Biomedical subjects
M Y Gordon
Publications and source records attributed to M Y Gordon.
Bone marrow fibroblastoid colony-forming cells (F-CFC) in aplastic anaemia: colony growth and stimulation of granulocyte-macrophage colony-forming cells (GM-CFC).
Colonies of fibroblast-like cells have been grown from the mononuclear cell fractions of bone marrow aspirated from normal individuals and patients with aplastic anaemia. Some of the characteristics of the fibroblastoid cells have been determined and their granulocyte-macrophage colony-stimulating activity (CSA) in semi-solid agar culture has been used as a functional test of their influence on granulopoiesis. The incidence and growth rates of fibroblastoid colony-forming cells (F-CFC) from aplastic patients' bone marrows were markedly different form normal either before or after treatment by allogeneic bone marrow transplantation or with antilymphocyte globulin (ALG). Confluent monolayers of fibroblastoid cells grown from normal marrow were, on the whole, poor stimulators of granulocyte-macrophage colony-forming cells (GM-CFC) and CSA was not detected in the supernatant medium. Fibroblastoid monolayers derived from many of the aplastic bone marrows studied were efficient stimulators of GM-CFC but, like the monolayers grown from normal cells, did not release CSA into the culture medium. Addition of methylprednisolone (MP) to the cultures had little effect on fibroblastoid cell growth, induced fat-accumulation by some of the fibroblastoid colonies comprising the monolayer and reduced the abilities of the monolayers to stimulate GM-CFC.
Abnormal adherent cell function in aplastic anaemia demonstrated using levamisole in cultures for T lymphocyte colony-forming cells (TL-CFC).
The effect of levamisole on T lymphocyte colony-forming cells (TL-CFC) is determined by the numbers or function of plastic-adherent mononuclear cells in the culture. Using levamisole in cultures of TL-CFC from patients with aplastic anaemia, we have detected a response which is not shown by cells from healthy individuals. Normal TL-CFC produced a biphasic dose-response curve made up of an initial reduction and a secondary return to control values. Similar results were obtained when plastic-adherent cells were treated with the drug before being incorporated into cultures of adherent cell-depleted, untreated TL-CFC. In contrast, colony yields were enhanced by levamisole if plastic-adherent cells were removed before culture or treated, non-adherent TL-CFC were cultured with untreated adherent cells. Cells from aplastic patients contained few TL-CFC but their numbers were enhanced by levamisole and the dose-response curves were similar to those of adherent cell-depleted normal cells and those seen when TL-CFC, but not adherent cells, were exposed to the compound. However, when normal adherent cells were added to cultures of patients' cells, the response resembled the normal biphasic curve. The results suggest that certain T cell functions may be compromised in aplastic anaemia as a result of monocyte dysfunction.
Effects of levamisole on T lymphocyte colony formation by cells from bone marrow aspirates.
Levamisole has been added to cultures of bone marrow and peripheral blood mononuclear cells stimulated by phytohaemagglutinin (PHA). T lymphocytes colony-forming cells (TL-CFC) in the peripheral blood produce a characteristic biphasic dose--response curve in cultures containing levamisole but the characteristics of the dose--response curve seen when levamisole is added to mononuclear cells obtained from bone marrow aspirates are strikingly different. The results suggest that the mixtures of bone marrow and blood obtained by aspiration contain different proportions of the cells which influence TL-CFC than either blood, or by implication, bone marrow alone.
Mononuclear phagocytes and the production of colony-stimulating activity by T-lymphocytes.
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Bone marrow fibroblasts, fat cells and colony-stimulating activity.
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The use of a T lymphocyte colony assay to measure mononuclear phagocyte function.
The control of colony formation of normal PHA-stimulated lymphocytes has been investigated using a liquid-on-agar culture system (Lowenberg & De Zeeuw, 1979). Optimal colony formation requires the presence of mononuclear cells which were characterized by their ability to adhere to plastic surfaces. This finding suggests that the assay system can be used to estimate the co-operative function of mononuclear phagocytes as well as to enumerate T lymphocyte colony-forming cells (TL-CFC). Both the capacities of the mononuclear cells to promote colony formation and the colony-forming abilities of T cells varied widely between different normal individuals. Studies in patients with haemopoietic deficiencies showed that the growth of TL-CFC can be used to distinguish between a real lack of colony-forming cells and an apparent reduction, secondary to mononuclear cell depletion.
A simple method for quantitating endogenous CSA.
The enhanced colony-formation by human bone marrow cells in vitro, produced by the addition of lysed rat red blood cells, has been shown to be due to an increase in the sensitivity of the colony-forming cells (CFUc) to colony-stimulating activity (CSA). Rat red cell lysate does not contain CSA, nor does it increase CSA production by cells. The sensitivity of colong-forming cells is sufficiently increased by the lysate to give colony-formation in the absence of any added source of CSA. Consequently, it is possible to assay for locally produced (endogenous) CSA without the need for cell separation and the complications this entails. Furthermore, the linear relationship between the numbers of cells plated and the colony yield simplifies the quantitative interpretation of the results.
Selective effects of cyclosporin A on colony-forming lymphoid and myeloid cells in man.
THE properties of the fungus metabolite, cyclosporin A, have suggested its potential as a clinically valuable immunosup-pressive agent(1,2). Experiments in animals have demonstrated that its suppressive action against cell-mediated and humoral immunity is not accompanied by any appreciable myelotoxicity(3,4). In this respect, cyclosporin A contrasts with other immunosuppressants in current use, such as antilymphocyte globulin and azathioprine. There are, however, few data to substantiate a selective toxicity of cyclosporin A against human lymphocytes. Here, we have compared its effects against human lymphoid and myeloid cells, using colony formation by the different cell types as the end point. We found that the compound exhibited far greater toxicity towards a sub-population of T cells than towards either B lymphocytes or haematopoietic precursor cells.
Serum inhibitors in aplastic anaemia.
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Marrow autotransplantation accelerates haematological recovery in patients with malignant melanoma treated with high-dose melphalan.
In a Phase I study, melphalan 140 mg/m2 was administered to 8 patients with disseminated malignant melanoma. Marrow was removed from the patients immediately before melphalan administration and returned i.v. 8 h later. Studies on marrow culture and melphalan pharmacokinetics predicted that this was a safe time to administer non-cryopreserved marrow. Four patients received lower doses of i.v. melphalan without autologous marrow. In the group receiving autologous marrow the time for recovery of peripheral-blood granulocytes to 800/mm2 or greater was significantly less (P = 0.01) than in those not receiving marrow. In 7 patients the tumour showed evidence of response to the drug and there was 1 complete remission. This treatment deserves investigation in patients with tumours more sensitive to drugs than melanoma.
Removal of myelotoxicity from antilymphocytic sera.
Antilymphocyte sera (ALS) were prepared by different methods and examined for their myelotoxicity by bone marrow colony-forming assay, both before and after absorption with B cell antigens. The results show that myelotoxicity can readily be removed from some, but not all, ALS. The source of antigen and the immunisation protocol used determine the degree of myelotoxicity and hence the number of absorptions required. Non-myelotoxic ALS may be suitable for the prevention of graft-versus-host disease (GVHD) by in vitro treatment of bone marrow before transplantation.
Relevance of colony forming assays to bone marrow transplanation with particular reference to grafting for aplastic anaemia.
The value of bone marrow colony-forming assays in monitoring transplanted patients has been assessed by comparing results from two pairs of bone marrow recipients. One pair received marrow from their identical twins for acute lymphoblastic leukaemia; the other pair were grafted with allogeneic marrow from their siblings for aplastic anaemia. One of each pair showed successful engraftment while in the others the grafts failed. The colony-forming assay was then used to investigate marrow function in five grafted aplastic patients. Of these, four rejected their first grafts and required further immunosuppression before engraftment could be accomplished. The remaining patient was immunosuppressed at the outset with antithymocyte globulin (ATG) and her first graft was successful. Sera from all five patients inhibited colony formation by normal human marrow and it is suggested that this activity was related to graft rejection as well as to the pathogenesis of the condition.
High dose melphalan and non-cryopreserved autologous bone marrow treatment of malignant melanoma and neuroblastoma.
Autologous non-cryopreserved bone marrow infused 8 hours after an intravenous injection of melphalan, 140 mg/m2, accelerates bone marrow recovery. This effect is most noticeable in the recovery of peripheral blood granulocytes. Twenty patients with disseminated malignant melanoma were treated with this regimen: there were 12 responses, two of them complete but the toxicity of the treatment was not sufficient to justify using this method of treatment routinely since survival was little influenced by treatment (4-11 months). In 8 patients with disseminated neuroblastoma, high dose melphalan/autograft was used in a program of combined modality treatment. Three of the patients are disease free at 16, 11 and 6 months and in one the disease is 'static', not having grown for 13 months. The treatment for this tumour deserves further exploration, and perhaps similar treatment ought to be explored for other tumours.
Acceleration of bone-marrow recovery by pre-treatment with cyclophosphamide in patients receiving high-dose melphalan.
7 patients with advanced malignant melanoma who were given cyclophosphamide (500 mg intravenously) 7 days before a high dose of melphalan (140 mg/m2) had a more rapid recovery of the peripheral white-cell count than did 4 patients who received melphalan alone. "Priming" by cyclophosphamide might be a practicable means of offsetting the bone-marrow toxicity of some chemotherapy regimens and it may permit higher doses of drugs to be given safely.
Effect of medium conditioned by acute myeloid leukaemia cells on normal marrow colony-forming ability and sensitivity to cytosine arabinoside.
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Human bone marrow colony formation in diffusion chambers. Normal values.
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Circulating inhibitors of granulopoiesis in patients with aplastic anaemia.
An inhibitor of granulopoiesis has been detected in the serum of aplastic patients by its ability to reduce colony formation by normal human marrow cells in culture. The inhibitory activity in the serum was abolished when a patient was treated with azathioprine and exposure of aplastic marrow to antithymocyte globulin (ATG) in vitro released the colony forming cells from suppression. The clinical findings in three of the patients studied support the idea that the inhibitory activity detected in vitro is associated with normal marrow suppression in vivo.