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L L Sensenbrenner

Publications and source records attributed to L L Sensenbrenner.

At least 55 records · Page 3Linked to original sources
PubMed1987

Progenitor cell assays predict hematopoietic reconstitution after syngeneic transplantation in mice.

Hematopoietic reconstitution following syngeneic bone marrow transplantation with graded doses of untreated and drug-treated bone marrow was studied in B6D2F1 mice. Granulocyte-macrophage colony-forming units (CFU-GM) and spleen colony-forming units (CFU-S) showed similar in vitro drug sensitivities. Both the speed of hematologic recovery and survival of mice transplanted with untreated or drug-treated bone marrow were directly related to the number of CFU-GM or CFU-S transplanted. Similar hematologic recovery was seen for untreated marrow transplants and treated transplants that had similar CFU-GM or CFU-S content. There is a minimum number of transplanted CFU-GM or CFU-S that allows survival of lethally irradiated mice. This number is present in a marrow transplant containing the equivalent of 5 X 10(3) untreated cells or producing one to two spleen colonies. There also exists a maximum value for the number of hematopoietic progenitors in a marrow graft, above which the rate of hematologic recovery following transplantation is rapid and no detectable increase in the rate is seen with increasing CFU-GM or CFU-S content. The presence of this maximum value for transplanted progenitors and variations in culture techniques are probably the reasons previous studies have not always shown a correlation between CFU-GM content and hematologic recovery after bone marrow transplantation.

Animals↗
PubMed1987

Variability in 4-hydroperoxycyclophosphamide activity during clinical purging for autologous bone marrow transplantation.

We examined the effects of varying incubation conditions on the in vitro activity of 4-hydroperoxycyclophosphamide (4HC). 4HC activity against CFU-GM and against the K562 tumor cell line decreased with increasing the RBC concentration of the incubation mixture. Increasing the concentration of nucleated bone marrow cells in the incubation mixture also decreased the 4HC activity. Evaluation of 53 consecutive patients undergoing autologous bone marrow transplantation (BMT) revealed that the incubation RBC concentration during clinical purging showed a similar effect on CFU-GM recovery. Aldehyde dehydrogenase content of RBCs and nucleated marrow cells appears to be the cause of the inhibition of 4HC activity. Although there was no difference in individual CFU-GM sensitivity to 4HC among normals, previously treated patients undergoing autologous BMT showed significant variability in CFU-GM sensitivity to 4HC. The combined effects of incubation RBC concentration and individual patient 4HC sensitivity appear to account for most of the variability in CFU-GM recovery and speed of hematologic recovery after clinical purging with 4HC.

Bone Marrow↗
PubMed1987

Culture from human bone marrow of blast progenitor cells with an extensive proliferative capacity.

The investigation of human hematopoiesis is limited by the lack of an in vitro assay for the most primitive hematopoietic stem cell. In this report, we describe the culture from normal human bone marrow of unique colonies of morphologically immature cells with scanty, agranular, cytoplasm and a primitive nucleus with nucleoli. These "blast" cells demonstrate a significant ability for the generation of secondary colonies of multiple lineages, including additional blast cell colonies. These colonies are detected at various times during the culture period of up to 28 days. Neither the time of appearance in primary culture nor any feature of the morphological appearance of the blast cells is correlated with replating ability or the differentiation pathway followed. The progenitor cell giving rise to these colonies may represent the earliest pluripotent hematopoietic stem cell yet grown in culture.

Bone Marrow Cells↗
PubMed1986

Incidence of aplastic anemia in a three county area in South Carolina.

An apparent cluster of four aplastic anemia (AA) cases in teenagers residing in a small South Carolina town was further investigated. Incidence of AA in all age groups in a surrounding three county area (TCA) over a 12-year time interval was determined and compared with AA incidence rates in Baltimore, representing the only known population based United States incidence data. The same general age-specific incidence pattern (based on 27 cases in the TCA and 118 in Baltimore) was found in the two areas, both overall and for the four race-sex groups. Although based on small numbers, nonwhite average annual age-adjusted rates for males and females were higher in the TCA (6.8 and 13.7 per million) than in Baltimore (4.7 and 7.3). For whites, TCA rates were 11.7 and 5.4 (for males and females) and Baltimore rates were 7.1 and 5.4. The differences for non-whites in the two areas may indicate a greater prevalence of risk factors for AA in the TCA than in Baltimore, but the small numbers of cases and the lack of comparable data from other areas of the country, together with the possibility of misdiagnosis of the disease, make definitive conclusions impossible.

Age Factors↗
PubMed1985

An apparent cluster of aplastic anemia in a small population of teenagers.

Four teenagers with severe aplastic anemia, initially diagnosed and evaluated over a seven-year period at The Johns Hopkins Bone Marrow Transplant Unit, Baltimore, were residents of the same small town in South Carolina. Estimated annual incidence for that age group in the town, based on the four cases, was 100 times the expected rate. All four of the teenagers had attended one of two junior high schools. An exploratory survey of all high-school students, comparing risk factors of those who had attended the "affected" junior high school with those who had attended the "unaffected" junior high school, showed no associations with exposure to glue, paint or varnishes, pesticides, history of hepatitis or infectious mononucleosis, or use of chloramphenicol or other suspected drugs. Weak associations were found between the affected junior high school and employment in the textile industry and in agriculture (specifically peach orchards).

Adolescent↗
PubMed1984

Effects of neuraminidase on the regulation of erythropoiesis.

In this article, we present evidence that sialic acid-containing surface components play a role in the regulation of erythropoiesis. A 1-hr exposure of mouse bone marrow cells to high concentrations of neuraminidase reduced erythroid colony formation. Coculture of 10(6) untreated thymocytes with neuraminidase-treated bone marrow cells restored erythroid colony growth. Neuraminidase-treated thymocytes retained their ability to suppress erythroid colony formation by untreated marrow cells, but lost their ability to enhance erythroid colony formation. Continuous exposure to low concentrations of neuraminidase enhanced erythroid bone marrow cell colony growth in response to a suboptimal dose of erythropoietin.

Animals↗
PubMed1983

Phorbol ester-stimulated murine myelopoiesis: role of colony-stimulating factors.

Tumor promoting phorbol esters, such as 12-0-tetradecanoyl-phorbol-13-acetate (TPA), stimulate colony formation in vitro by murine granulocyte-macrophage progenitors (GM-CFC) without added colony stimulating factors (CSF). To determine whether TPA induces CSF production in vitro, marrow cells were cultured for 1 to 7 days in liquid medium with or without TPA. No CSF was detected in any sample by a double antibody radioimmunoassay (sensitivity = 2 units/0.1 ml), however, colony-stimulating activity was detected in supernatant fluid from all TPA containing cultures by bioassay. This activity appeared to result from a direct effect of TPA rather than from production of CSF, as equivalent activity was found in TPA-containing medium incubated in the absence of marrow cells. Rabbit antiserum to purified L-cell CSF inhibited colony formation stimulated by L-cell CSF and WEHI-3 CSF, but had no effect on colony formation induced by TPA. Cells from long-term marrow cultures responded to TPA with colony formation, despite culture conditions and cell fractionation procedures that reduced the frequency of CSF-producing macrophages to less than 1.0%. TPA inhibited binding of radioiodinated L-cell CSF to marrow cells, especially if the cells were first exposed to TPA. These results do not support induction of CSF production as the major mechanism of phorbol ester stimulation of myelopoiesis. Phorbol esters may directly stimulate GM-CFC and/or enhance their response to CSF by a mechanism involving CSF binding sites.

Animals↗
PubMed1983

Regulation of hematopoiesis II: the role of polyamine inhibition on helper or suppressor influences of the thymus.

We have previously suggested in murine model systems, that two cell subpopulations with differing proliferative capacity, from the thymus, modify the growth of erythroid progenitor cells in vitro. In order to further characterize these populations, we have specifically inhibited polyamine biosynthesis; this pathway is essential for the process of cell replication. Thus, alpha-difluoromethyl ornithine (DFMO) was used to block the conversion of ornithine to putrescine, the first and rate-limiting step in polyamine biosynthesis. We observed a threefold increase in hematopoietic progenitors (CFU-S and CFU-E) from bone marrow in animals treated with DFMO. We further examined the effect of DFMO on accessory "helper" and "suppressor" cells from the thymus and observed an increase in helper activity with an elimination of suppressor activity. All of these effects of DFMO were specific for inhibition of polyamine biosynthesis, since simultaneous addition of the depleted biosynthetic product, putrescine, restored suppressor activity. We conclude that polyamine biosynthesis is required acutely for accessory cell regulation of hematopoiesis.

Animals↗
PubMed1983

Anticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro.

A 53-yr-old man sequentially developed aplastic anemia from phenytoin and carbamazepine. Both compounds undergo metabolism to potentially toxic arene oxide intermediates. We tested the hypothesis that the patient's adverse reactions were due to a defect in detoxification of such metabolites by challenging his peripheral lymphocytes with drug metabolites generated by a murine hepatic microsomal system in vitro. The patient's cell viability was normal in the absence of drugs. However, his cells showed greater toxicity from both phenytoin and carbamazepine metabolites than did controls. Toxicity was dependent on microsomes and NADPH. Intermediate toxicity was noted in cells from the patient's mother. The results provide the first evidence for a role of arene oxide drug metabolites in aplastic anemia in humans and suggest that enhanced susceptibility to toxicity may be based on an inherited abnormality in metabolite detoxification.

Anemia, Aplastic↗
PubMed1983

Predictive values of the in vivo diffusion chamber for cyclophosphamide treatment of L1210 murine leukemia.

In vivo culture of tumor cells using the Millipore diffusion chamber implanted i.p. into female C57BL X DBA/2 F1 (hereafter called BD2F1) mice provides a means for direct examination of drug effect on tumor cells. The effect of various doses and schedules of i.p. cyclophosphamide (CY) on murine L1210 leukemia cell count in the chambers was compared to survival of leukemia-bearing animals treated similarly. Tumor cell viability was assessed by transfer of chamber contents to recipient animals who were then observed for survival. Unless perturbed by CY, L1210 cells grew in log phase within chambers to 10(8) cells/cu mm. The effect of CY on chamber cell count was dose related, quantifiable, reproducible, and predictive of survival of leukemia-bearing animals treated similarly. Single doses proved to be more effective than were equally divided doses in decreasing chamber cell number and prolonged leukemic animal survival. Reinjection of L1210 cells rescued from chambers after hosts had been treated with CY revealed that many could not produce tumors. Results suggest that this technique provides reproducible information on drug effects and may be a valuable tool for designing clinically useful dose schedules.

Animals↗
PubMed1982

Effect of radiation and 4-hydroperoxycyclophosphamide on thymic regulators of erythropoietic growth.

In vitro growth of erythroid progenitors (BFU-e and CFU-e) from mouse bone marrow (BM) can be influenced by the addition of graded doses of thymocytes (THY). At low THY:BM ratios (1:50), inhibition of erythroid growth occurred, whereas at high THY:BM ratios (20:1), enhancement of erythroid growth was observed. Experiments were designed to examine the sensitivity of the thymocytes to gamma radiation or treatment in vitro with an alkylating agent, 4-hydroperoxycyclophosphamide (4HC), to determine if two subpopulations with different physical characteristics were responsible for these observations. We reasoned that if there were selective effects of either radiation or drug treatment on enhancement or inhibition, this would provide evidence for separate populations which regulated erythroid cell growth by cell-cell interaction. At the small doses of drug or X-ray studies (i.e., 10 microM 4HC or 3.0 Gys), elimination of the inhibitory effect of low THY:BM ratios resulted. Enhancement of erythroid growth was unaffected by drug or radiation until 80 microM 4HC or 30.0 Gys were employed. Fresh putative inhibitory thymocytes (low numbers) added to either 4HC or radiation-treated inhibitory cells restored the suppressor effect on erythroid growth. The helper effect, however, was not restored by the addition of fresh thymocytes. We conclude that there are at least two populations which provide (a) an inhibitory influence that is relatively sensitive to radiation and cyclophosphamide in vitro, and (b) an enhancing effect which is relatively insensitive to these treatments.

Animals↗
PubMed1982

Bone marrow transplantation with major ABO blood group incompatibility using erythrocyte depletion of marrow prior to infusion.

Twenty-five patients with major ABO blood group incompatibility between donor and recipient underwent allogeneic bone marrow transplantation using erythrocyte depletion of the bone marrow infusate prior to administration. Over 95% of the original erythrocyte content of the marrows was removed, while retaining 75% of the mononuclear cell content and 57% of the granulocyte-monocyte colony-forming units. Recipients, well hydrated and premedicated with corticosteroids, diphenhydramine, and mannitol, tolerated infusions well. The frequency of engraftment, rate of recovery of peripheral blood leukocytes, granulocytes, and platelets, and the incidence of graft-versus-host disease was similar to that observed following ABO blood group compatible bone marrow transplantation. Erythroid development following ABO blood group incompatible transplantation was significantly impaired until hemagglutinins fell to 1:4 or lower, at which time recovery of erythrocytes was detected in the peripheral blood. The erythrocyte hypoplasia associated with incompatible hemagglutinins was temporary. Erythrocyte purging is a safe and effective technique to perform bone marrow transplantation across major ABO blood group incompatibilities.

ABO Blood-Group System↗
PubMed1980

Regulation of hematopoiesis: helper and suppressor influences of the thymus.

Thymocytes from normal mice strains as well as from genetically determined stem cell defective W/Wv anemic mice were cocultured with syngeneic (or congeneic) bone marrow cells. We assayed these cocultures for the proliferation of erythroid progenitor cell types (BFU-E and CFU-E) using the plasma clot technique. Results indicate that when concentrations of thymocytes were lower than bone marrow cells, significant suppression of erythroid growth was observed. However, when the concentration of thymocytes exceeded that of the bone marrow cells in culture (greater than 1:1), significant enhancement of erythroid growth was demonstrated. The W/Wv anemic bone marrow appears to respond to this interaction by enhancement at all concentrations of added normal thymocytes. The regulatory functions observed can be diminished by treatment of the thymocytes in vitro with anti-theta serum plus complement. Thus, we establish regulatory functions for anti-theta-sensitive regulatory cells (TSRC) with both positive (enhancement) and negative (suppression) components.

Animals↗
PubMed1979

Comparative effects of cyclophosphamide, isophosphamide, 4-methylcyclophosphamide, and phosphoramide mustard on murine hematopoietic and immunocompetent cells.

The effects of equimolal doses of cyclophosphamide (CY), isophosphamide (IP), 4-methylcyclophosphamide (4-MCY), and phosphoramide mustard (PM) on murine hematopoietic spleen colonies and adoptively transferred antibody-forming cells in vivo were compared. Equimolal doses of the drugs produced significantly different effects. All the drugs exerted an increasing effect against the ability of adoptively transferred immunocompetent cells to produce a significant anti-sheep red blood cell titer as the length of time between cell transfer and drug administration was increased. The maximum effect was seen when a drug was given 48--72 hours after antigen and spleen cell transfer. CY and IP produced significantly greater immunosuppressive effects than did the other drugs at all times after cell transfer and at all doses administered. PM had the least immunosuppressive effect at each dose evaluated. Against hematopoietic spleen colonies, the cytotoxic effects of 4-MCY and PM were similar and, at most doses studied, significantly greater than the effect of either CY or IP. Inasmuch as PM is an active metabolite of CY, it appeared either that one of the prior metabolites of CY was responsible for this marked immunosuppressive effect or that due to differences in polarity, PM was differentially distributed within the two cell systems as compared to CY. The differences in hematopoietic effects among all drugs were much less than those seen against immunocompetent cells and were not dependent on time of drug administration.

Animals↗