopoietic stem cell transplantation (HSCT). We prospectively investigated BK virus reactivation in children who underwent HSCT from a matched related donor for thalassemia or sickle cell anemia following busulfan-cyclophosphamide-based conditioning regimens and analyzed risk factors for development of HC and its treatment with CDV. Grade 2-4 HC occurred in 30 patients with a cumulative incidence of 26% (95% confidence interval [CI] = 18%-34%). The cumulative incidences of BK viruria and viremia were 81% (95% CI = 69%-89%) and 28% (95% CI = 18%-40%), respectively. Multivariate analysis revealed that use of antithymocyte globulin (ATG) (hazard ratio [HR] = 10.5; P = .001), peak BK viruria >100,000 copies/mL (HR = 6.2; P = .004), and grade II-IV acute graft-versus-host disease (HR = 5.3; P = .007) were predictive factors for HC. Nineteen patients with HC were given CDV at 1.5 mg/kg/day 3 times a week, or 5 mg/kg/week. The median duration of therapy was 27 days (range, 21-180 days), and a median of 9 doses were given (range, 6-22). All patients had a complete clinical response (CCR), and 69% had a microbiological response at 4 weeks. Eleven patients with BK virus-related HC receiving supportive care also had CCR. The median duration of HC in these patients was similar to that in patients treated with CDV. None of the patients with HC cleared BK viruria when CCR was achieved. We conclude that late-onset HC is more prevalent in children with sustained high BK viruria who are treated with ATG or who develop graft-versus-host disease. Randomized clinical trials are urgently needed to better define the role of CDV in treating BK virus-related HC.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2009; 16(5):662-71. · 3.15 Impact Factor
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Pietro Sodani,
Antonella Isgrò,
Javid Gaziev,
Paola Polchi,
Katia Paciaroni,
Marco Marziali,
Maria Domenica Simone,
Andrea Roveda,
Aldo Montuoro,
Cecilia Alfieri, [......],
Cristiano Gallucci,
Buket Erer,
Giancarlo Isacchi,
Francesco Zinno,
Gaspare Adorno,
Alessandro Lanti,
Lawrence Faulkner,
Manuela Testi,
Marco Andreani, Guido Lucarelli
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ABSTRACT: Fetomaternal microchimerism suggests immunological tolerance between mother and fetus. Thus, we performed primary hematopoietic stem cell transplantation from a mismatched mother to thalassemic patient without an human leukocyte antigen-identical donor. Twenty-two patients with thalassemia major were conditioned with 60 mg/kg hydroxyurea and 3 mg/kg azathioprine from day -59 to -11; 30 mg/m(2) fludarabine from day -17 to -11; 14 mg/kg busulfan starting on day -10; and 200 mg/kg cyclophosphamide, 10 mg/kg thiotepa, and 12.5 mg/kg antithymocyte globulin daily from day -5 to -2. Fourteen patients received CD34(+)-mobilized peripheral blood and bone marrow progenitor cells; 8 patients received marrow graft-selected peripheral blood stem cells CD34(+) and bone marrow CD3/CD19-depleted cells. T-cell dose was adjusted to 2 x 10(5)/kg by fresh marrow cell addback at the time of transplantation. Both groups received cyclosporine for graft-versus-host disease prophylaxis for 2 months after transplantation. Two patients died (cerebral Epstein-Barr virus lymphoma or cytomegalovirus pneumonia), 6 patients reject their grafts, and 14 showed full chimerism with functioning grafts at a median follow-up of 40 months. None of the 14 patients who showed full chimerism developed acute or chronic graft-versus-host disease. These results suggest that maternal haploidentical hematopoietic stem cell transplantation is feasible in patients with thalassemia who lack a matched related donor.
Blood 11/2009; 115(6):1296-302. · 9.90 Impact Factor
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ABSTRACT: Immunomagnetic CD34(+) cell selection (ICS) is utilized in autologous and allogeneic transplants. In the first case it is used to reduce the neoplastic contamination of concentrates, while in the second case it is needed to carry out a T-depletion of cell concentrates in order to reduce the incidence of graft-versus-host disease (GvHD) in patients who have undergone haplo-identical transplants.
The efficacy of CliniMACS technology, after reduction of platelet contamination, incubation of monoclonal antibodies (MAb) and successive washings of concentrates, performed in 16 ICS using the standard method without reducing platelet content, was compared with the use of the automated system CytoMate, which was carried out in 46 ICS.
In the group of ICS carried out after automatic manipulation, a significant statistical difference in purity was noted (91.39% versus 83.57, P = 0.017) compared with the group of ICS carried out with the standard procedure. The same significant difference was noted in relation to the remaining percentages of CD3(+) and CD19(+) cells (2.31% versus 5.68%, P = 0.012, and 1.58% versus 2.71%, P = 0.014, respectively). Recovery of CD34+ cells overlapped in the two groups (70.49% versus 68.39%, P = 0.774).
Immunomagnetic selection carried out using the automated procedure was more efficient, producing a purer sample, more efficient T-depletion and optimal reduction of B cells, without influencing cell recovery. Furthermore, conforming to good manufacturing practice (GMP) guidelines, the entire procedure with CytoMate took place in a contamination-controlled environment.
Cytotherapy 11/2009; 12(1):60-6. · 3.63 Impact Factor
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ABSTRACT: Infection with human polyomaviruses BKV and JCV is asymptomatic, and lifelong and widespread, among the general population. However, in the setting of immunosuppression, secondary to medications or viral infection, for example, with HIV, reactivation can occur and result in severe disease. In this study, stool specimens from 31 patients with hematological disorders (25 transplanted and 6 non-transplanted) were examined prospectively to determine whether the novel polyomaviruses KIV and WUV reactivated and were excreted in the gastrointestinal tract. Reactivation was correlated with the appearance of gastrointestinal and respiratory symptoms. Of the 31 patients examined, KIV and WUV were detected in 13 transplanted patients as single infection or in combination with BKV, cytomegalovirus (CMV), and adenovirus (Adv). Because of frequent co-infections, a clear correlation between novel polyomaviruses and clinical symptoms could not be established. There was no correlation between demographic variables and detection of KIV and WUV. Phylogenetic analysis of the small t-antigen gene of KIV and WUV isolates showed that the novel polyomaviruses identified in feces clustered with those identified in the respiratory tract suggesting an oral-fecal transmission of these viruses. The novel polyomaviruses KI and WU may have a pathogenic role in immunocompromised patients.
Journal of Medical Virology 10/2009; 81(9):1668-73. · 2.82 Impact Factor
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Giorgia Serafini,
Marco Andreani,
Manuela Testi,
MariaRosa Battarra,
Andrea Bontadini,
Eika Biral,
Katharina Fleischhauer,
Sarah Marktel, Guido Lucarelli,
Maria Grazia Roncarolo,
Rosa Bacchetta
[show abstract]
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ABSTRACT: Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood.
The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor.
Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro.
Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.
Haematologica 08/2009; 94(10):1415-26. · 6.42 Impact Factor
