Biomedical subjects

S Burdach

Publications and source records attributed to S Burdach.

124 records · Page 7Linked to original sources

PubMedDate not supplied

[Immune stimulation with interleukin-2 after autologous stem cell transplantation in children and adolescents with solid tumors].

Children with solid tumors of poor prognosis have benefitted from autologous bone marrow transplantation as a treatment modality. Adjuvant interleukin-2 (IL2) therapy has previously been shown to improve prognosis in adults with some solid tumors. In this setting improved survival probability has been attributed to IL2-mediated augmentation of antineoplastic activity of the immune system. In this study 8 pediatric patients in complete remission after autologous stem cell transplantation were treated with recombinant IL2 administered in 3 cycles of 5 days continuous intravenous infusions and a two week rest in between. We demonstrated that IL2 therapy increased transplantation-related activation of the immune system both on cellular and humoral levels. Peripheral blood T and NK cell number increased by the factors 1.7 and 6.0 respectively. NK and T cell activation were further enhanced as indicated by elevated levels of soluble IL2 receptor. The production of tumor cytotoxic cytokines like alpha TNF and gamma INF was stimulated. The elevated aTNF and gamma INF cytokine synthesis seemed to be mainly related to the activation and proliferation of NK cells, as T cells obtained from patients after IL2 therapy showed a definite cytokine production deficiency after T cell specific stimulation.

Adolescent↗

PubMedDate not supplied

The granulocyte/macrophage-colony stimulating factor (GM-CSF): basic science and clinical application.

Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) stimulates the production as well as the function of myeloid cells, i.e. granulocytes and macrophages. Proliferative effects are exerted on the level of the multipotent as well as the unipotent progenitor cell. Functional effects on mature phagocytes comprise bactericidal and tumoricidal mechanisms including induction of cytokine release. GM-CSF receptors are present on normal hematopoietic progenitors as well as on mature granulocytes, on leukemic cells and some non-hematopoietic cells. Alteration of the GM-CSF gene has been associated with distinct features of AML and ALL. The glycosilated molecule is produced by various hemolymphopoietic and possibly non-hematopoietic cells, amongst whom T-lymphocytes and marrow stroma may be most relevant for myelopoiesis. The regulation of gene expression is exerted on both transcriptional and posttranscriptional levels of gene expression. GM-CSF production may play a role in steady state as well as in stress hematopoiesis. In vivo application of GM-CSF leads to a marked increase of phagocytes, in particular granulocytes. GM-CSF reduces the duration of neutropenia following aplasiogenic and ablative therapy. GM-CSF may possibly be helpful in the treatment of victims of radiation accidents and in patients with acquired neutropenias and glykogenosis IB. The curative potential for the underlying malignant disease is to be investigated in the present cooperative european Ewing's sarcoma study.

Child↗

PubMedDate not supplied

[Transient myeloproliferation and acute myeloid leukemia in infants with Down's syndrome].

Transient neonatal myeloproliferative disorders (TMD's) indistinguishable from acute leukaemia by clinical and morphological criteria have been described in neonates with Down's syndrome. To analyse its clinical significance, 10 infants under 1 year of age presenting with Down's syndrome and the morphological picture of acute myelogenous leukaemia were reviewed. 3 of these children had true AML leading to death after 2, 8 and 11 months. In the other 7 children the diagnosis TMD was suggested as spontaneous or in one case interferon-induced remission occurred within 4 to 25 weeks after diagnosis. The interferon-treated patient died of SIDS at the age of 11 months. Another one of the TMD children developed fatal erythroleukaemia at the age of 2 years. Regarding initial clinical and haematological parameters, TMD was indistinguishable from true congenital leukaemie. In all patients classification according to the FAB criteria was difficult, as mainly undifferentiated or poorly differentiated myeloid blasts were seen, sometimes with erythro- or megakaryocytic features. Because of the difficulties in the differential diagnosis of TMD and true AML it is recommended to delay specific cytostatic therapy in neonates with Down's syndrome, until definite progression of the leukaemic process is observed or cytogenetic analyses suggesting true AML are available.

Antigens, CD↗

PubMedDate not supplied

The role of chemotherapy in the treatment of children with neuroblastoma stage IV: the GPO (German Pediatric Oncology Society) experience.

340 consecutive patients with neuroblastoma stage IV were analyzed for the possible impact of chemotherapy on general condition, remission status, event free survival and survival. The children entered the trials NB 79, NB 82 and NB 85 of the German Pediatric Oncology Society (GPO). The patients did benefit from chemotherapy by considerable improvement of the general condition, by achievement of 30-40% complete and 60-70% partial remissions. The event free survival (EFS) rate 5-8 years after diagnosis was 13% for all 299 protocol patients, the survival (S) rate 10%. The median/mean EFS time were 11.6/23.8 months, the median/mean S time 17.0/29.4 months. The use of response rates as early predictors for long term survival is challenged. Addition of PCVm (cisplatinum, cyclophosphamide, Vm 26) to ACVD (adriamycine, cyclophosphamide, vincristine, dacarbazine) in trial NB 82 resulted in an improvement of the long term EFS rate from 5% to 18% (S rates 7----21%). The introduction of IVp (ifosfamide, VP16) and increase of doses (cisplatinum, Vm 26) did not further improve the results. Maintenance therapy (NB 82) revealed a positive influence on the outcome. Shorter intervals for realization of chemotherapy were associated with a trend for better EFS (NB 85). Although the group of children with bone marrow transplantation showed better EFS and S data compared to the unselected chemotherapy group, the advantage was less clear if matched pairs (remission status at the time of BMT) were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

[Molecular mechanisms of cellular interaction in immune regulation of hematopoiesis].

Studies are reviewed, which establish a novel regulatory role for the T cell lymphokine IL2: Immunoregulation of hematopoiesis. IL2 induces a receptor-specific inhibition of early erythroid progenitors. IL2-induced inhibition of erythropoiesis is mediated by Interferon-gamma protein release preceded by Interferon-gamma mRNA accumulation. Triggering of the antigen receptor complex induces p55 IL2 receptor expression, which is a prerequisite for IL2-induced erythropoietic inhibition. P55 protein expression on the T cell surface is preceded by an increase of p55 mRNA levels. The studies demonstrate that the regulatory role of IL2 extends beyond governance of the immune system itself and can subserve to control red cell production in vitro.

Animals↗

PubMedDate not supplied

[High-dosage chemotherapy in primary metastasized and relapsed Ewing's sarcoma. (EI)CESS].

BACKGROUND: Patients (pts) with primary metastatic Ewing tumours (ET) have a poor prognosis for event free survival (EFS) compared to pts with localised disease. Following relapse the prognosis is extremely poor. Therefore these primary metastatic and relapsed pts were piloted for high dose therapy (HDT) for the last years. PATIENTS AND METHODS: Between April 1984 and May 1997, 131 ET pts who underwent HDT were registered in the German CESS/EICESS office: 79 pts with primary metastases and 52 pts with relapsed tumours. After induction therapy, consisting of chemotherapy and local therapy, pts received high dose regimens, mainly based on melphalan and/or etoposide (92%). Stem cell rescue was applied from allogeneic bone marrow (n = 13), autologous bone marrow (n = 17), or peripheral blood stem cells (n = 95). The date of analysis was September 1st, 1998. Outcome was calculated by Kaplan-Meier-analyses. RESULTS: The median time under study since high dose therapy was 3.7 years. 35/131 pts (26.7%) were in continuous complete remission, 80/131 pts (61.1%) had relapsed or progressed, 11/131 pts (8.4%) died of complications and 5/131 pts (3.8%) presented with secondary malignancies. For the total group of primary metastatic pts, EFS five years after diagnosis was 19% for pts with HDT and 27% for those without (p = 0.9209). The subgroup of pts with primary lung and bone metastases seemed to benefit from HDT (EFS five years after diagnosis: 34% versus 5%, p = 0.0001). Outcome of pts with an early ET relapse (< 2 years) was also improved by HDT (EFS four years after relapse: 17% versus 2%, p = 0.0001). CONCLUSIONS: The total group of primary metastatic ET pts showed no obvious benefit from HDT, based on melphalan and/or etoposide. Pts with metastases to multiple organ systems, and early relapse seemed to benefit from HDT. The value of HDT should be assessed in prospective clinical trials.

Adolescent↗

PubMedDate not supplied

Fanconi anemia and beta c deficiency-associated pulmonary alveolar proteinosis as two hereditary diseases of childhood which are potentially curable by stem cell gene therapy but require different therapeutic approaches.

Fanconi anemia (FANC) and pulmonary alveolar proteinosis associated with deficiency of the beta-chain common to the GM-CSF/IL3/IL5 receptors (beta c-PAP) are rare inherited disorders of childhood or adolescence. Hematopoietic stem cell gene therapy aiming at reintroducing the wildtype cDNA as a new concept for the treatment of hereditary diseases may be applicable to FANC and PAP, as both disorders can be successfully treated by allogeneic stem cell transplantation. However, there are important distinctions to be made between the two diseases: FANC seems to be a disorder with functional stem cell deficiency. Thus, introduction of the wildtype cDNA should provide an in vivo growth advantage to genetically corrected stem cells so that corrected cells and their progeny may expand in vivo and slowly repopulate the entire hematopoietic system. In beta c-PAP, the defect has no major impact on proliferation or differentiation of stem cells. Therefore, introduction of the wildtype gene will probably not provide any selective growth advantage and the percentage of corrected cells in the hematopoietic compartment depend on the percentage of stem cells initially transduced as the current technology only allows for transduction of stem cells with low efficiency. The introduction of a second selectable cDNA into the vector might be used to provide selective growth for modified cells and thus overcome a low gene transfer efficiency of stem cells. The correction of rare monogenetic diseases may serve as a model for gene therapy prior to attempts to treat more common and complex polygenetic diseases. The studies outlined here will be helpful envisioning new treatment strategies for other inherited monogenetic diseases such as mucopolysaccharidosis, Gauchers disease or adrenoleukodystrophy.

Animals↗

PubMedDate not supplied

Defunct hematopoietic progenitor growth and heterogeneous immunological phenotypes in acquired aplastic anemia of childhood: identification of subsets with decreased hematopoietic progenitors and increased IL15 or IL10 production.

Acquired aplastic anemia (AAA) is a disorder with multiple causes. The pathogenetic mechanisms leading to marrow failure are diverse. The clinical finding, that most patients respond to immunosuppressive therapy implicates an immune pathophysiology of AAA. On the other hand successful and long lasting reconstitution after allogeneic stem cell transplantation implicates, that a stem cell defect is a major pathogenetic factor. We analyzed immunological and hematological parameters on 91 pediatric patients with AAA at time of diagnosis. We defined three distinct pathogenetic subgroups by analyzing the frequency of hematopoietic progenitors and the frequency of activated T-cells in patients bone marrow: type I: decreased percentage of hematopoietic progenitors; type II: increased percentage of activated T-cells; type III: increased percentage of pluripotent progenitors. In 51% of the AAA patients we found a relative decreased frequency of hematopoietic progenitors and 29% of the patients demonstrated an increased percentage of activated T-cells, 25% patients showed an increased percentage of pluripotent hematopoietic progenitors. In order to characterize these distinct immunological subgroups, we investigated the plasma levels of IFN-gamma and IL15 as inhibitors and IL10 as stimulator of hematopoiesis. IL15 plasma levels were significantly elevated in AAA patients when compared to controls. In contrast we could not demonstrate a difference between IFN-gamma or IL10 plasma levels in AAA patients when compared to controls. However for IL10 and IL15 we were able to define subgroups of patients with highly elevated plasma levels of the cytokines. These data indicate that the immunopathogenesis of AAA can be heterogeneous. This heterogeneity might reflect exposure to different exogenous agents or heterogeneity in intrinsic susceptibility. The clinical impact of our findings needs to be assessed in long-term follow up of the patients.

Anemia, Aplastic↗

PubMedDate not supplied

Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group.

Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.

Adolescent↗

PubMedDate not supplied

Does megatherapy contribute to survival in metastatic neuroblastoma? A retrospective analysis. German Cooperative Neuroblastoma Study Group.

To evaluate the impact of megatherapy on the outcome of high risk neuroblastoma, 39 patients with stage IV neuroblastoma, who underwent megatherapy, were analyzed retrospectively and compared to 49 patients, who continued chemotherapy according to the German cooperative trial NB85. The groups were comparable concerning age, primary localisation, pattern of metastases, clinical risk groups and response to induction therapy. Overall survival of the megatherapy group was 0.23 +/- 0.07 compared to 0.14 +/- 0.05 of the chemotherapy group (p = 0.0149). In particular patients with partial response to induction chemotherapy appeared to gain from megatherapy, while patients in complete remission did not benefit. Subset analysis confirmed the superiority of megatherapy in patients with bone marrow infiltration at diagnosis, in patients with or without bone metastases at diagnosis and in patients older than 2 years. On the background of the poor prognosis of stage 4 neuroblastoma and lack of other effective treatment modalities these data support the utilization of megatherapy in treatment strategies for stage IV neuroblastoma.

Bone Marrow Transplantation↗

PubMedDate not supplied

Humoral coagulation and early complications after allogeneic bone marrow transplantation.

Alterations of the coagulation system that may lead to coagulation activation and thrombosis are common sequelae after allogeneic bone marrow transplantation (BMT). We performed prophylactic anticoagulation by low dose heparin (50 units/kg/day) and substitution of antithrombin (AT) concentrate to sustain plasma levels above 90% of pooled normal human plasma. Conventional tests for plasmatic hemostasis and substitution of AT concentrate were recorded for 50 patients until day +50 after BMT. Incidence of sepsis, graft-versus-host-disease [GVHD], capillary leakage syndrome [CLS] and veno-occlusive disease of the liver [VOD] were investigated and compared with the results of patients without any of these complications. Patients with proven sepsis (n = 6) showed decreased activity of AT, and a prolonged activated partial thromboplastin time (aPTT), while fibrinogen levels were slightly increased. This constellation was interpreted as mild to moderate activation of the humoral coagulation cascade. Patients with VOD (n = 10) showed an increased consumption of AT concentrate at day +7 followed by a decrease of prothrombin time, of clotting factors II and VII, and a prolongation of aPTT at days +11 to +18 after BMT. This suggests, that activation of coagulation precedes decreased synthesis of coagulation factors. Patients with CLS (n = 15) or GVHD > or = II degree (n = 14) showed no major alterations of coagulation parameters. In conclusion, after BMT, two types of coagulopathy were observed: (i) an activation of the coagulation cascade (i.e. sepsis and VOD) which was followed by (ii) a diminished synthesis of coagulation factors (VOD). In order to perform timely therapeutic interventions in the coagulation system in patients with sepsis and/or VOD it appears to be important to assess the clinical value of parameters for early detection of coagulation activation as thrombin-AT complexes, D-dimers and F1 + 2 fragments.

Adolescent↗

PubMedDate not supplied

[Significance of interleukin 10 for acute graft versus host disease in children and adolescents after allogenic bone marrow transplantation].

BACKGROUND: It has been shown that Interleukin 10 (IL-10) is able to inhibit alloreactivity in a mixed lymphocyte culture. Therefore, here IL-10 production in patients after allogeneic BMT was investigated and correlated with the incidence of acute GvHD. PATIENTS: 14 patients after allogeneic BMT have been investigated. Patients' age ranged from 2.6 to 22 yrs. (median 7 yrs.). Patients were diagnosed with Ewing's sarcoma (1), ALL (4), AML (3), CML (2), Wiskott-Aldrich Syndrome (WAS;1), MDS (1) and SAA (2). GvHD > II degrees occurred in 5/14 patients. As control served 20 healthy volunteers. METHODS: Mononuclear cells (MNC's) isolated from patients and 20 healthy controls were stimulated with an anti-CD3 monoclonal antibody for 72 hr. IL-10 was detected in cell-free supernatants by ELISA. RESULTS: Anti-CD3-induced IL-10 production in MNC's isolated from patients (range/median: 0-1579 pg/10(6) MNC; 221 pg/10(6) MNC) was significantly reduced compared to healthy controls (160-5093 pg/10(6) MNC; 1250 pg/10(6) MNC; p < 0.01). 4/5 patients with low IL-10 production, but only 1/9 with a normal IL-10 production presented with GvHD > II degrees (p < 0.05). CONCLUSION: Ex vivo IL-10 production was decreased in about one third of patients early after allogeneic BMT. The low IL-10 production was associated with a significantly increased risk of severe GvHD. Thus, supplementation of IL-10 might become a useful therapy to prevent GvHD.

Adolescent↗

PubMedDate not supplied

[Experimental principles of therapy-oriented pathogenetic classification of aplastic anemia in childhood].

Growth and differentiation of hematopoietic progenitor cells is regulated by a complex network of stimulatory and inhibitory cytokines. Bone marrow failures can be due to a decrease of stimulators or an increase of inhibitors. T cells produce both, hematopoiesis stimulating and inhibiting cytokines. Therefore, a role of T cells in regulating hematopoiesis can only be assumed if the gene expression of these antagonistic acting cytokines can be differentially induced in T cells. To establish a model of selective cytokine induction, we investigated the induction of IFN gamma as inhibitor and GM-CSF as stimulator of hematopoiesis in T cells. Our results showed that IFN gamma mRNA accumulates in T cells which have been pre-activated via the signal transduction unit CD3, but not in unstimulated T cells. This accumulation depends on the expression of the high affinity IL2 receptor which is including the IL2 receptor alpha-chain (IL2R alpha, CD25). In a study on children with constitutional (CAA) versus acquired aplastic (EAA) anemia, we investigated the relevance of this model for the pathogenesis of aplastic anemia in childhood. We compared the following parameters: 1. Incidence of hematopoietic progenitor cells and cloning efficiency, 2. activation status and IL2R alpha expression of bone marrow T cells, 3. T cell cytokine expression profile. Our results show: 1. The relative incidence of bone marrow progenitor cells is decreased in children with CAA and normal in children with EAA. 2. Clonogenic growth of hematopoietic progenitor cells is suppressed in children with EAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗

PubMedDate not supplied

Interleukin 10 induced c-fos expression in human B cells by activation of divergent protein kinases.

IL-10 is a potent mediator of human B cell growth and plasma cell formation. However, signal transduction of IL-10 in B cells is poorly understood. In this study the effect of IL-10 on the expression of the protooncogene c-fos was investigated, because Fos plays a potential role in the regulation of B cell proliferation and differentiation. B cells were purified from buffy coat preparations of healthy blood donors by positive selection using an anti CD20 monoclonal antibody and a MiniMACS separation unit. B cells were prestimulated with SAC for 48 hrs. Then, cells were incubated with medium or IL-10 (100 ng/ml) for 10 to 120 min. RNA was extracted by phenol/chloroform and c-fos expression was analyzed by PCR assisted mRNA assay. A significant 2-4 fold increase of c-fos expression was observed within 30 min of stimulation with IL-10 (p < 0.01). After 2 hrs c-fos expression declined to basal levels. The effect of IL-10 was dose-dependent with a maximum stimulation using 100 ng/ml of IL-10. The IL-10 effect on c-fos expression was not blocked by polymyxin B. Using the tyrosine kinase inhibitor genistein (10 microM) a complete inhibition of IL-10 induced c-fos expression was observed. In addition, H-7 (10 microM), a specific inhibitor of serine/threonine kinases, significantly blocked IL-10 mediated c-fos expression (p < 0.05). In conclusion, these data show that IL-10 induces c-fos expression in human B-cells by activation of tyrosine and serine/threonine kinases. Since this is the first report on IL-10 induced signal transduction, these data may help to identify the intracellular mechanisms by which IL-10 stimulates human B-cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMedDate not supplied

Release of the soluble interleukin-6 receptor from human T-cells.

The soluble Interleukin-6 receptor (sIL-6R) is capable of conferring the Interleukin-6 (IL-6) signal onto cells lacking the gp80 ligand binding protein. Here we investigate the release of sIL-6R from T-cells. After 2 h stimulation with PMA, a release of sIL-6R from peripheral human T-cells was observed which was insensitive to the protein synthesis inhibitor cycloheximide. This release was accompanied by a decrease of membrane-bound (mb) IL-6R. After 24 h, however, the observed sIL6-R release did prove to be sensitive to cycloheximide. These results suggest that both shedding and denovo-synthesis may be responsible for the PMA-induced sIL-6R release. In contrast to PMA, neither anti-CD3, a positive, nor IL-10, a negative regulator of IL-6 release from T-cells affected the production of the sIL-6R. The differential regulation of sIL-6R and IL-6 production by T-cells might be relevant for the immunomodulatory potential of the sIL-6R with respect to the interaction of T- and non-T-cells.

CD3 Complex↗

PubMedDate not supplied

Interaction between interleukin 10 and interleukin 6 in human B-cell differentiation.

Contrary to their opposing action on human T-lymphocytes and monocytes, both Interleukin (IL-)10 and IL-6 are potent differentiation factors of human B-cells. Both are known to induce immunoglobulin (Ig) production. The precise mechanism of this converging effect of IL-6 and IL-10 remains elusive, however. Here we investigated the role of IL-6 in the IL-10 dependent B-cell differentiation into Ig secreting cells. We found that co-stimulation of SAC-stimulated human peripheral B-lymphocytes with IL-10 and IL-6 exhibited no additive effect on Ig production over stimulation with IL-10 alone, and that IL-6 receptor blockade only mildly inhibited IL-10 induced Ig synthesis. In fact, we could show that stimulation of B-cells with IL-10 somewhat suppressed SAC induced autocrine IL-6 production. Despite this suppression IL-6 levels remained sufficiently high to stimulate its receptor, and IL-6 binding to the B-cell surface was not affected. The failure of IL-6 to exert an additional effect on SAC+IL-10 induced Ig production suggests that IL-10 may recruit components of the IL-6 intracellular pathway for Ig induction. In conclusion we could demonstrate that IL-10 acts on B-cell differentiation independently of autocrine IL-6 and that it had a considerably mild effect on B lymphocytic autocrine IL-6 secretion. This still allows an IL-6 effect in the presence of IL-10 which appears adaptive with a view to the converging effects of these two cytokines on human B lymphocytes. Our study thus adds to the appreciation of the complex cytokine regulation of the immune system.

Antibodies↗