Regeneration of granulopoiesis with recombinant human granulocyte-macrophage colony-stimulating factor after bone marrow transplantation.
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Agranulocytosis↗
Biomedical subjects
S Burdach
Publications and source records attributed to S Burdach.
High efficiency of a new immunological magnetic cell sorting method for T cell depletion of human bone marrow.
Fresh human bone marrow (BM) mononuclear cells containing a mean of 11% T cells underwent T cell depletion utilizing a newly developed magnetic cell sorter. In order to remove T cells, 10(8) cells were labeled with either a specific CD3 monoclonal antibody or a cocktail of monoclonal CD2 + CD5 + CD7 antibodies and biotin-conjugated magnetic microparticles (size 100-150 nm) employing a streptavidin-FITC complex. Labeled cells were removed by using columns filled with a ferromagnetic matrix and placed within a recess in a strong permanent magnet. Recovery of non-T cells was 79% after the first passage and 61% after the second. The absolute recovery of BFU-E and CFU-GM was 70% and 51% respectively (n = 11). Limiting dilution analysis revealed less than 0.1% residual clonable BM T cells (cloning efficiency greater than 50%) which corresponds to a 2.1 (1st passage) and to a 2.3 (2nd passage) log depletion. This new separating system is a highly efficient, reproducible, and quick method of depleting T cells from human BM. It could be easily adapted to process large scale marrow specimens or for the elimination of residual tumor cells from BM in autologous transplantation.
Antibodies, Monoclonal↗
Histidine-rich glycoprotein blocks T cell rosette formation and modulates both T cell activation and immunoregulation.
Histidine-rich glycoprotein (HRGP) is a plasma and platelet protein with undefined function in vivo. It has been reported to inhibit rosette formation between murine T cells and erythrocytes. We have shown that HRGP binds specifically to human T lymphocytes but not sheep erythrocytes and have demonstrated a 56-kDa HRGP-binding protein on the T cell surface which is distinct from the CD2 sheep erythrocyte receptor. We have now investigated whether HRGP can inhibit human T cell-sheep erythrocyte rosette formation and whether HRGP can modulate T cell activation. HRGP at physiologic concentrations specifically inhibited rosette formation between human T lymphocytes and sheep erythrocytes. HRGP suppressed proliferation of antigen receptor (CD3)-triggered T cells induced by interleukin 2; this suppression was specifically reversed by prior incubation of HRGP with affinity-purified anti-HRGP IgG. Addition of HRGP 12-24 h after CD3 triggering no longer suppressed T cell proliferation, suggesting HRGP suppressed T cell division by interfering with one or more early events in the process of T cell activation. Human serum (containing 100-150 micrograms/ml HRGP) was also capable of suppressing T cell proliferation; serum which had been immunodepleted of HRGP no longer inhibited T cell proliferation. Furthermore, HRGP inhibited interleukin 2 receptor expression on activated T cells, causing decreased T cell interferon-gamma release and altered T cell-dependent inhibition of erythropoiesis. HRGP is thus capable of modulating T cell activation and T cell immunoregulation; HRGP may function as a natural suppressive regulator of human T lymphocyte activation.
Animals↗
Hematopoietic growth control by the T-cell CD2 determinant is exerted at a pretranslational level.
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Antigens, CD↗
[Lymphokine-induced suppression of erythropoiesis by normal T lymphocytes and retrovirus-associated lymphoproliferative disease].
Activation of genes for interleukin 2 (IL2) and its receptor by the tat gene product of the human retrovirus HTLV-I has been linked to the pathogenesis of adult T cell leukemia. In earlier studies we have demonstrated that IL2-induced inhibition of erythropoiesis is mediated by activated T-Lymphocytes expressing the IL2-receptor. We have now examined the role of activated T cells and interferon-gamma (IF gamma) in inhibition of normal erythropoiesis and in HTLV-I associated lymphoproliferative disease. T cells were activated by triggering of the antigen receptor complex with CD3 monoclonal antibody. Incubation with CD5 antibody recognizing a T cell epitope distinct from the antigen receptor served as a control. Supernatants derived from CD3 activated T cells generated in the presence of IL2 caused a dose-dependent suppression of erythropoiesis. Treatment of supernatant interferon-gamma neutralizing antibody caused a greater than 95% abrogation of inhibition. Next we investigated the mechanisms for acquired pure red cell aplasia in a patient with T gamma-lymphoproliferative disease (T gamma-LPD). Patient marrow erythroid progenitors were 17 +/- 9% of control and increased to 88-102% of control following marrow T cell depletion. Myeloid progenitors were normal. Patient suppressor T cells inhibited growth of autologous and allogeneic marrow erythroid but not myeloid progenitors and produced high titers of IF gamma. The inhibitory factor in patient T cell supernatant was acid labile and sensitive to trypsin, consistent with properties of IF gamma. Prior depletion of activated T cells abrogated the suppressive effect of patient T cell-derived supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)
Anemia, Aplastic↗
The T-cell CD2 determinant mediates inhibition of erythropoiesis by the lymphokine cascade.
We examined the role of the T-cell antigen CD2 in the regulation of erythropoiesis by the lymphokine cascade. T-cell interleukin-2 (IL-2) receptors (p55) were induced via triggering of the antigen receptor-associated CD3 epitope. Before CD3 triggering T cells were preincubated with a CD2-blocking (Leu-5b) or isotype control antibody. T-cell pellets were employed during incubation to facilitate interaction between T-cell LFA-3 and CD2. CD2 blockade caused a 66% to 79% inhibition of p55 expression after three to six days of culture with IL-2. Next we assessed the effect of CD2 blockade on IL-2. Next we assessed the effect of CD2 blockade on IL-2-induced inhibition of BFU-E in autologous cocultures containing CD3-triggered T cells. IL-2 caused a dose-dependent inhibition (52% to 92%) of BFU-E in the presence but not in the absence of CD3-triggered T cells. T-cell CD2 blockade prior to CD3 triggering caused a 65% to 87% abrogation of IL-2-induced inhibition of BFU-E at 10 to 10(2) U/mL IL-2. Preincubation of CD3-triggered T cells with isotype control antibody had no effect on IL-2-induced erythroid inhibition. Day 3 supernatants from CD3-triggered T cells or CD2-blocked, CD3-triggered T cells established in the presence of IL-2 were next assessed for modulation of BFU-E. CD3-triggered T-cell supernatants caused a 77% +/- 9% inhibition of BFU-E. Blockade of CD2 caused a 95% abrogation of T-cell-mediated BFU-E inhibition. In addition, CD2 blockade reduced interferon-gamma (IF gamma) release (84 to 128 U/mL) from CD3-triggered T cells by 81% at day 3 of culture. In control experiments, the addition of IF gamma-neutralizing monoclonal antibody to CD3-triggered T-cell supernatant established in the presence of IL-2 caused 75% abrogation of IL-2 inhibition of BFU-E. We conclude that blockade of the CD2 T-cell determinant induces down modulation of (a) T-cell p55 IL-2 receptor expression, (b) IL-2-induced inhibition of BFU-E, and (c) IL-2-induced marrow T-cell IF gamma release. These data suggest that the T-cell CD2 determinant can exert a regulatory effect on the control of erythropoiesis by the lymphokine cascade.
Antigens, Differentiation↗
T cell regulated hematopoiesis--molecular interactions in hematopoietic control by CD2 and interleukin 2.
Studies are reviewed, which establish a novel regulatory role for the T cell surface molecule CD2 and the T cell lymphokine IL-2: Immunoregulation of hematopoiesis. IL-2 induces a receptor-specific inhibition of early erythroid progenitors. IL-2-induced inhibition of erythropoiesis is mediated by interferon-gamma protein release and is associated with interferon-gamma mRNA accumulation. CD3-triggered p55 IL-2 receptor expression is a prerequisite for IL-2-induced erythropoietic inhibition and is associated with p55 mRNA synthesis. Hematopoietic effects of IL-2 are mediated by CD2/LFA-3 receptor ligand interactions. The studies demonstrate that the regulatory roles of IL-2 and CD2 extend beyond governance of the immune system itself and can subserve to control red cell production in vitro.
Antigens, Differentiation, T-Lymphocyte↗
Receptor-specific modulation of myelopoiesis by recombinant DNA-derived interleukin 2.
T cells and T cell-derived lymphokines have been implicated in the regulation of myelopoiesis. This study examines the regulatory effects of recombinant DNA-derived human IL 2 on the phagocyte progenitor cell (CFU-GM), utilizing a receptor-specific model for T cell regulation of myelopoiesis. IL 2 receptors were induced on immunopurified marrow T cells by triggering the T cell antigen receptor complex with CD3 monoclonal antibody. IL 2 receptor expression was assessed by cytofluorography with IL 2 receptor monoclonal antibody. IL 2 receptor-positive and IL 2 receptor-negative marrow T cells were cocultured with autologous adherent and T cell-depleted marrow mononuclear cells in the absence and presence of various concentrations of IL 2. In the presence of IL 2 receptor-positive T cells, IL 2 caused a dose-dependent inhibition of CFU-GM (86% at 10(2) U/ml). IL 2 did not inhibit CFU-GM in the absence of T cells or in the presence of IL 2 receptor-negative T cells. The addition of IL 2 receptor blocking monoclonal antibody completely abrogated IL 2-induced inhibition of CFU-GM. Conditioned media prepared from IL 2 receptor-positive marrow T cells in the presence of IL 2 also inhibited CFU-GM expression from marrow NAB-T cells (50% +/- 16). In contrast, conditioned media from IL 2 receptor-positive T cells prepared in the absence of IL 2 or from IL 2 receptor-negative T cells prepared in the presence or absence of IL 2 did not significantly affect CFU-GM growth. IL 2 receptor-positive, but not IL 2 receptor-negative, T cells released large amounts (190 +/- 60 U/10(6) cells X ml-1) of IFN-gamma but only low amounts of tumor necrosis factor beta (less than 10 U/ml) in response to IL 2. In control experiments, recombinant DNA-derived IFN-gamma caused a 37% +/- 19 inhibition of CFU-GM in the presence of resting T cells and adherent cells. However, IFN-gamma failed to inhibit CFU-GM in the presence of activated (IL 2 receptor-positive) T cells, indicating that release of IFN-gamma cannot solely explain IL 2-induced inhibition of CFU-GM. The addition of neutralizing IFN-gamma monoclonal antibody partially abrogated IL 2-induced inhibition of CFU-GM (41 to 60%) in the presence of CD3-triggered T cells, suggesting that although IFN-gamma participates in IL 2-induced inhibition of myelopoiesis, it is not the sole mediator of that inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)
Antigen-Presenting Cells↗
Malignant peripheral neuroectodermal tumours of childhood and adolescence.
Seventeen cases of malignant peripheral neuroectodermal tumour (MPNT) were studied by means of light microscopy, immunohistochemistry and electron microscopy. There were nine males and eight females. The mean age of the 17 patients was 10 years with a range of seven months to 20 years. The vast majority of tumours was located in the trunk. Histologically, they closely resembled Ewing's sarcoma, although minor differences were obvious. Special findings included ganglion cells and Flexner rosettes. In 10/11 cases positive staining for neuron-specific enolase (NSE) was obtained. Five of 10 tumours were positive for protein S-100. Three contained vimentin, two neurofilaments and one vimentin, neurofilaments and GFAP. Neurosecretory granules were noted in the three cases studied. Five patients died, three are alive with disease and five patients are alive without evidence of disease. It is concluded that these tumours form a homogeneous group, although the grade of differentiation varies. The prognosis in most cases is poor. Distinction from Ewing's sarcoma is possible by staining for NSE and by electron microscopy.
Adolescent↗
[Damages to health in schools. Complaints caused by the use of formaldehyde-emitting materials in school buildings].
Low formaldehyd-concentrations were measured in three Cologne schools (mean 1 = 0,4425; mean 2 = 0,5725; mean 3 = 0,1292 ppm). As the main sources of emission were identified formaldehyd-urea-bound chip-plates in acoustic-ceilings and wainscots. To study the connection between the complaints of pupils and CH20-emissions 1594 pupils of these schools were questioned using a specially elaborated questionnaire. The questions concerned multiple complaints and disturbances of health as well as their anamnesis in chronological relationship with school attendance. Compared to controls consisting of 497 pupils of a school, where no CH2O-emitting chip-plates were used, the inquiry showed a significant increase (p less than 0,00005) of so-called functional disturbances (headache, disorder of concentrating ability, dizziness, nausea), affections of the respiratory tract (irritation of the mucosa of the nose and the pharynx, dry cough) and irritation of the conjunctiva. In regard to the anamneses, the difference between the investigation-group and the control-group was even more significant and additional complaints such as somnipathy, abdominal pain, skin disease were observed frequently. Comparing the normal distribution of so-called functional disturbances in pupils found in literature, the examined group of this study showed an even higher rate of the relative accumulation. The repeated investigation in one school (n = 328) 8 months after removal of the emission-sources demonstrated a very clear reduction of complaints by an average of 71,2 per cent.
Adult↗
Tolerability of piperacillin/tazobactam in children and adolescents after high dose radio-/chemotherapy and autologous stem cell transplantation.
The combination of piperacillin with tazobactam (PIP/TAZ) extends the activity of piperacillin against gram-positive, gram-negative, and anaerobic bacteria. The broad-spectrum of this formulation, together with its low degree of organ toxicity observed in adults, makes PIP/TAZ a tempting choice for children with radio-/chemotherapy-induced neutropenia. However, the use of PIP/TAZ is not yet approved for children under 12 years of age. The tolerability of PIP/TAZ was assessed in 19 children and adolescents between 2 and 18 years of age who developed a fever during aplasia after high dose radio-/chemotherapy and autologous stem cell transplantation (HD-SCT) for primary multifocal or relapsed solid tumours. Treatment with PIP/TAZ was initiated on average 3 days after HD-SCT, and the treatment was continued for approximately 10 days. Both clinical observation and laboratory studies showed no relevant alterations that would have been attributable to PIP/TAZ treatment. These results indicate that PIP/TAZ appears to be well tolerated in children during the acute phase of HD-SCT.
Adolescent↗
[Prader-Labhart-Willi syndrome in infants].
We report an infant with severe hypotonia, feeding problems and failure to thrive in the neonatal period, followed by developmental delay. In addition, pale skin, eyelid and pedal edema, cryptorchidism and micrognathia were present. The tentative diagnosis of Prader-Labhart-Willi syndrome was made and confirmed by specific molecular testing at the age of 5 months. The Prader-Labhart-Willi syndrome is usually diagnosed in older infants when the main clinical features such as obesity, short stature, hypogonadism and developmental delay become obvious, in most of the patients typical clinical features are present already in the neonatal period. In conclusion, in neonates and young infants presenting with hypotonia and feeding problems, the Prader-Labhart-Willi syndrome should be considered.
Autoantigens↗
[Guillain-Barré syndrome as a rare cause of acute respiratory insufficiency].
BACKGROUND: Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating disease of peripheral nerves. Antibodies acting against antigens on the myelin or the axons seem to play a causative role. In up to 80 % the onset of GBS follows an antecedent respiratory or gastrointestinal infection. CASE REPORT: An 20 month old boy was referred to our hospital because of meningism and aspiration pneumonia. 10 days earlier the patient had experienced a period of fever. Because of respiratory insufficiency the patient was intubated, sedated and received mechanical ventilation. That's why a major neurological examination was not possible. The patient demonstrated a flaccid tetraplegic paralysis and autonomic dysfunction with elevated blood pressure, tachycardia, elevated ADH level and hyperglycaemia. Decreased motor nerve conduction and an increased CSF protein with normal CSF cell count confirmed diagnosis of GBS. Active CMV infection was diagnosed by PCR as the possible trigger factor. Intravenous immunoglobulins were given and the patient reached a complete remission except a slight disturbance of peroneal nerve. CONCLUSIONS: IVIG and PP therapy are equally effective in GBS. In contrast corticosteroids are not of benefit. Prognosis of childhood GBS is good. Only 4 % of affected children demonstrate persistent muscular weakness. The long interval between admission and diagnosis in the reported case emphasized the importance of neurological examination especially in sedated patients.
Acute Disease↗
[Therapy of osteoid osteomas -- always surgically?].
Osteoidosteomas are common bone tumours in childhood. Frequently they occur in the long bones of the lower extremities, less frequent in the humeri, phalanxes or the axial skeleton. The tumour is benign and noninfiltrative. Metastases do not occur. Typical complaints are nightly pain attacks, which are relieved by nonsteroidal antiinflammatory drugs. On X-ray, the classic finding is a small radiolucent area surrounded by sclerotic bone in the cortex. Surgical excision is often recommended, providing the possibility for a histological diagnosis. Therapeutic alternatives are percutaneous coagulation of the nidus by alcohol or laser, thermo-coagulation or high-frequency radioablation. Spontaneous remissions are well documented. Therefore the decision to wait and see and to treat with antiinflammatory medication is a considerable therapeutic option. We present two patient with an ostoidosteoma in the proximal femur. One of them underwent an unsuccessful trial for surgical extirpation and histological examination but afterwards developed a severe hip contraction with scoliosis. In the case of the other patient a primary operation was abandoned. Pain was completely controlled upon treatment with nonsteroidal antiinflammatory drugs in both patients. The contractions also disappeared completely upon physiotherapy. Serial MRI showed a significant regression of the inflammatory reaction in one case and the disappearance of the tumour in the other one. In conclusion, pharmacomedical therapy can be recommended, if the diagnosis is doubtlessly and a close follow up is established. The risk of anaesthesia and surgical treatment should be weighted against the risk of nonsteroidal antiinflammatory drug treatment.
Anti-Inflammatory Agents, Non-Steroidal↗
DNA-microarrays as tools for the identification of tumor specific gene expression profiles: applications in tumor biology, diagnosis and therapy.
DNA-microarrays allow the analysis of almost the complete gene expression program of tumor samples and normal control samples in a single experiment. This allows the processing of a large number of samples in a reasonable short time. Tumor specific gene expression profiles can be used for molecular tumor classification and as a new diagnostic tool. In addition, the identification of tumor specific genes can help to understand the biology of tumor cells and identified genes can be used for the development of new therapeutic strategies. However, the huge amount of data generated by DNA-microarrays creates new challenges for data analysis. In addition, accuracy and reproducibility of the available techniques require complementary methods for verification of DNA-microarray data.
Child↗
[Oncology patients in a pediatric intensive care unit--a 7-year experience].
BACKGROUND: As a result of improved therapeutic and diagnostic modalities the survival rate of children with neoplastic disease has increased dramatically. The consequences of these scientific advances have led to increased malignancy-related critical complications requiring the expertise of intensive care practitioners. PATIENTS: From all children admitted to the pediatric intensive care unit (PICU) of the Martin-Luther University Halle those with hematologic-oncologic condition were evaluated. RESULTS: From 4068 PICU admissions 196 (4.8%) oncologic patients were identified. Most of them were admitted for postoperative care, monitoring or intervention. 24 patients were admitted because of severe disease or treatment related complications. 14 out of 24 (58%) patients died on PICU. Mortality was significant higher in a subgroup requiring mechanical ventilation or suffering from sepsis. All patients but two with multi-organ system failure (> or = 2 organs) died. CONCLUSIONS: Children with neoplastic disease can benefit from pediatric intensive care unit (PICU) support. Successful treatment of life-threatening complications requires a close cooperation of pediatric oncology and PICU. Further studies are necessary to improve therapeutic strategies in oncology patients requiring PICU admission.
Adolescent↗
Long-time survival after unrelated bone marrow transplantation in children and adolescents and targeted therapy with CD25 blockade to prevent GVHD.
To evaluate longtime survival after matched unrelated donor (MUD) transplantation a group of patients (n = 10) with intensified GVHD prophylaxis were compared to patients receiving matched sibling (MSD) transplantation (n = 10); all transplantations were done between 1989 and 1995 in the same institution. A murine monoclonal antibody against CD25 was assessed in addition to standard GVHD prophylaxis for reducing GVHD in children with advanced leukemia after MUD BMT (group I). We compared the incidence of GVHD, relapse and survival under prophylaxis with either anti-CD25 (group I, n = 10) or MSD BMT without anti-CD25 (group II, n = 10) with respect to known risk factors of transplant related morbidity, mortality and outcome. 3/10 leukemia patients in both groups were in CR3 or in relapse at time of transplant. Whereas incidence of acute GVHD grade III and IV was significantly higher in group I compared to group II (0.4 vs. 0.0), no differences in engraftment, or chronic GVHD were seen between both groups. In addition, overall (0.5 vs. 0.6) and leukemia free survival (0.5 vs. 0.6) was not different after 8 respectively 10 years from transplant. Murine anti-CD25 therapy may have contributed to matching outcome of MUD vs. MSD marrow transplants in children with advanced leukemia. In conclusion, the use of anti-CD25 in modulation of CD25+ regulatory and effector T cells in allo- and leukemia recognition merrits further exploration of its potential to improve both tolerance and leukemia control. Since the outcome of children with leukemia that received intensified GVHD prophylaxis in MUD BMT was similar to children with MSD transplants, MUD BMT has to be considered as an equivalent therapeutic option for patients, who have no HLA-identical sibling donor.
Acute Disease↗
[Results of treatment of primary exclusively pulmonary metastatic Ewing sarcoma. A retrospective analysis of 41 patients].
41 patients presenting with primary metastatic Ewing's sarcoma or malignant peripheral neuroectodermal tumor (PNET) with initial metastases restricted to the lungs and/or pleural space were analysed with respect to clinical manifestation and treatment results retrospectively. All patients were treated according to the protocols CESS 81 and CESS 86 of the German Society of Pediatric Oncology and Hematology (GPOH). The time since diagnosis ranges from 19 to 137 months, with a median of 72 months. Median relapse-free survival time was 21.8 months. 18 patients were female, 23 were male. The majority of primary tumors exceeded 100 ml of volume. Preferred sites were the pelvis with 16 cases, the limbs with 14 cases and the chest wall with 6 cases. The histological specification of the tumor was Ewing's sarcoma in 22 and PNET in 11 patients, in 8 cases no specific distinction was given. As to local therapy of the primary tumor, 12 patients underwent radiotherapy, 11 surgery, and 18 a combination of both. Patients were allocated to one of these three options on an individual basis. Cytostatic drug treatment was given according to the GPOH-CESS 81 and CESS 86 protocols. As calculated by means of the Kaplan-Meier analysis, relapse-free survival was 30% ten years after diagnosis. Surgery or pulmonary irradiation of 12-20 Gy was applied to lung metastases. 12 of 27 patients are in continuous complete remission following this therapeutic approach.
Adolescent↗