Key Points• KIR haplotype B donors and high KIR B content score confer better protection against relapse after HLAhaploidentical transplantation in pediatric acute lymphoblastic leukemia.• Haploidentical donor selection criteria for childhood acute lymphoblastic leukemia should include KIR haplotype and KIR B-content score.We analyzed the influence of donor killer-cell immunoglobulin-like receptor (KIR) gene haplotypes on the risk for relapse and the probability of event-free survival (EFS) in children with acute lymphoblastic leukemia who received human leukocyte antigenhaploidentical transplantation of ex vivo T-cell-depleted peripheral blood stem cells. The KIR gene haplotype was evaluated in 85 donors, and the KIR B content score was determined in the 63 KIR haplotype B donors. Patients transplanted from a KIR haplotype B donor had a significantly better EFS than those transplanted from a KIR haplotype A donor (50.6% vs 29.5%, respectively; P 5 .033). Moreover, a high donor KIR B-content score was associated with a significantly reduced risk for relapse (Log-rank test for trend, P 5 .026). These data indicate that KIR genotyping should be included in the donor selection algorithm for haploidentical transplantation in children with acute lymphoblastic leukemia with the aim of choosing, whenever possible, a KIR haplotype B donor with a high KIR B-content score. (Blood. 2014;124(17):2744-2747
Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach in cancer therapy. However, since not all tumor cells are sensitive to TRAIL, there is a need for the development of strategies to overcome TRAIL-resistance. The results of the present study show that the anti-diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to TRAIL-induced apoptosis. This process is accompanied by a substantial increase of active caspase 8 and active caspase 3, but it is independent of troglitazone's effects on the nuclear receptor PPAR-gamma. Troglitazone induces a pronounced reduction in protein expression levels of the anti-apoptotic FLICE-inhibitory protein (FLIP) without affecting FLIP mRNA levels. Further, protein and mRNA expression levels of the anti-apoptotic protein Survivin significantly decrease upon treatment with troglitazone. Moreover, sensitization to TRAIL is partly accompanied by an up-regulation of the TRAIL receptor, TRAIL-R2. A combined treatment with troglitazone and TRAIL might be a promising experimental therapy because troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via various mechanisms, thereby minimizing the risk of acquired tumor cell resistance.
Haploidentical hematopoietic stem cell transplantation is a curative alternative option for patients without an otherwise suitable stem cell donor. In order to prevent graft-versus-host disease (GvHD), different in vitro and in vivo T cell-depletion strategies have been developed. A delayed immune reconstitution is common to all these strategies, and an impaired immune function after haploidentical transplantation with subsequent infections is a major cause of deaths in these patients. In addition to in vitro and in vivo T cell-depletion methods, posttransplant strategies to rapidly rebuild the immune system have been introduced in order to improve the outcome. Advances in in vitro and in vivo T cell-depletion methods, and adoptive transfer of immune cells of the innate and specific immune system, will contribute to reduce the risk of GvHD, lethal infections, and the risk of relapse of the underlying malignant disease.
Several types of peripheral blood cells express ABC transporters. ABCC4 (MRP4) and ABCC5 (MRP5) localize to different cellular sites and fulfill lineage-specific functions such as mediator storage in platelets' dense granules. All mature blood cells originate from the same precursor and specific functionalities arise during differentiation. To characterize this process, expression, localization and function of MRP4 and MRP5 were assessed in differentiating human CD341 progenitors and leukemia cell lines using real time polymerase chain reaction (PCR), immunofluorescence microscopy and cell viability assays. Median MRP4 mRNA copy numbers were significantly enhanced by megakaryocytic differentiation from 7.9 3 10 3 to 5.8 3 10 4 copies per nanograms of total RNA (p < 0.05) in CD341 progenitors and in M-07e cells (MRP4 mRNA/18S rRNA ratios: 5.4 6 3.8 3 10 24 vs. 2.7 6 0.9 3 10 23 for native and differentiated cells, respectively, p < 0.05), and MRP4 protein was localized to granular structures and to the plasma membrane both in differentiated progenitors and bone marrow megakaryocytes. In contrast, expression of MRP4 decreased during maturation to leukocytes (MRP4 mRNA/18S rRNA ratios: 5.2 3 10 23 for native vs. 3.5 3 10 23 for CD341 cells in the presence of G-CSF, p < 0.05) and was significantly reduced in mature monocytes and granulocytes compared with progenitors (MRP4 mRNA/18S rRNA ratios: 8.1 6 5.4 3 10 25 and 2.8 6 1.6 3 10 24 vs. 1.2 6 0.7 3 10 23, respectively, p < 0.05). Expression of MRP5 was not significantly altered under all differentiation conditions. These results indicate that MRP4 expression is differentially regulated during hematopoiesis. The increase of MRP4 together with its specific localization during differentiation toward megakaryocytes supports the concept of platelet specific functions whereas decreased transporter expression in leukocyte differentiation may have implications for chemotherapy. ' 2008 Wiley-Liss, Inc.Key words: drug transporters; hematopoietic system; differentiation; megakaryocytes; monocytes ATP binding cassette (ABC) drug transporters are expressed in a range of mature peripheral blood cells and fulfill different functions. In lymphocytes, several studies have indicated substantial variability of P-glycoprotein (P-gp, ABCB1) expression 1-3 and a relationship between P-gp and IL-2 release.4,5 In addition to P-gp and BCRP (ABCG2), members of the C-branch of ABC transporters termed MRPs, which mediate the unidirectional transport of amphiphilic anions are expressed in peripheral blood cells. 6 The role of MRP1 has been investigated in detail in various populations of human lymphocytes.7 Inhibition of MRP1 abrogated the secretion of interferon-g, interleukin (IL)-10, IL-2 and tumor necrosis factor (TNF)-a, and reduced T-cell activation, indicating a functional role of MRP1-associated transport activity for T-cell function.8 MRP1 has also been detected in human erythrocytes, 9 playing a role in the maintenance of lipid asymmetry 10 and the efflux of reduced and oxidized glu...
Natural killer (NK)-cell alloreactivity after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. We investigated the influence of donor KIR haplotype and KIR-ligand mismatch (MM) on relapse in 57 patients with hematologic malignancies receiving haploidentical HCT after reduced intensity conditioning and graft CD3/CD19 depletion. Of the 57 donors, 17 had KIR haplotype A (29.8 %) and 40 had KIR haplotype B (70.2 %). A KIR-ligand MM was found in 34 of 57 patients (59.6 %). There was no difference between donor KIR haplotypes in non-relapse mortality (NRM, p = 0.200) but had a significantly reduced incidence of relapse for patients with a haplotype B donor (p = 0.001). In particular, patients in partial remission (PR) benefited more from a haplotype B graft (p = 0.008) than patients in complete remission (CR, p = 0.297). Evaluating KIR-ligand MM cumulative incidences of relapse (p = 0.680) or NRM (p = 0.579), we found no significant difference. In conclusion, in the setting of reduced intensity conditioning (RIC) and CD3/CD19-depleted haploidentical HCT, we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor.
Several controlled studies have evidenced good efficacy and short-term and midterm safety profiles for hydroxyurea (HU), which has become the cornerstone for prevention of sickle-cell disease (SCD)-related vaso-occlusive crises. However, there are few large-scale reports on its long-term use and certain caregivers and patients have concerns about its safety. Following the licensing of HU in Europe for children and adults with severe forms of SCD, ESCORT-HU was designed as a Phase IV observational cohort study. It included 1906 participants, of whom 55% were adults.The most common hemoglobin (Hb) genotypes were HbSS (84.7%) and HbSβ+ (7.0%). The median duration of follow-up was 45 months, for a total of 7309 patientyears of observation. The dose of HU after 1 year was 20.6 mg/kg/d for children and 16.3 mg/kg/d for adults. There was a statistically significant decrease in the number of vaso-occlusive episodes lasting >48 h, acute chest syndrome episodes, hospitalizations, and the percentage of patients requiring blood transfusions within the first 12 months relative to the year before enrolment. Neutropenia and thrombocytopenia were the most commonly reported adverse effects. No new HU toxicity was identified. Overall, 125 pregnancies were reported in 101 women and no malformations were observed in the neonates. There were 12 pregnancies for partners of male patients treated with HU. One case of fatal myelodysplastic syndrome was reported, for which a causal association with HU could not be excluded. This cohort study of patients with SCD highlights the positive benefit-to-risk ratio of HU in children and adults.
Background Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. Procedure A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. Results Most patients had homozygous SCD (HbSS 75.1%, HbS/β‐thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6‐4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/β thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. Conclusion With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.
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