Biomedical subjects
Publications and source records attributed to A Marmont.
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The aim of the present study was to compare the response of bone marrow (BM) lymphocytes from patients with aplastic anemia (AA) or normal controls to increasing doses of antilymphocyte globulin (ALG) or phytohemagglutinin (PHA). For this purpose BM T-enriched cells from 11 AA patients and 9 normal individuals were incubated with ALG (0-1000 micrograms/ml) or PHA (0%-10%) for 1 day, and the supernatants were tested for suppression/enhancement of granulocyte-macrophage colony-forming unit (CFU-GM) growth and for release of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) assayed with the enzyme-amplified sensitivity immunoassay (EASI). The production of colony-stimulating activity (CSA) by T cells primed with ALG and tested in the absence of exogenous GM-CSF correlated with the dose of ALG in priming cultures up to 14% EG (100% EG = CFU-GM growth with 30 ng/ml of GM-CSF). The amount of GM-CSF in the supernatants paralleled their capacity to sustain CFU-GM growth (up to 3.5 ng/ml of GM-CSF). Production of CSA or GM-CSF from T cells primed with PHA was significantly lower. Supernatants of PHA-primed T cells, when added to normal BM cells in the presence of exogenous GM-CSF, produced a dose-dependent inhibition of CFU-GM growth (down to 13% +/- 10% EG). The same supernatants contained detectable amounts of IFN-gamma and TNF-alpha (21 +/- 6.7 IU/ml and 4.6 +/- 2.9 ng/ml, respectively). IFN-gamma production from severe AA (SAA) T cells in response to PHA was significantly superior to the IFN-gamma production from normal T cells (21 +/- 6.7 IU/ml vs 9.5 +/- 7.1 IU/ml, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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Thirty-nine patients with acute myeloblastic leukemia (AML) in first complete remission (CR) were treated by autologous bone marrow transplantation. All patients received the same induction and consolidation chemotherapy consisting of a combination of daunorubicin (DNR) and cytarabine (Ara-C) followed by four courses of DNR, Ara-C and 6-thioguanine (6-TG). Two different conditioning regimens were used; 25 patients were submitted to the BAVC regimen (BCNU, amsacrine, VP-16 (etoposide) and Ara-C) and 14 to a cyclophosphamide/total body irradiation (CY + TBI) regimen. Six patients (one treated with BAVC and five treated with CY + TBI) died in aplasia. Twelve of the 25 BAVC treated patients and one of the nine CY + TBI treated patients relapsed; 12 (48%) of the BAVC treated patients are in CR with a median follow-up of 45 months and eight (57%) of the CY + TBI treated patients are in CR with a median follow-up of 50 months. All patients in CR have survived for more than 2 years since transplant.
T cell clones (n = 456) were derived from 9 patients following allogeneic bone marrow transplantation (BMT) with or without acute graft versus host disease (aGVHD) and from 4 healthy donors. The cloning efficiency was 63.2% in controls, 13.2% and 12.1% in patients with or without aGVHD. Once established, T cell clones were typed for surface markers (CD3, CD4, CD8) and tested for production of IL-2 and expression of cytolytic activities in a lectin-dependent cellular cytotoxicity assay (LDCC) and against the K562 target cell line to detect natural killer activity. We found the expected imbalance of CD4/CD8 clones in BMT patients, as compared to controls. A higher proportion of IL-2-producing clones was observed in patients with aGVHD (83.5%; P less than 0.02) as compared to patients without aGVHD (64.8%) and controls (68.5%). No major differences were found in terms of LDCC, whereas an increased percentage of clones with NK-like activity was found in patients with aGVHD (34.7%, P less than 0.05) as compared to patients without aGVHD (29.5%) and controls (21.3%). The clones were also tested for inhibition of IL-2 production mediated by cyclosporine. Such inhibition could be obtained in virtually all clones both in patients with or without aGVHD, suggesting that the latter is probably not due to the emergence of CsA-resistant clones. In conclusion, this study demonstrates a low cloning efficiency in BMT patients associated with the well-known CD4/CD8 imbalance. A higher production of IL-2, an increased NK activity, but not the presence of CsA-resistant clones appear to differentiate patients with from patients without aGVHD.
UNLABELLED: The aim of this study was twofold: (a) to test the effect of antilymphocyte globulin (ALG) on bone marrow (BM) T/non-T cells, and (b) to look for a possible differential response of cells from severe aplastic anaemia (SAA) patients and controls. For this purpose bone marrow T/non-T cells from normal individuals (n = 7) or aplastic patients (SAA, n = 13) were kept in liquid culture with or without ALG. Supernatants were then tested for enhancement/suppression on colony forming unit, granulocyte-macrophage (CFU-GM) growth (in the presence of exogenous recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF)), or for their ability to support CFU-GM growth (in the absence of exogenous rGM-CSF). Supernatants from SAA T cells suppressed CFU-GM growth of normal bone marrow cells in 5/12 patients (mean expected growth (EG) 71 +/- 16%), but not after incubation with ALG (mean 110 +/- 29% EG, P = 0.03). No inhibition could be obtained with the supernatants from untreated normal T cells. Significant enhancement was seen with ALG treated versus untreated SAA T cells (142 +/- 28% EG v. 105 +/- 61% EG, P = 0.01) and with ALG treated versus untreated SAA non-T cells (165 +/- 26% EG v. 105 +/- 23% EG, P = 0.01), but not in controls. Supernatants from SAA and control T/non-T cells were capable of promoting colony formation in the absence of rGM-CSF (colony-stimulating activity (CSA) production): 16 +/- 14% for SAA-T cells and 19 +/- 18% EG for non-T cells (100% = 30 ng rGM-CSF/ml). The addition of ALG increased CSA production in T cells to 37 +/- 23% EG (P = 0.04) and in non-T cells to 40 +/- 13% EG (P = 0.04). Similar results could be obtained in controls. IN CONCLUSION: (a) ALG interacts in vitro with bone marrow T and non-T cells from SAA patients, down-regulating the production of negative lymphokines and enhancing the release of haemopoietins; (b) the latter, but not the former effect, can be shown also with cells from normal controls. The two effects are not mutually exclusive, and are likely to provide maximal benefit in vivo.
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The cytogenetic and clinical course of three patients allografted for Ph positive chronic myeloid leukaemia are reported. All patients had a peculiar pattern of relapse. Two out of three patients had donor marrow graft pretreated with monoclonal antibody for graft versus host prevention. The cytogenetic relapse was invariably associated with major morphological changes in the marrow indicating that these were also haematological relapses. However, no changes in the peripheral blood count were observed. When relapse occurred in these patients, Ph positive marrow metaphases and host red blood cells ranged from 75% to 100% of the total cell population: thereafter they spontaneously reverted to complete chimaerism. Therefore the presence of leukaemic cells even in considerable amount was not sufficient, per se, to prevail over normal marrow. In addition these observations indicate that relapse was not associated with elimination of the graft: while haemopoiesis was entirely of recipient origin the donor normal stem cells were present and vital although functionally silent. These data suggest that, although TBI remains the more effective tool for eradicating the majority of leukaemic cells, haemopoietic competition between host and donor marrow may have a major impact on leukaemic relapse.
One hundred patients with chronic myeloid leukemia (CML) submitted to bone marrow transplantation (BMT) were included in a cooperative cytogenetic study. Relapse (defined on the basis of hematological and cytogenetic findings) occurred in 24 (24%) patients at different intervals after BMT. In 18 of these patients (studied on average 3.3 times between BMT and relapse) no Ph-positive metaphases were detected before relapse. Sixteen (75%) of the patients relapsed with the same chromosomal pattern as that seen before BMT; eight patients, of whom five relapsed in blast crisis, showed additional chromosomal abnormalities resembling those seen in non-transplanted patients. One of these patients relapsed in cells of donor origin. After recognition of relapse, various hematological and cytogenetic patterns were observed. Four patients showed spontaneous reversion to normal (donor-type) chromosomes and hematology. Two other patients were followed for prolonged periods with hypercellular marrows with more than 50% Ph-positive cells but with normal peripheral blood values. The majority of patients proceeded to clinical relapse and required treatment with chemotherapy. We conclude that the isolated finding of a minority of Ph-positive metaphases after BMT should not be classified as relapse; for patients who do relapse, the sequence of cytogenetic and hematological events thereafter is variable.
Bone-marrow transplantation has been used in patients with acute lymphoblastic leukaemia (ALL) thought to be at high risk of relapse if managed with chemotherapy. Data from 444 ALL patients with one or more high-risk features at diagnosis were analysed to evaluate outcome after HLA-identical bone-marrow transplantation during first or during second remission. The 4-year actuarial probability of leukaemia-free survival was 45% (95% confidence interval 36-54%) for transplants in first remission compared with 22% (15-29%) for those in second remission (p less than 0.0002). The 4-year probabilities of relapse were 26% (14-38%) and 56% (45-67%) respectively (p less than 0.0001). For high-risk ALL, transplantation in first remission had clearly superior results to transplantation in second remission. Further studies are needed to determine whether patients with high-risk ALL should receive transplants during first remission or should initially receive chemotherapy, with transplantation being reserved for patients who relapse.
Treatment of severe aplastic anemia (SAA) in Europe between 1970 and 1986 is reviewed. 487 patients received an HLA-identical BMT: results are encouraging and currently suggest a 65% survival. However, many patients cannot be offered this procedure because of the absence of an appropriate donor. Forty-five patients were given a non-HLA identical BMT: results are dependent on the degree of mismatch. Immunosuppression (IS) was given to 509 patients: 50% of these survive. Some mechanisms regulating in vitro hematopoiesis are discussed, together with their relevance in the treatment of SAA.
High-resolution chromosome banding studies were carried out on leukemic cells from a young patient with acute nonlymphocytic leukemia (ANLL), M2 of the FAB classification. A new chromosomal abnormality involving a translocation between chromosomes 3 and 21 was observed, i.e., t(3;21)(p14;q22). A complete remission was never obtained in spite of aggressive chemotherapy and the patient died 8 months after diagnosis.
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