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Biomedical subjects

A R Zander

Publications and source records attributed to A R Zander.

At least 199 records · Page 11Linked to original sources
PubMed1979

Human leukocyte interferon preparation blocks granulopoietic differentiation.

Since interferon administration in the treatment of some malignant conditions has been reported to cause leukopenia, we studied the effects of human leukocyte interferon preparation (HLIF) on myelopoiesis in vitro. The continual presence of HLIF in semisolid agar cultures caused a progressive decline in colony and a rise in cluster incidence with increasing concentrations of interferon. The total plating efficiency, however, remained nearly constant, regardless of the HLIF doses used. Morphological examination of the clusters demonstrated a progressively increasing percentage of immature granulocytic precursors with increasing HLIF concentrations. This suggests that HLIF causes leukopenia by blocking differentiation of marrow myeloid precursors.

Cell Aggregation↗
PubMed1979

The collection, preservation and function of peripheral blood hematopoietic cells in dogs.

Semicontinuous flow centrifugation (SFC) was employed in canines to obtain adequate numbers of cells for autologous marrow repopulation following supralethal cyclophosphamide administration (100 mg per kg). Four cycles using a 225 ml bowl and 30 ml per minute flow rate were carried out for procurement. Collections averaged 8.4 +/- 0.4 x 10(9) (n = 30) leukocytes. Mononuclear cells (MNC) comprised 75 +/- 2% of the population and granulocyte colony-forming units (CFU-C) totaled 1.9 +/- 0.09 x 10(5) colonies per collection. Eighty-six percent of mononuclear cells were "T" cells in the 30 to 90 second fraction compared to 49% at 150 to 120 seconds. CFU-C fractionation revealed a peak at 30-210 seconds and a second peak at 120-210 seconds. Following programed freezing and rapid thawing 77.7 +/- 11.4% of CFU-C were recovered. Using a dose of 1 x10(9) MNC per kg for reinfusion, marrow repopulation and clinical recovery occurred in four out of four dogs. It was concluded that 1) SFC was effective for obtaining adequate numbers of peripheral blood stem cells for autologous marrow repopulation. 2) A rapid thawing and direct transfusion technique appears satisfactory for administration. 3) Some separation of "T", "B" and CFU-C peripheral blood components is possible by centrifugation.

Animals↗
PubMed1979

Autologous bone marrow transplantation in relapsed adult acute leukemia.

From March, 1976 to February, 1979, 28 cases of adult acute leukemia of which 24 were evaluable were treated in irreversible relapse with high dose chemotherapy (piperazinedione) and supra-lethal total body irradiation (TBI) in conjunction with autologous bone marrow transplantation (ABMT). The marrow cells grafted were collected and stored in liquid nitrogen at the time of remission. In 12 patients the marrow cells were fractionated using discontinuous albumin gradients in an attempt to separate normal cells from residual leukemic cells. Twelve patients achieved complete remission (CR); in 9 additional patients signs of engraftment were evident but death occurred before achievement of CR. Seven of 12 AML patients, which were treated with bone marrow transplantation as first treatment of their relapse, achieved CR. Four of 5 patients with ALL, whose bone marrows were collected during first remission, reached CR. The median CR duration was 4+ months and the median survival of the patients reaching CR was 6+ months. Autologous bone marrow transplantation offers a good chance of CR (66%), when marrow is collected during first remission and used as first treatment for AML in third relapse and ALL in second relapse.

Adolescent↗
PubMed1979

Myelopoietic enhancement by immunoadjuvants: in vitro studies for their rational use in neutropenic patients.

Following marrow transplantation, the clinical course of the patients is invariably complicated by severe infections due to neutropenia and immuno-incompetence. With a view to explore means of alleviating these complications, Bacillus Calmette-Guerin (BCG), methanol extraction residue of BCG (MER), Corynebacterium parvum (C. parvum) and Pyran were examined for their myelopoietic activity on human marrow. Light density (less than or equal to 1.077 g/ml) unfractionated (UF) cells (2 X 10(6)/ml and 2ml/dish), and adherent (Ad) and non-adherent (N-Ad) cells alone (derived from 4 X 10(6) UF cells per dish) were incubated with and without the above agents. The conditioned media (CM) were harvested at 24, 72, 96, and 168 hours and colony stimulating activity (CSA) assayed against light density non-adherent human marrow cells using double layer agar-culture system. CSA was maximum at 72 and 96 hours followed by an invariable decline at 168 hours' incubation. The optimal concentrations releasing maximum CSA varied for each agent. CM prepared with higher concentrations were less active. CM prepared in the presence of Pyran had no CSA. Comparisons of the maximally released CSA by the optimal concentrations of these agents revealed BCG and MER to be the most active. The CSA elaborated by UF cells was more than the total combined activity from separately incubated Ad and N-Ad cells. Re-addition studies revealed that almost full CSA could be recovered when Ad and N-Ad cells were incubated together at a ratio of 1:3. Different immunoadjuvants have a differing capacity to elaborate CSA from human marrow cells and each has an optimal concentration for maximum CSA release. This may require a cell-cell and/or humoral interaction(s) between Ad and N-Ad cells.

Adjuvants, Immunologic↗
PubMed1978

Cytogenetic evidence for recurrence of acute myelogenous leukemia after allogeneic bone marrow transplantation in donor hematopoietic cells.

A 22-yr-old man with acute myelocytic leukemia received a bone marrow transplant from a genotypically HLA-identical female sibling after cyclophosphamide preparation. He remained in complete remission for 18 mo, when he developed a chloroma in the perineum. The chloroma was treated with local radiotherapy. The chloroma recurred 8 mo later and was treated with radiotherapy followed by combination chemotherapy. At 34 mo after transplant, marrow relapse and chloroma were documented. The first chloroma contained host cells by fluorescent Y-chromatin body analyses of interphase nuclei. All metaphase cells and karyotypes from peripheral blood and marrow samples showed no evidence of host cells from 3 wk after transplant through the time of marrow relapse. Data from autosomal and sex chromosome studies indicate that the marrow relapse occurred in cells of donor origin. A new consistent chromosome abnormality [45, X, -X, t(8;21) (q22; q22)] was observed in a majority of donor cells. The patient received a second bone marrow transplant from the same donor after preparation with busulfan and cyclophosphamide and attained a complete remission with full hematologic engraftment.

Adult↗
PubMed1977

Intralesional Bacillus Calmette-Guérin immunotherapy of canine venereal tumors.

Canine transmissible venereal tumors were studied for response to intralesional Bacillus Calmette-Guérin (BCG) therapy. Six pairs of littermates, identical for the major histocompatibility complex, were evaluated. One member of each pair received intralesional BCG to one of two growing tumors. Lesions of control animals received 0.9% NaCl solution. Both injected and noninjected lesions of BCG-treated animals underwent regression within 63 days, as compared to an extended period of tumor growth (beyond 100 days) for controls (p less than 0.05). Serial in vitro assays during therapy included; (a) mixed lymphocyte-tumor culture, (b) phytohemagglutinin stimulation, and (c) assessment of lymphocyte surface markers. Lymphocytes from BCG-treated dogs were significantly more responsive to tumor cells in mixed lymphocyte-tumor culture assay than were those from controls (p less than 0.05). Maximal responses occurred during tumor regression. T- and B-lymphocyte levels as assayed by rosette formation and surface marker immunoglobulins were not influenced by BCG therapy. It was concluded that intralesional BCG therapy of canine venereal tumors was highly effective in causing regression of injected and noninjected lesions. This tumor model system may be useful for the evaluation of the effectiveness of new immunotherapeutic approaches on established neoplasms in large, randomly bred animals.

Animals↗
PubMed1976

Combined pre-immunization and granulocyte transfusion therapy for treatment of pseudomonas septicemia in neutropenic dogs.

An experimental model was designed to evaluate a combined protocol of active immunization and granulocyte transfusions for treatment of Pseudomonas aeruginosa sepsis in the neutropenic host. One member of a pair of dogs was immunized with P. aeruginosa vaccine. Both dogs were then rendered transiently neutropenic with a single intravenous dose of cyclophosphamide (40 mg. per kilogram) and challenged with an intravenous inoculum of P. aeruginosa. Twenty-four and 48 hours after pseudomonas challenge each animal received granulocyte transfusions. Effectiveness of therapy was evaluated by observation of survival time, febrile response, and quantitative blood cultures. Results showed a significant increase in the survival period (P is less than 0.05), a lower febrile response (P is less than 0.025), negative blood cultures, and a greater recovery rate in the immune group. Immune dogs that died had negative blood cultures or less than or equal to 10 pseudomonas per milliliter of blood despite the presence of P. aeruginosa in tissues. In contrast, control dogs had septic deaths within 67 hours of pseudomonas challenge, marked febrile responses with 24 hours of infection, and positive blood cultures with 4,000 to 25,800 pseudomonas per milliliter of blood. These data show that combined therapy with immunization and granulocyte transfusions is effective in reducing the severity of P. aeruginosa infection and in preventing bacteremia during periods of leukopenia.

Agranulocytosis↗
PubMedDate not supplied

Hepatocytic gene expression in cultured rat mesenchymal stem cells.

The origin of liver cells from distinct bone marrow stem cells, eg, hematopoietic stem cells or multipotent adult progenitor cells has been recently described using in vitro studies. Cell culture experiments revealed the key role of growth factors and the organ-specific environment for the induction of liver-specific genes. We investigated the in vitro potential of rat mesenchymal stem cells to differentiate into hepatocytic cells in cocultures with isolated rat liver cells. Rat mesenchymal stem cells (MSCs) propagated in culture, and transduced with green fluorescent protein (GFP) were cloned. Cells from selected clones were either cultured under liver-stimulating conditions, using serum free medium supplemented with HGF, EGF, SCF, and FGF-4 alone on fibronectin-coated surfaces, or cocultured with freshly isolated rat liver cells. Cocultured cells were harvested after two weeks and sorted into GFP-positive (GFP+) and GFP-negative (GFP-) cells. RT-PCR for liver specific markers CK-18 and albumin were performed on the different cell populations. After 2 weeks, the specified culture conditions led to the expression of albumin and CK-18 RNA in GFP-positive sorted MSCs from the cocultures, whereas MSCs cultured without liver cells did not express the studied genes. The results indicate, that when cocultured with liver cells MSCs from the bone marrow have the potential to differentiate toward hepatocytic cells in vitro. We conclude that MSC may possess an enhanced capacity to differentiate into functional liver cells. Additionally, environmental factors seem to be crucial for specific and directed differentiation.

Animals↗
PubMedDate not supplied

Rescue by peripheral blood mononuclear cells in dogs from bone marrow failure after total-body irradiation.

In order to determine the minimum dose of buffy coat cells necessary to achieve hematopoietic rescue following supralethal irradiation, mongrel dogs under general anesthesia were subjected to leukacytapheresis using three different techniques of cell separation. The buffy coats were frozen with dimethylsulfoxide and stored at -196 degrees C until transfused. Sixteen dogs were irradiated with 800 rads and were supported with antibiotics and transfusions of irradiated homologous blood. They were transfused with the frozen and thawed buffy coat cells, and, if they survived, they were followed for 100 days, sacrificed, and their tissues studied. The mean yield of mononuclear cells during leukocytapheresis ranged from 4.1 +/- 2.0 X 10(9) (mean +/- SD) to 6.0 +/- 4.0 X 10(9) for the three leukacytapheresis methods; one technique was not as satisfactory as the other two. Six of the 16 dogs fully recovered with evidence of marrow rescue; however, only one had a dose of mononuclear cells less than 11.1 X 10(9). These data indicate that seven to 17 leukacytapheresis procedures would be required to reconstitute a 70 kilogram patient. These preliminary findings suggest that, because the yields of transplantable cells with current technology are not adequate, the transplantation potential of buffy coat cells exposed to mobilizing agents should be evaluated.

Animals↗
PubMedDate not supplied

[Unrelated donor stem cell transplantation in children: low toxicity using a GvHD-prophylaxis regimen with CSA, MTX, metronidazole,iv-immunoglobulin and ATG].

BACKGROUND: Unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) is accepted as a therapy for leukaemic diseases and varying inborn diseases if a suitable related donor cannot be found. The goal of immunosuppressive therapy with UD-HSCT is an effective prevention of graft-versus-host-disease (GvHD) on one hand. On the other hand an optimal balance with immunocompetence of the transplanted bone marrow is desirable in order to prevent graft failure, infection and, in the case of leukaemic diseases, potentially control the underlying disease. PATIENTS AND METHODS: Between 1992 and 2000 49 patients aged 11 months to 16.7 years received an UD-HSCT in Hamburg. Underlying diseases were leukaemia or MDS in 35, of these ALL in 21, hemophagocytic lymphohistiocytosis (HLH) in 9, immunodeficiency or inborn error of metabolism in 5 patients. GvHD-prophylaxis consisted of a combination of Cyclosporin A (CSA), methotrexate (MTX), metronidazole, IgM-enriched iv-immunoglobulin (ivIg) (Pentaglobin(R)) or ivIgG and anti-thymocyte-globulin (ATG). Within the same time span 10 patients with ALL received a matched related donor HSCT (MRD-HSCT). GvHD-prophylaxis in these patients was done without ATG in 8 of 10 cases. UD-HSCT were analyzed for survival, relapse and toxicity. Probability of survival of the patients with ALL after UD-HSCT was compared with results of MRD-HSCT in children with ALL. RESULTS: The Kaplan-Meier estimates of three year overall-survival (OS) were 74 % for all patients. Probability of disease-free survival (DFS) at three years was 62 % for leukaemia/MDS-patients and 100 % for the HLH-patients. Acute GvHD (aGvHD) grades II or III occurred in 51 % of patients. Chronic GvHD (cGvHD) occurred in 22 % of patients. There were 5 cases of treatment-related mortality (TRM). Probability of DFS for patients with ALL at three years was 65 % after UD-HSCT and 30 % in the patients after MRD-HSCT. CONCLUSIONS: UD-HSCT in children is an effective and safe therapy. A GvHD-prophylaxis regimen combining the standard immunosuppressive agents CSA and MTX with ivIg, metronidazole and serotherapy using ATG may result in a low incidence of severe GvHD-complications and low TRM rate without increase in relapse rates.

Adolescent↗
PubMedDate not supplied

[Treatment of hemophagocytic lymphohistiocytosis, HLH, with bone marrow transplantation].

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease of infancy and young childhood. The clinical presentation includes recurrent unexplained fever with hepatosplenomegaly. Cytopenia, hypofibrinogenemia and/or hypertriglyceridemia and hemophagocytosis in bone marrow, spleen and lymphnode confirm the diagnosis. Hemophagocytosis may not be present at the beginning. In these cases, diagnosis is facilitated by a positive family history, a relapsing course of the disease, the frequent involvement of the central nervous system and positive findings on immunological work-up. Treatment by chemotherapy and immunosuppressants can achieve sustained remissions in most patients and reinduction of remission after relapse is possible. Most children however, eventually die from progressive disease. At present, allogeneic bone marrow transplantation is the only curative therapeutic option. Between August 1992 and May 1997 eleven consecutive patients with HLH received bone marrow from unrelated (n = 7) or matched sibling donors (n = 4). The conditioning regimen consisted of busulfan, VP-16 and cyclophosphamide. Patients engrafted after a median time of 16 days (13-43). Only one patient developed grade III acute GVHD, another patient, grade II acute GVHD. Although regimen-related toxicity was extensive, all patients have survived without signs of HLH after a median follow up of 20 months (8-63). One patient suffers from chronic GVHD, three patients reveal psychomotoric retardation and one patient has severe impairment with spastic tetraparesis, amaurosis and seizures. Our experience shows that HLH can be successfully treated by allogeneic BMT from unrelated donors.

Bone Marrow↗
PubMedDate not supplied

Fetal and adult liver stem cells for liver regeneration and tissue engineering.

For the development of innovative cell-based liver directed therapies, e.g. liver tissue engineering, the use of stem cells might be very attractive to overcome the limitation of donor liver tissue. Liver specific differentiation of embryonic, fetal or adult stem cells is currently under investigation. Different types of fetal liver (stem) cells during development were identified, and their advantageous growth potential and bipotential differentiation capacity were shown. However, ethical and legal issues have to be addressed before using fetal cells. Use of adult stem cells is clinically established, e.g. transplantation of hematopoietic stem cells. Other bone marrow derived liver stem cells might be mesenchymal stem cells (MSC). However, the transdifferentiation potential is still in question due to the observation of cellular fusion in several in vivo experiments. In vitro experiments revealed a crucial role of the environment (e.g. growth factors and extracellular matrix) for specific differentiation of stem cells. Co-cultured liver cells also seemed to be important for hepatic gene expression of MSC. For successful liver cell transplantation, a novel approach of tissue engineering by orthotopic transplantation of gel-immobilized cells could be promising, providing optimal environment for the injected cells. Moreover, an orthotopic tissue engineering approach using bipotential stem cells could lead to a repopulation of the recipients liver with healthy liver and biliary cells, thus providing both hepatic functions and biliary excretion. Future studies have to investigate, which stem cell and environmental conditions would be most suitable for the use of stem cells for liver regeneration or tissue engineering approaches.

Animals↗
PubMedDate not supplied

Early pulmonary toxicity after administration of high-dose BCNU.

Patients with solid tumor malignancies who failed extensive front-line treatments were treated with high-dose BCNU followed by autologous bone marrow transplantation. Since 1976, 14 patients were treated in this program with BCNU doses ranging from 600 to 1500 mg/m2 over 2 days. Three patients developed pulmonary toxicity only a few weeks after receiving high-dose BCNU at total doses of 900, 1000, and 1500 mg/m2. Two of the three patients had had prior irradiation to the primary tumor. The third patient did not have prior irradiation to the chest but had received prior nitrosourea therapy. The use of high-dose BCNU in transplantation may be limited to early pulmonary toxicity.

Adenocarcinoma↗
PubMedDate not supplied

Combination of high-dose cyclophosphamide, BCNU, and VP-16-213 followed by autologous marrow rescue in the treatment of relapsed leukemia.

The combination of high-dose cyclophosphamide, BCNU, and VP-16-213 followed by autologous marrow rescue was evaluated in the treatment of relapsed leukemia refractory to normal-dose chemotherapy. Cyclophosphamide was given at a total dose of 4.5 g/m2, BCNU at a dose of 300 mg/m2, and VP-16-213 at a dose of 600 mg/m2. Seven high-dose treatments followed by marrow rescue were administered to six patients. Two patients achieved complete remissions, three had partial remissions, and one achieved a minimal response. The toxicity of this regimen was moderate.

Acute Disease↗
PubMedDate not supplied

Maintenance and expansion of erythropoiesis in human long-term bone marrow cultures in presence of erythropoietin plus stem cell factor and interleukin-3 or interleukin-11.

Recently there has been great interest in the ex vivo expansion and/or purging of human bone marrow cells prior to transplantation in order to obtain a long-lasting restoration of normal hematopoiesis and freedom from relapse. Long-term human bone marrow cultures (LTHBMC) represent the best available approximation of in vivo hematopoiesis. In the traditional LTHBMC, erythropoiesis is short lived (about 2 weeks). The longevity and productivity of erythropoiesis in LTHBMC may be limited by the insufficient production of certain cytokines such as Erythropoietin (Epo), SCF, IL-3 and/or IL-11 by the stromal and hematopoietic cells ex vivo and/or suboptimal addition of these cytokines. Therefore, we have investigated the optimal presence of erythropoietin plus SCF, IL-3, and/or IL-11 as requirements for the maintenance and expansion of erythropoiesis in LTHBMC in an effort to overcome the defective erythropoiesis of the traditional LTHBMC. In LTHBMC containing Epo alone and its combinations with SCF, IL-3, and/or IL-11, the nonadherent cells consisted mainly of erythroblast and normoblast cells which became the majority in the third and fourth weeks whereas granulocytes and macrophages declined steadily from the second week. A significant increase in the number of erythroblast and normoblast cells was produced throughout the whole period of LTHBMC containing Epo + IL-11 or Epo + SCF + IL-11 or Epo + SCF + IL-3 + IL-11. In the presence of Epo alone, BFU-E decreased steadily throughout LTHBMC. However, the erythroid clonogenic cells were successfully maintained in cultures containing Epo + SCF IL-3 or Epo + SCF + IL-11 or Epo + SCF + IL-3 + IL-11 for the 4 weeks and even significantly expanded by 4.5-5.7, 8.1-10 and 5-7-fold more than in the presence of Epo alone in the second, third and fourth weeks, respectively, p < 0.01. Our optimum cultures, including Epo + SCF + IL-3 or Epo + SCF + IL-11, maintained the production of nonadherent erythroid clonogenic cells for 4 weeks in culture, representing a significant improvement over the traditional LTHBMC that exhibits a progressive decline in erythropoiesis during the first 2 weeks. We conclude that Epo alone could not maintain erythroid clonogenic cell production and the supplementation with either of the two combinations: Epo + SCF + IL-3 or Epo + SCF + IL-11 is sufficient for maintaining erythropoiesis in LTHBMC. The present LTHBMC system should have applications to the analysis and manipulation of human erythropoiesis.

Bone Marrow↗