Wiskott-Aldrich syndrome protein deficiency in B cells results in impaired peripheral homeostasis
; ; Humblet, Stéphanie et al
in Blood (2008), 112(10), 4158-69
To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central ... [more ▼]
To more precisely identify the B-cell phenotype in Wiskott-Aldrich syndrome (WAS), we used 3 distinct murine in vivo models to define the cell intrinsic requirements for WAS protein (WASp) in central versus peripheral B-cell development. Whereas WASp is dispensable for early bone marrow B-cell development, WASp deficiency results in a marked reduction in each of the major mature peripheral B-cell subsets, exerting the greatest impact on marginal zone and B1a B cells. Using in vivo bromodeoxyuridine labeling and in vitro funtcional assays, we show that these dificits reflect altered peripheral homeostasis, partially resulting from an impairment in integrin function, rather than a developmental defect. Consistent with these observations, we also show that : (1) WASp expression levels increase with cell maturaity, peaking in those subsets exhibiting the greatest sensitivity to WASp deficiency; (2) WASp+ murine B cells exhibit a marked selective advantage beginning at the late transitional B-cell stage; and (3) a similar in vivo selective advantage is manifest by mature WASp+ human B cells. Together, our data provide a better understanding of the clinical phenotype of WAS and suggest that gene therapy might be a useful approach to rescue altered B-cell homeostasis in this disease. [less ▲]Detailed reference viewed: 5 (0 ULg)
The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (T-FH) cells
de Leval, Laurence ; ; Thielen, Caroline et al
in Blood (2007), 109(11), 4952-4963
The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ... [more ▼]
The molecular alterations underlying the pathogenesis of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, unspecified (PTCL-u) are largely unknown. In order to characterize the ontogeny and molecular differences between both entities, a series of AITLs (n = 18) and PTCLs-u (n = 16) was analyzed using gene expression profiling. Unsupervised clustering correlated with the pathological classification and with CD30 expression in PTCL-u. The molecular profile of AITLs was characterized by a strong microenvironment imprint (overexpression of B-cell- and follicular dendritic cell-related genes, chemokines, and genes related to extracellular matrix and vascular biology), and overexpression of several genes characteristic of normal follicular helper T (T-FH) cells (CXCL13, BCL6, PDCD1, CD40L, NFATC1). By gene set enrichment analysis, the AITL molecular signature was significantly enriched in published T-FH-specific genes. The enrichment was higher for sorted AITL cells than for tissue samples. Overexpression of several T-FH genes was validated by immunohistochemistry in AITLs. A few cases with molecular T-FH-like features were identified among CD30(-) PTCLs-u. Our findings strongly support that TFH cells represent the normal counterpart of AITL, and suggest that the AITL spectrum may be wider than suspected, as a subset of CD30(-) PTCLs-u may derive from or be related to AITL. [less ▲]Detailed reference viewed: 47 (10 ULg)
Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
; ; et al
in Blood (2007), 109(5), 1834-1840
Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly ... [more ▼]
Angiogenesis plays a key role in various physiologic and pathologic conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here, we identify Drm/gremlin as a novel proangiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial-cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial-cell migration and invasion in fibrin and collagen gels, binds with high affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium, and both molecules exert a proangiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice, and it is highly expressed in endothelial cells of human lung tumor vasculature when compared with nonneoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis. [less ▲]Detailed reference viewed: 54 (3 ULg)
Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients.
; Gillet, Nicolas ; et al
in Blood (2007), 110(10), 3722-8
Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated ... [more ▼]
Epigenetic modifications of chromatin may play a role in maintaining viral latency and thus persistence of the human T-lymphotropic virus type 1 (HTLV-1), which is responsible for HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A major determinant of disease progression is increased peripheral blood proviral load (PVL), possibly via the accumulation of infected cells in the central nervous system (CNS) creating a damaging inflammatory response. Current therapeutic approaches that focus on reducing either cell proliferation, viral replication, or tissue invasion are still unsatisfactory. Contrasting with these inhibitory strategies, we evaluated the efficacy of a novel approach aimed, paradoxically, at activating viral gene expression to expose virus-positive cells to the host immune response. We used valproate (VPA), a histone deacetylase inhibitor that has been used for decades as a chronic, safe treatment for epileptic disorders. Based on in vitro and in vivo data, we provide evidence that transient activation of the latent viral reservoir causes its collapse, a process that may alleviate the condition of HAM/TSP. This represents the first such approach to treating HAM/TSP, using gene activation therapy to tilt the host-pathogen balance in favor of an existing antiviral response. This trial is registered at http://clinicaltrials.gov/as no. NCT00519181. [less ▲]Detailed reference viewed: 45 (19 ULg)
Human T-cell leukemia virus type-1 Tax oncoprotein regulates G-protein signaling.
Twizere, Jean-Claude ; ; Boxus, Mathieu et al
in Blood (2007), 109(3), 1051-60
Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene ... [more ▼]
Human T-cell leukemia virus type-1 (HTLV-1) is associated with adult T-cell leukemia (ATL) and neurological syndromes. HTLV-1 encodes the oncoprotein Tax-1, which modulates viral and cellular gene expression leading to T-cell transformation. Guanine nucleotide-binding proteins (G proteins) and G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins known and are involved in the regulation of most biological functions. Here, we report an interaction between HTLV-1 Tax oncoprotein and the G-protein beta subunit. Interestingly, though the G-protein beta subunit inhibits Tax-mediated viral transcription, Tax-1 perturbs G-protein beta subcellular localization. Functional evidence for these observations was obtained using conditional Tax-1-expressing transformed T-lymphocytes, where Tax expression correlated with activation of the SDF-1/CXCR4 axis. Our data indicated that HTLV-1 developed a strategy based on the activation of the SDF-1/CXCR4 axis in the infected cell; this could have tremendous implications for new therapeutic strategies. [less ▲]Detailed reference viewed: 265 (40 ULg)
Diffuse Large B-cell Lymphomas of the waldeyer's ring frequently have a germinal center-like phenotype: a clinico-pathological study of 209 patients from the groupe d'étude des lymphomes de l'adulte (GELA).
; Bonnet, Christophe ; et al
in Blood (2007)Detailed reference viewed: 10 (0 ULg)
What is the role for donor NK cells after nonmyeloablative conditioning ?
Baron, Frédéric ; ; et al
in Blood (2007), 110
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of ... [more ▼]
Background: The potential role of donor NK cells after nonmyeloablative conditioning for allogeneic hematopoietic cell transplantation (HCT) is not defined. We investigated the impact of the kinetics of donor NK cell engraftment as well as the impact of missing recipient KIR ligands and the number of donor inhibitory and activating KIR genes on HCT outcomes in 282 patients (153 with HLA-matched related donors and 129 with unrelated donors) conditioned with 2 Gy TBI +/– fludarabine. Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil. Diagnoses were hematological malignancies (n=274) or solid tumors (8). Methods: NK cells were isolated from peripheral blood by flow cytometry on days 14, 28 and 42 after HCT. The proportions of cells of donor and host origin were assessed by FISH or by VNTR-PCR. High-resolution HLA-typing was performed using oligonucleotide probe and/or direct sequencing methods. Donor KIR genotyping was performed using a commercial PCR-SSP kit (Invitrogen) following manufacturers protocol. Results: High numbers of T (P=0.01) and CD34+ (P=0.009) cells in the graft, as well as lower numbers of donor inhibitory KIR genes (P=0.01) were each associated with higher levels of donor NK cell chimerism. There was a suggestion of an association between lower numbers of activating KIR genes and higher CD56 chimerism, however this was not statistically significant. NK cell chimerism levels were comparable in patients who had all KIR ligands present vs. in those who were missing any ligand, and there was no association between the specific missing ligand and NK chimerism. A day-14 NK cell chimerism level of < 50% was associated with increased risks of graft rejection (P=.009). Modeling chimerism levels as a continuous linear variable, there was no association between NK cell chimerism levels on day 14 and occurrence of grade II-IV acute GVHD. In contrast, high levels of donor NK cell chimerism on days 14–42 were associated with a lower risk of relapse (P=0.006) and better progression-free survival (P=0.003) in time-dependent analyses. The qualitative associations between donor NK cell chimerism and graft rejection, GVHD, relapse or progression-free survival did not change after adjustment for the presence of recipient KIR ligands nor after adjustment for the number of donor inhibitory or activating KIR genes. Finally, the 3-year cumulative incidence of relapse was 42% in patients who have all ligand for donor NK cell KIR, versus 38% in patients who miss one or more ligand for donor NK cell KIR (adjusted hazard ratio = 1.05; 95% confidence interval 0.65–1.68; p=0.85). Conclusions: Robust engraftment of donor NK cells correlated with low risk of graft rejection, low risk of relapse and high progression-free survival but not with acute GVHD. The clinical importance of donor KIR inhibitory and activating genes on post-transplant donor NK chimerism merits further study. Footnotes Disclosure: Off Label Use: Fludarabine, Mycophenolate mofetil, Cyclosporine. [less ▲]Detailed reference viewed: 10 (0 ULg)
Array-CGH analysis of T-ALL patients and cell lines
; ; et al
in Blood (2006, November 16), 108(11, Part 2), 195-196Detailed reference viewed: 42 (1 ULg)
New role for ATP P2X1 receptors in the control of neutrophil apoptosis and respiratory burst activity.
Faccinetto, Céline ; Lecut, Christelle ; Greimers, Roland et al
in Blood (2006), 108(11, Part 1), 1647Detailed reference viewed: 32 (12 ULg)
Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience.
; ; et al
in Blood (2005), 105(7), 2685-90
Hydroxyurea (HU) is considered to be the most successful drug therapy for severe sickle cell disease (SCD). Nevertheless, questions remain regarding its benefits in very young children and its role in the ... [more ▼]
Hydroxyurea (HU) is considered to be the most successful drug therapy for severe sickle cell disease (SCD). Nevertheless, questions remain regarding its benefits in very young children and its role in the prevention of cerebrovascular events.There were 127 SCD patients treated with no attempt to reach maximal tolerated doses who entered the Belgian Registry:109 for standard criteria and 18 who were at risk of stroke only. During 426 patient-years of follow-up for patients with standard criteria, 3.3 acute chest syndromes, 1.3 cerebrovascular events, and 1.1 osteonecrosis per 100 patient-years were observed.A subgroup of 32 patients followed for 6 years experienced significant benefit over this period. In each subgroup of children (younger than 2 years, 2-5, 6-9, and 10-19 years) followed for 2 years,clinical and biologic changes were similar,except for children younger than 2 years who had no total hemoglobin increase and remained at risk of severe anemia. In 72 patients evaluated by transcranial Doppler studies (TCD), 34 patients were at risk of primary stroke and only 1had a cerebrovascular event after a follow-up of 96 patient-years. These results confirm the benefit of HU, even in very young children, and its possible role in primary stroke prevention. [less ▲]Detailed reference viewed: 33 (1 ULg)
Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia : final results of AML-13, a randomized phase-3 study
; ; et al
in Blood (2005), 106Detailed reference viewed: 23 (4 ULg)
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
; ; et al
in Blood (2005), 106(8), 2912-9
We previously reported that the Charlson Comorbidity Index (CCI) was useful for predicting outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). However, the sample size of ... [more ▼]
We previously reported that the Charlson Comorbidity Index (CCI) was useful for predicting outcomes in patients undergoing allogeneic hematopoietic cell transplantation (HCT). However, the sample size of patients with scores of 1 or more, captured by the CCI, did not exceed 35%. Further, some comorbidities were rarely found among patients who underwent HCT. Therefore, the current study was designed to (1) better define previously identified comorbidities using pretransplant laboratory data, (2) investigate additional HCT-related comorbidities, and (3) establish comorbidity scores that were suited for HCT. Data were collected from 1055 patients, and then randomly divided into training and validation sets. Weights were assigned to individual comorbidities according to their prognostic significance in Cox proportional hazard models. The new index was then validated. The new index proved to be more sensitive than the CCI since it captured 62% of patients with scores more than 0 compared with 12%, respectively. Further, the new index showed better survival prediction than the CCI (likelihood ratio of 23.7 versus 7.1 and c statistics of 0.661 versus 0.561, respectively, P < .001). In conclusion, the new simple index provided valid and reliable scoring of pretransplant comorbidities that predicted nonrelapse mortality and survival. This index will be useful for clinical trials and patient counseling before HCT. [less ▲]Detailed reference viewed: 35 (1 ULg)
No role for chemoradiotherapy when compared with chemotherapy alone in elderly patients with localized low risk aggressive lymphoma: final results of the LNH93-4 GELA study.
Fillet, Georges ; Bonnet, Christophe ; et al
in Blood (2005), 106 (15)Detailed reference viewed: 23 (1 ULg)
Nonmyeloablative stem cell transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a prospective randomized trial.
WILLEMS, Evelyne ; CASTERMANS, Emilie ; Baron, Frédéric et al
in Blood (2005), 106 (1075)Detailed reference viewed: 15 (6 ULg)
Thrombopoietin responsiveness reflects the number of doublings undergone by megakaryocyte progenitors
Paulus, Jean-Michel ; ; et al
in Blood (2004), 104(8), 2291-2298
To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34 ... [more ▼]
To assess the variation of thrombopoietin (TPO) responsiveness associated with megakaryocyte (MK) progenitor amplification, TPO dose-response curves were obtained for normal human, single-cell plated CD34(+)CD41(+) cells. The number of MKs per well was determined in situ and expressed as number of doublings (NbD). Dose-response curves of the mean frequency of clones of each size versus log TPO concentration showed highly significant differences in the TPO concentration needed for half-maximum generation of clones of different sizes (TPO50): 1.89 +/- 0.51 pg/mL for 1 MK clones; 7.75 +/- 0.81 pg/mL for 2 to 3 MK clones; 38.5 +/- 5.04 pg/mL for 4 to 7 MK clones, and 91.8 +/- 16.0 pg/mL for 8 to 15 MK clones. These results were consistent with a prediction of the generation-age model, because the number of previous doublings in vivo was inversely correlated with the number of residual doublings in vitro. TPO responsiveness decreased in vitro by a factor of 3.5 per doubling, reflecting the recruitment of progressively more ancestral progenitors. In support of this hypothesis, the more mature CD34(+)CD41(+)CD42(+) cell fraction had a lower TPO50 (P <.001), underwent fewer NbD (P <.001), and expressed a 2.8-fold greater median Mpl receptor density (P <.001) than the CD34(+)CD41(+)CD42(-) fraction. Progenitors that have completed their proliferative program have maximum factor responsiveness and are preferentially induced to terminal differentiation. (C) 2004 by The American Society of Hematology. [less ▲]Detailed reference viewed: 6 (1 ULg)
Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies
; ; et al
in Blood (2004), 103(1), 229-235
MLL amplification was recently recognized as a recurrent aberration in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), associated with adverse prognosis and karyotype complexity. Here we ... [more ▼]
MLL amplification was recently recognized as a recurrent aberration in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), associated with adverse prognosis and karyotype complexity. Here we present detailed results of fluorescence in situ hybridization (FISH) and expression analyses of MLL and 5 selected 11q candidate oncogenes (CBL, DDX6, ETS1, FLI1, and PLZF) in 31 patient samples and one cell line with 11q23 gain. FISH analyses revealed that the 11q23 amplicon invariably encompassed MLL, DDX6, ETS1, and FLI1, whereas expression analyses identified MLL and DDX6 as the most differentially expressed genes among samples with and without 11q23 copy gain or amplification. In MLL-amplified samples, a significant transcriptional up-regulation of MEIS1, PROML1, ADAM10, NKG2D, and ITPA was noted. Further analyses, designed to elucidate a possible role of the 11q overexpressed genes (MLL, DDX6, FLI1, and ETS1) in unselected MDS and AML samples, revealed a significant upregulation of MLL in MDS. Our findings confirm the MLL gene as a prominent target of 11q23 amplification and provide further evidence for an etiologic role for MLL gain of function in myeloid malignancies. In addition, our results indicate that the transcriptional program associated with MLL rearrangements and MLL overexpression displays significant similarities. [less ▲]Detailed reference viewed: 14 (0 ULg)
Severe deficiency of glycoprotein VI in a patient with gray platelet syndrome.
; ; et al
in Blood (2004), 104(1), 107-14
We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and ... [more ▼]
We report a novel case of gray platelet syndrome (GPS) where a severe deficiency of the platelet collagen receptor, glycoprotein (GP) VI, accompanies classical symptoms of a low platelet count and platelets lacking alpha-granules. Dense granules were normally present. Platelet aggregation with collagen was severely decreased, as was the response to convulxin (Cvx), a GPVI agonist. Quantitative analysis of GPVI using fluorescein isothiocyanate (FITC)-Cvx in flow cytometry showed its virtual absence on the patient's platelets. The GPVI deficiency was confirmed using monoclonal antibodies in Western blotting and in immunogold labeling on frozen thin sections where internal pools of GPVI were confirmed for normal platelets. The Fc receptor gamma-chain, constitutively associated with GPVI in normal platelets, was present in subnormal amounts, and the phospholipase C gamma 2-dependent activation pathway appeared to function normally. No autoantibodies to GPVI were found in the patient's serum using monoclonal antibody immobilization of platelet antigen (MAIPA). Sequencing of coding regions of the GPVI gene failed to show abnormalities, and mRNA for GPVI was present in the patient's platelets, pointing to a probable acquired defect in GPVI expression. Our results may provide a molecular explanation for the subgroup of patients with severely deficient collagen-induced platelet aggregation as previously described for GPS in the literature. [less ▲]Detailed reference viewed: 52 (2 ULg)
Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.
Baron, Frédéric ; ; et al
in Blood (2004), 104(8), 2254-62
We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic ... [more ▼]
We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression. [less ▲]Detailed reference viewed: 15 (0 ULg)
Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning
Baron, Frédéric ; ; et al
in Blood (2004), 104
We have used a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation +/– fludarabine, 30 mg/m²/day x 3 days, to condition elderly or ill patients (pts) with hematological ... [more ▼]
We have used a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation +/– fludarabine, 30 mg/m²/day x 3 days, to condition elderly or ill patients (pts) with hematological malignancies for allogeneic hematopoietic cell transplantation (HCT). This approach relies almost exclusively on graft-versus-tumor (GVT) effects for control of malignancy. Here, we analyzed GVT effects in 322 pts with hematological malignancies given grafts from HLA-matched related (n=192) or unrelated (n=130) donors. Grades I, II, III and IV acute GVHD were seen in 26 (8.1%), 141 (43.8%), 34 (10.6%) and 11 (3.4%) pts, respectively. Extensive chronic GVHD was seen in 181 (56.2%) pts and of these, 64 (19.9%) cases had de novo chronic GVHD. Putative GVT effects were evaluated using time-dependent Cox regression models. Of the 221 pts with measurable disease at HCT, 126 (57%) achieved complete (n=98) or partial (n=28) remissions. Multivariate analysis identified chemosensitivity for B-cell malignancies (p=.02), and tandem autologous/allogeneic HCT (p=.04) as pre-transplant factors associated with higher probabilities of achieving complete remissions (CR) after HCT. After adjusting for these factors, acute GVHD of any grade was not found to be associated with an increased probability of achieving CR. There was a trend for a higher probability of achieving CR in pts with chronic GVHD (p=.07). Progression/relapse was observed in 108 pts. Multivariate analysis identified that lower disease-risk (p=.0004), tandem autologous/allogeneic HCT (p=.02) and adapted Charlson comorbidity index (CCI) score at transplant < 3 (p=.002) resulted in significantly decreased risk of progression/relapse. After correcting for these factors, extensive chronic GVHD was associated with a decreased risk of progression/relapse (p=.006). Pts with grade 1 acute GVHD tended to have less progression/relapse (p=.07). Conversely, grade II–IV acute GVHD did not significantly affect the risk of progression/relapse. Nonrelapse mortality was observed in 70 pts. Multivariate analysis showed that lower disease-risk (p=. 001), tandem autologous/allogeneic HCT (p=.002) and CCI score at transplant < 3 (p<.0001) significantly decreased nonrelapse mortality. After adjusting for these variables, grade II (p=.04) and grade III–IV (p<.0001) acute GVHD increased nonrelapse mortality while extensive chronic GVHD did not. The 3-year probability of progression-free survival (PFS) was 38.5%. In multivariate analysis, lower disease-risk (p<.0001), tandem autologous/allogeneic HCT (p=.0008) and CCI score at transplant < 3 (p<.0001) resulted in significantly better PFS. After adjusting for theses variables, grade 1 acute GVHD (p=.02) and chronic extensive GVHD (p=.003) were both associated with significantly better PFS, while grade III–IV acute GVHD (p<.0001) was associated with decreased PFS. In summary, chronic GVHD in pts given nonmyeloablative conditioning was associated with substantial GVT effects which led to improved PFS. Conversely, any potential GVT benefits from grade II–IV acute GVHD were offset by higher nonrelapse mortality resulting in worse PFS. Efforts should be directed at reducing the risk of grade II–IV acute GVHD while allowing de novo chronic GVHD for best PFS after allogeneic HCT with nonmyeloablative conditioning. [less ▲]Detailed reference viewed: 11 (0 ULg)
Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer
; ; et al
in Blood (2004), 104(5), 1281-90
X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum ... [more ▼]
X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacteria infections. Using Btk- and Tec-deficient mice (BtkTec-/-) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)-treated BtkTec-/- mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec-/- recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, revocery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG3 levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA. [less ▲]Detailed reference viewed: 6 (0 ULg)