Neutrophil products that inhibit cell proliferation: relation to granulocytic "chalone".
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Bone Marrow Cells↗
Biomedical subjects
M J Cline
Publications and source records attributed to M J Cline.
Inhibitors of myelopoiesis.
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Anemia, Aplastic↗
Hormonal interactions with hematopoietic cells in vitro.
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Animals↗
Inhibitor of hematopoietic cell proliferation derived from a human leukemic cell line.
A continuously growing human myeloid leukemia cell line (K562) produced a potent high-molecular-weight inhibitor of hematopoietic cell proliferation. It was most active against myeloid stem cells (CFU-C) and proliferating T lymphocytes; it was less active against erythroid precursors (CFU-E) and did not inhibit fibroblasts or established lines of epithelioid cells or B lymphocytes. Inhibition of CFU-C was by direct interaction rather than by modulation of production of colony-stimulating activity and probably occurred at restricted points in the cell cycle. Inhibition could, within limits, be reversed by washing the target cells. Production of inhibitors of hematopoiesis is not a general property of established cell lines, and only two have thus far been identified in screening of 30 such lines.
Bone Marrow Cells↗
Human T lymphocyte cell line producing colony-stimulating activity.
We derived a permanent human T lymphocyte cell line that elaborates a potent colony-stimulating activity (CSA). The line was established with spleen cells from a patient with a T lymphocyte variant of hairy-cell leukemia. These cells form rosettes with sheep erythrocytes, show a proliferative response to phytohemagglutinin, and are lysed by antithymocyte globulin. They do not synthesize immunoglobulin, nor do they contain Epstein-Barr virus. CSA is regularly detected in the supernatant medium after 3 days culture. In the presence of PHA there is augmented elaboration of CSA; maximal activity is reached by 2 days and is 20% greater than that produced by a feeder layer of 1 X 10(6) peripheral blood leukocytes. One microliter of the supernatant material stimulated colony formation from the light-density nonadherent fraction of human bone marrow; there was maximal activity between 10 and 50 microliter/ml. Conditioned medium from these cells has little effect in stimulating CFU-C from murine bone marrow. The availability of a human T lymphocyte line producing CSA will provide a source for large quantities of the lymphocyte-derived hormone and permit a definition of factors modulating the interaction of T lymphocytes with granulocyte and monocyte stem cells.
Cell Line↗
Mechanism of nonspecific macrophage-mediated cytotoxicity: evidence for lack of dependence upon oxygen.
Peritoneal macrophages elicited in C3H/HJ mice by the i.p. injection of Corynebacterium parvum were cytotoxic to allogeneic virus-transformed fibroblasts in vitro. Cytotoxicity was demonstrated in a morphologic (plaque) assay, and quantitated by measuring macrophage-mediated inhibition of incorporation of 3H-thymidine by the target cells. The cytotoxic effect was well established by 6 hr of macrophage-fibroblast interaction, and was retained in cultures from which the supernatant was removed before the addition of 3H-thymidine. Cytotoxic activity of macrophages diminished rapidly after 22 hr of cultivation in vitro. Maximal cytotoxic effect could be prolonged by addition of C. parvum, 50 microgram/ml to macrophage monolayers preincubated in vitro for 22 hr. It could neither be retained nor regenerated when C. parvum was added to monolayers greater than 22-hr old. C. parvum-activated macrophages, grown under anaerobic conditions for 8 hr, retained the ability to phagocytize heat-killed Candida albicans and to exclude trypan blue dye. There was a small but significant reduction in the ability of macrophages to inhibit 3H-thymidine incorporation by target fibroblasts under anaerobic conditions. The cytotoxic effect of activated macrophages in air was not altered by the presence of catalase and was enhanced by enzymatically active superoxide dismutase. We conclude that the processes involved in macrophage-mediated cytotoxicity against allogeneic fibroblasts in this system are largely independent of oxygen.
Anaerobiosis↗
Chemo-immunotherapy for unresectable bronchogenic carcinoma.
Seventy-nine patients with metastatic or unresectable bronchogenic carcinoma were treated with a regimen of combination chemotherapy which included methotrexate, Oncovin (vincristine), cyclophosphamide, and adriamycin (MOCA), and were randomized to receive no additional therapy, immunotherapy with bacillus Calmette-Guérin, or immunotherapy with Corynebacterium parvum (C. parvum). The response rate and estimated median survival time were 68% and 42 weeks in small cell carcinoma and 18% and 29 weeks in other histologic types. Improved survival correlated with high performance status and response to therapy. Immunotherapy did not improve response, time to progression, or hematopoietic tolerance of chemotherapy. C. parvum was associated with significant morbidity and was poorly tolerated. MOCA appears to be of modest value in the treatment of bronchogenic carcinoma, particularly of the small cell type. A role for immunotherapy remains unproven.
BCG Vaccine↗
Effect of glucan, a macrophage activator, on murine hemopoietic cell proliferation in diffusion chambers in mice.
Pretreatment of mice with glucan, a potent macrophage activator, resulted in enhanced myeloid cluster and colony formation by bone marrow cells in diffusion chambers implanted into the peritoneal cavity. Simultaneously, erythroid colony formation was also augmented. In some experiments the plasma clots formed inside the chambers were dissolved, and the number of hematopoietic cells was determined. An increased yield of early proliferative cells, granulocytes, and macrophages was found in glucan-treated hosts. Concomitantly, higher leukocyte counts were noted in the peripheral blood of treated animals. These results suggest that glucan has a strong stimulatory effect on hematopoiesis. This stimulation is probably mediated by humoral factors of host animal origin rather than by direct interaction with proliferating hematopoietic precursors enclosed within the chambers.
Animals↗
Bone-marrow transplantation in acute leukaemia.
Survival in 33 patients with resistant leukaemia treated by marrow transplantation was compared with that of 37 matched patients treated by conventional and experimental chemotherapy. All patients in the transplant group were rendered free of detectable leukaemia for periods of from 36 days to more than 2 1/2 years, while only 6 patients in the chemotherapy group achieved a haematological remission. Overall survival in both groups was poor; however, 5 patients (15%) in the transplant group remain alive and in haematological remission 1--2 1/2 years after transplantation, while no patient in the chemotherapy group survived longer than 13 months. Bone-marrow transplantation appears to offer a small but distinct possibility of long-term survival in patients with acute leukaemia resistant to conventional therapy.
Adolescent↗
Antigens expressed by human B lymphocytes and myeloid stem cells.
Antisera prepared against papain-digested spleen cell membranes were known to by cytotoxic for normal and neoplastic human B lymphocytes and for a majority of acute and chronic myeloid leukemic cells. It is now shown that these antisera are also cytotoxic for normal myeloid stem cells (CFU-C), thus providing a probable explanation for their occurrence in myeloid neoplasia.
B-Lymphocytes↗
High remission-induction rate in acute myeloid leukaemia.
28 adult patients with acute myeloid leukaemia (A.M.L.) received T.A.D., a high-dose sequential chemotherapeutic remission-induction regimen consisting of 7-day courses of cytosine arabinoside, 6-thioguanine, and daunorubicin. Overall response-rate was 82%. 22 patients (79%) achieved complete remission, and 1 had a partial remission. Median remission duration was 280 days and median survival 375 days. 10 patients remain in remission. These induction results are superior to those reported in most studies and indicate that disease remission can be achieved in a high proportion of patients with A.M.L. treated with an intensive multi-agent chemotherapeutic regimen, provided support facilities are adequate.
Administration, Oral↗
Organ interactions in the regulation of hematopoiesis: in vitro interactions of bone, thymus, and spleen with bone marrow stem cells in normal, Sl/Sld and W/Wv mice.
Hematopoietic cell differentiation is influenced by organ-dependent microenvironmental factors as well as humoral regulators. A technique is described for examining certain aspects of the hemopoietic inductive microenvironment in vitro. Suspension and agar cultures of mouse bone marrow were used to study the effects of organ stromal factors on cellular proliferation and differentiation. Bone, spleen, and thymus fragments from irradiated mice were placed in direct contact with or separated by a Nuclepore membrane from syngeneic marrow cells growing in suspension cultures. Normal adult mouse bone and spleen influenced granulocytic differentiation as well as cell proliferation. In this system, bone marrow and organ fragments from W/Wv and SlSld mice behaved like those of their non-anemic littermates. The most prominent difference between W/Wv and Sl/Sla mice and their normal counterparts was observed in the inductionof CFU-C from splenic precursors un-er the influence of CSA. In both types of anemic mice, in vitro generation of CFU-C from spleen was abnormal in young animals but was corrected by four months of age.
Animals↗
Experience with incompatible maternal donors for bone marrow transplantation.
Marrow transplantation in aplastic anemia and leukemia has generally been limited to siblings who have been histocompatible at both the serological (A and B) and lymphocyte determined (D or MLC) loci of the HLA system. We studied three male patients, two with aplastic anemia and one with acute myelogenous leukemia, who received transplants from their histoincompatible mothers. MLC studies between donors and recipients showed varying degrees of stimulation. Definite engraftment occurred in one patient and transient engraftment in another. Engraftment in the third patient could not be evaluated. In the patient with sustained engraftment, there was clinical evidence of severe graft versus host disease (GVHD) however, this was not substantiated by histologic findings. This preliminary study suggests that MLC incompatibility may be more of an indicator of the risk of GVHD than of bone marrow rejection. If more effective control of GVHD can be accomplished, marrow transplantation between MLC-reactive individuals may become feasible.
Adult↗
Characterization of functionally distinct lymphoid and myeloid cells from human blood and bone marrow. I. Separation by a buoyant density gradient technique.
A buoyant density gradient procedure for mammalian cell separation is described. Gradients of Ficoll and Hypaque in balanced salt solution were used in a zonal rotor to separate distinct leukocyte populations from human peripheral blood and bone marrow. This method possesses the advantages of uniform osmolarity, density determination by refractometry, ease of preparation of gradient solutions, large sample capacity, and low viscosity with consequent ease of sterilization. Granulocyte-monocyte colony-forming units (CFU-C) from blood and bone marrow banded as a homogeneous peak with a density of 1.056 g cm-3 on steep gradients. Recovery of CFU-C was 36% with a 7- to 9-fold enrichment on shallow gradients. Both fractionated and unfractionated peripheral blood cells were stimulated by phytohemagglutinin (PHA), Concanavalin A (Con A), and allogeneic lymphocytes. In contrast, cells from unfractionated bone marrow and cells from the light density fraction of marrow were inhibited by Con A and responded variably to PHA.
Blood Cells↗
Characterization of functionally distinct lymphoid and myeloid cells from human blood and bone marrow. II. Separation by velocity sedimentation.
Velocity sedimentation in a zonal rotor using gradients of uniform osmolarity was used to separate leukocyte subpopulations from human blood and bone marrow. The separations were performed at high sedimentation rates having the advantage of rapidity over conventional unit gravity separations. Myeloid stem cells (CFU-C) and cells reactive with phytohemagglutinin (PHA), Concanavalin A (Con A), and in mixed leukocyte culture (MLC) were separated and their sedimentation profiles obtained. CFU-C sedimented ahead of lymphoid cells and behind mature myeloid elements. Two distinct marrow subpopulations separated by velocity sedimentation were consistently stimulated by Con A, and variably stimulated by PHA and MLC reactions. Both large cells (predominantly myeloid) and small cells (predominantly lymphoid) from bone marrow were stimulated by Con A in [3H]thymidine incorporation assays. When separated subpopulations showing stimulation by Con A were mixed, inhibition of [3H]thymidine incorporation resulted.
Blood Cells↗
Effect of hypertransfusion on granulopoiesis in bone marrow depression: studies in the irradiated mouse.
The response of granulopoietic activity in bone marrow depression to a reduction in the demand for erythropoiesis has been examined by means of hypertransfusing C-57B mice which had been exposed to sublethal whole body irradiation. Multiple intraperitoneal injections of 0.5 ml packed red cells from irradiated donors were employed to maintain the haematocrit sufficiently above the normal range to produce significant suppression of erythropoietic activity for the duration of the bone marrow depression. This was associated with elevation above control values of 32--102% in the blood granulocyte count, 22--78% in total cells of the granulocytic series per femur, and up to 44% in total agar colony forming units per femur. Restoration of essentially normal values occurred 13 d after irradiation in contrast to 17--18 d in controls. Single transfusions which produced less suppression of erythroblast numbers per femur resulted in an intermediate degree of improvement in these parameters. Such changes in the granulocyte compartment indicate improved granulopoietic capacity in the hypertransfused group. It is suggested that this effect reflects increased production of granulocyte progenitors due to the reduction in competing demands on the compromised multipotential stem cell compartment for progenitors of the erythroid series. The findings raise the possibility that hypertransfusion might be capable of producing a beneficial effect on granulopoiesis in human bone marrow depression.
Agranulocytosis↗
Neutrophil function in bone marrow transplant recipients.
The neutrophil function of seven patients receiving allogeneic bone marrow transplantion was studied. Five of the patients had been transplanted for aplastic anaemia and two for acute leukaemia. Determinations were made of neutrophil phagocytosis, chemotaxis, random migration, and microbicidal activity for Candida albicans and Staphylococcus aureus. One patient showed a decreased ability to kill C. albicans at a time when she had active pneumonia due to Pneumocystis carinii. The remainder of the studies showed normal neutrophil functions. No differences were observed in the patients who had graft versus host disease [GvH] from those without GvH. These studies suggest that defects in phagocytic neutrophil function do not contribute significantly to the impaired host defenses in recipients of bone marrow transplantation.
Acute Disease↗