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author:("Ciceri, labio")
1.  Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells 
T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.
doi:10.3389/fimmu.2014.00016
PMCID: PMC3907718  PMID: 24550909
hematopoietic stem cell transplantation; haploidentical; IL-10; T regulatory type 1 cells; cell therapy; tolerance
2.  Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity 
Clinical Immunology (Orlando, Fla.)  2013;146(3):248-261.
Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.
Highlights
► CD25 deficiency leads to profound immune dysregulation. ► Preferential CD8+ T cell expansion and high cytokine serum levels were present. ► Proliferating CD8+ T cells infiltrated the skin but failed to respond to pathogens. ► CD4+FOXP3+CD127lowCD25null Tregs could be detected. ► Altered IL2 signaling events and failure of IL2 consumption contribute to autoimmunity.
doi:10.1016/j.clim.2013.01.004
PMCID: PMC3594590  PMID: 23416241
CD25;; IPEX-like;; Immunodeficiency;; Autoimmunity;; Tregs;; IL-2
3.  Quantitative muscle strength assessment in duchenne muscular dystrophy: longitudinal study and correlation with functional measures 
BMC Neurology  2012;12:91.
Background
The aim of this study was to perform a longitudinal assessment using Quantitative Muscle Testing (QMT) in a cohort of ambulant boys affected by Duchenne muscular dystrophy (DMD) and to correlate the results of QMT with functional measures. This study is to date the most thorough long-term evaluation of QMT in a cohort of DMD patients correlated with other measures, such as the North Star Ambulatory Assessment (NSAA) or thee 6-min walk test (6MWT).
Methods
This is a single centre, prospective, non-randomised, study assessing QMT using the Kin Com® 125 machine in a study cohort of 28 ambulant DMD boys, aged 5 to 12 years. This cohort was assessed longitudinally over a 12 months period of time with 3 monthly assessments for QMT and with assessment of functional abilities, using the NSAA and the 6MWT at baseline and at 12 months only. QMT was also used in a control group of 13 healthy age-matched boys examined at baseline and at 12 months.
Results
There was an increase in QMT over 12 months in boys below the age of 7.5 years while in boys above the age of 7.5 years, QMT showed a significant decrease. All the average one-year changes were significantly different than those experienced by healthy controls. We also found a good correlation between quantitative tests and the other measures that was more obvious in the stronger children.
Conclusion
Our longitudinal data using QMT in a cohort of DMD patients suggest that this could be used as an additional tool to monitor changes, providing additional information on segmental strength.
doi:10.1186/1471-2377-12-91
PMCID: PMC3482602  PMID: 22974002
4.  Genetically Modified Donor Leukocyte Transfusion and Graft-Versus-Leukemia Effect After Allogeneic Stem Cell Transplantation 
Human Gene Therapy  2010;22(7):829-841.
Abstract
Seven patients with acute myeloid leukemia (AML) and two patients with chronic myelogenous leukemia (CML) were transplanted from HLA-identical sibling donors with CD34+ cell-enriched stem cells (HSCTs) without further immunosuppression. The myeloablative standard transplantation protocol was adapted to include transfusion of gene-modified donor T cells after HSCT. Donor T cells were transduced with the replication-deficient retrovirus SFCMM-3, which expresses herpes simplex thymidine kinase (HSV-Tk) and a truncated version of low-affinity nerve growth factor receptor (ΔLNGFR) for selection and characterization of transduced cells. Transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. Proteomic screening for development of acute graft-versus-host disease (aGvHD) was applied to five of the seven patients with AML. No positivity for the aGvHD grade II-specific proteomic pattern was observed. Only one patient developed aGvHD grade I. To date, three of the patients with AML relapsed; one responded to three escalating transfusions of lymphocytes from the original donor and is in complete remission. Two were retransplanted with non-T cell-depleted peripheral blood stem cells from their original donors and died after retransplantation of septic complications or relapse, respectively. In one patient with CML, loss of bcr-abl gene expression was observed after an expansion of transduced cells. Seven of nine patients are alive and in complete remission.
Borchers and colleagues provide long-term follow-up data on seven patients with acute myeloid leukemia and two patients with chronic myelogenous leukemia who were transplanted from HLA-identical sibling donors with CD34+ cell-enriched stem cells. Donor-derived retroviral transduced T cells were also infused. The authors report that transduced T cells were detectable in all patients during follow-up for up to 5 years after transfusion. They also use proteomic screening to analyze the development of acute graft-versus-host disease in the research subjects.
doi:10.1089/hum.2010.162
PMCID: PMC3135250  PMID: 21091264
5.  Health related quality of life in Middle Eastern children with beta-thalassemia 
BMC Blood Disorders  2012;12:6.
Background
Thalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries.
Methods
We studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated.
Results
The scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007).
Conclusions
The PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children’s HRQoL.
doi:10.1186/1471-2326-12-6
PMCID: PMC3496588  PMID: 22726530
Quality of life; Thalassemia; PEDsQL 4.0
6.  Innovative Platforms for Haploidentical Stem Cell Transplantation: The Role of Unmanipulated Donor Graft 
Journal of Cancer  2011;2:339-340.
We exploited the dual positive effects of rapamycin to prevent GvHD and control malignant cells upon infusion of unmanipulated grafts from family haploidentical donors to patients affected by advanced hematological malignancies. Preliminary results on 45 patients show the feasibility of this platform with an appreciable low rate of GvHD.
PMCID: PMC3119399  PMID: 21716853
Stem Cell Transplantation; Haploidentical; Donor Graft
7.  Allogeneic Stem Cell Transplantation for Metastatic Renal Cell Cancer (RCC) 
Journal of Cancer  2011;2:347-349.
A variety of therapeutic options are now available for advanced renal cell cancer, including antiangiogenic and anti-mTOR agents. Allogeneic hematopoietic stem cell transplantation, through its graft-versus-tumor effect, can induce clinical responses and prolonged survival in selected cytokine-refractory patients. However, the still relevant transplant-related mortality due to toxicity and graft-versus-host disease is an obstacle to its widespread use.
PMCID: PMC3119401  PMID: 21716855
Allogeneic hematopoietic stem cell transplantation; advanced renal cell cancer; graft-versus-tumor.
8.  High-Definition Mapping of Retroviral Integration Sites Defines the Fate of Allogeneic T Cells After Donor Lymphocyte Infusion 
PLoS ONE  2010;5(12):e15688.
The infusion of donor lymphocytes transduced with a retroviral vector expressing the HSV-TK suicide gene in patients undergoing hematopoietic stem cell transplantation for leukemia/lymphoma promotes immune reconstitution and prevents infections and graft-versus-host disease. Analysis of the clonal dynamics of genetically modified lymphocytes in vivo is of crucial importance to understand the potential genotoxic risk of this therapeutic approach. We used linear amplification-mediated PCR and pyrosequencing to build a genome-wide, high-definition map of retroviral integration sites in the genome of peripheral blood T cells from two different donors and used gene expression profiling and bioinformatics to associate integration clusters to transcriptional activity and to genetic and epigenetic features of the T cell genome. Comparison with matched random controls and with integrations obtained from CD34+ hematopoietic stem/progenitor cells showed that integration clusters occur within chromatin regions bearing epigenetic marks associated with active promoters and regulatory elements in a cell-specific fashion. Analysis of integration sites in T cells obtained ex vivo two months after infusion showed no evidence of integration-related clonal expansion or dominance, but rather loss of cells harboring integration events interfering with RNA post-transcriptional processing. The study shows that high-definition maps of retroviral integration sites are a powerful tool to analyze the fate of genetically modified T cells in patients and the biological consequences of retroviral transduction.
doi:10.1371/journal.pone.0015688
PMCID: PMC3008730  PMID: 21203516
9.  High incidence of severe cyclosporine neurotoxicity in children affected by haemoglobinopaties undergoing myeloablative haematopoietic stem cell transplantation: early diagnosis and prompt intervention ameliorates neurological outcome 
Background
Neurotoxicity is a recognized complication of cyclosporine A (CSA) treatment. The incidence of severe CSA-related neurological complications following hematopoietic stem cell transplantation (HSCT) is 4-11%.
Methods
We describe 6 cases of CSA related neurotoxicity out of 67 matched related HSCT performed in paediatric Middle East patients affected by haemoglobinopaties (5 beta thalassemia major, 1 sickle cell disease-SCD). Conditioning regimen consisted of iv busulphan, cyclophosphamide and graft-versus-host-disease (GvHD) prophylaxis with CSA, methylprednisolone, methotrexate and ATG.
Results
All 6 patients presented prodromes such as arterial hypertension, headache, visual disturbances and vomiting, one to two days before overt CSA neurotoxicity. CSA neurotoxicity consisted of generalized seizures, signs of endocranial hypertension and visual disturbances at a median day of onset of 11 days after HSCT (range +1 to +40). Brain magnetic resonance imaging (MRI) performed in all subjects showed reversible leukoencephalopathy predominantly in the posterior regions of the brain (PRES) in 5/6 patients. EEG performed in 5/6 patients was always abnormal. Neurotoxicity was not explainable by high CSA blood levels, as all patients had CSA in the therapeutic range with a median of 178 ng/ml (range 69-250). CSA was promptly stopped and switched to tacrolimus with disappearance of clinical and radiological findings. All patients are symptoms-free at a median follow up of 882 days (range 60-1065).
Conclusions
Our experience suggests that paediatric patients with haemoglobinopaties have a high incidence of CSA related neurological events with no correlation between serum CSA levels and neurotoxicity. Prognosis is good following CSA removal. Specific prodromes such as arterial hypertension, headache or visual disturbances occurring in the early post-transplant period should be carefully evaluated with electrophysiological and MRI-based imaging in order to intervene promptly and avoid irreversible sequels.
doi:10.1186/1824-7288-36-14
PMCID: PMC2829572  PMID: 20181110
10.  Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity 
The Journal of Clinical Investigation  2007;117(10):3087-3096.
The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2–transduced (TRP-2–transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c+CD8α+ DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ–resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs.
doi:10.1172/JCI30605
PMCID: PMC1978420  PMID: 17885685

Results 1-10 (10)