Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.69 (BMT)
2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphokine activated killer cells have potent antitumor effect both in vitro and in vivo. They have been reported to suppress bone marrow (BM) progenitor cell activity (PCA) in vitro, thus raising concern about the feasibility of their use after autologous bone marrow transplantation. The present study was carried out to evaluate the effect of LAK cells on BM engraftment in a syngeneic BMT setting in mice. LAK cells supplemented with or without exogenous interleukin-2 therapy did not impair the hematopoietic reconstitution or survival of mice undergoing BMT. LAK cells also did not reduce the PCA of the engrafted BM. LAK cell therapy did not cause graft-versus-host disease. Finally, LAK cells supplemented with IL-2 therapy improved the graft-versus-leukemia effect. These findings suggest that LAK cells plus IL-2 therapy after BMT does not impede hematopoiesis and should be evaluated as an adjuvant therapy with the aim of eradication of minimal residual disease after autologous BMT.
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PMID:Lymphokine-activated killer cells in autologous bone marrow transplantation. Evidence against inhibition of engraftment in vivo. 146 68

The present experiments were designed to investigate whether it might be possible to combine their therapeutic benefits of autologous BMT and allogeneic BMT following administration of T-lymphocyte depleted marrow allografts with additional immunotherapy following BMT. The tumor model used for investigating graft vs leukemia (GVL) effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. Immunotherapy with high dose recombinant human interleukin-2 (IL2) (10(5) Cetus units x 3/day intraperitoneally (IP) for 5 days) produced significant anti-tumor effects in BCL1-bearing mice. BALB/c mice inoculated with 10(3) BCL1 leukemia cells received were treated on day -1 with cyclophosphamide 100 mg/kg and transplanted with normal syngenic BM cells on day 0. High-dose IL2 (100,000 Cetus Units x 3/day IP x 5 consecutive days) was initiated on day +1, +7, or +21 following BMT. Optimal time for administration of IL2 was noted at 3 weeks post-BMT with 90% of the mice surviving with no evidence of disease greater than 1 year. An experimental model designed to study GVL effects in a state of minimal residual disease following T-cell depleted allogeneic BMT indicated that mice receiving low dose of BCL1 challenge (10(4] were successfully treated by either IL2 (2 x 10(4) Cetus units x 2/day IP x 3 days), allogeneic spleen cells (10(6) on day +1, 10(7) on day +5 and 5 x 10(7) on day +9) alone and certainly following a combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:IL-2 activated cell-mediated immunotherapy: control of minimal residual disease in malignant disorders by allogeneic lymphocytes and IL-2. 239 Jun 44

In the present report we have attempted to examine immunologic reconstitution following high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-purged autologous bone marrow transplantation (ABMT). By cell-surface phenotypic analysis, the majority of patients had normal percentage of natural killer cells (NK), monocytes, and CD8+ T cells at one month post-ABMT. In contrast, the percentage of CD4+ T cells was reduced for at least 3 years, and the CD4:CD8 ratio reflected this imbalance. B-cell reconstitution was slightly prolonged, with normal percentage and absolute numbers of CD20+ B cells evident by 3 months. Although B cells returned by 3 months, in vitro assessment of B-cell function demonstrated impairment of proliferative responses to either anti-immunoglobulins bound to beads (anti-Ig), Epstein-Barr virus (EBV), or interleukin-2 (IL-2) for approximately 1 year and low molecular B-cell growth factor (BCGF) for approximately 2 or more years. Moreover, in vivo B-cell reconstitution demonstrated a more selective defect, with normal levels of immunoglobulin IgM returning at 6 months, IgG at 12 months, and IgA after 2 years. Despite normal numbers of B cells and relative normal levels of Ig early following ABMT, our in vitro data suggest an intrinsic defect in B-cell responsiveness. Moreover, these defects are similar to those observed following nonpurged autologous and allogeneic BMT, although the interval of immune impairment appears more prolonged.
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PMID:Anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation for B-cell non-Hodgkin's lymphoma: phenotypic reconstitution and B-cell function. 247 24

After marrow transplantation, major histocompatibility complex (MHC)-unrestricted natural killer (NK) lymphocytes are among the first cells to appear in the circulation. After T-cell-depleted bone marrow transplantation (TD-BMT), these cells have an activated pattern of target cell killing; they also secrete lymphokines including gamma-interferon (gamma-IFN), interleukin-2 (IL-2), and tumor necrosis factor (TNF) and may have a significant role as a primary defense against viral reactivation and in the elimination of residual host malignancy. We studied 43 patients with hematologic malignancy, treated by allogeneic TD-BMT, autologous nondepleted BMT, or chemotherapy alone to investigate (a) the mechanisms underlying the generation of these activated killer cells, (b) the range of conditions under which they are produced, and (c) their surface phenotype. We showed that gamma-IFN-secreting activated killer cells with the capacity to kill MHC-nonidentical NK-resistant targets are generated 4 to 6 weeks after either allogeneic TD-BMT or autologous BMT but do not appear after treatment with chemotherapy. Production therefore is not owing to T-cell depletion per se or to host donor alloreactivity, nor is it caused by stimulation by alloantigens contained in blood product support since no significant difference exists between allograft and chemotherapy patients in the number of units of blood platelet support given in the posttreatment period. Because most patients had no evidence of stimulation from virus reactivation/infection, the phenomenon of activation therefore appears to represent posttransplant immune disregulation following repopulation of the host immune system with lymphoid subsets derived exclusively from blood and marrow. Activated killing is predominantly mediated by the CD16+ CD3- subset, but substantial activity remains in the CD16- CD3+ cell fraction. Monoclonal antibodies (MoAbs) that block interaction with class-I MHC molecules at the level of target cell (W6/32 anti-HLA class I) or effector cell (CD8) do not inhibit killing by CD16- CD3+ cells. Activated killer cells may contribute to the lower risk of relapse after marrow transplantation as compared with intensive chemotherapy.
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PMID:Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy. 249 37

We have recently reported that a combination of lymphokine-activated killer (LAK) cells and bispecific antibodies (BsAb) efficiently lysed autologous and allogeneic leukemic blasts that had surface antigens reactive with the BsAb. The effector cells used in that experiment were peripheral blood mononuclear cells stimulated with interleukin-2 (IL-2) for 2 weeks, with the initial addition of anti-CD3 moAb; these were termed T3-LAK effector cells. In this study, we examined the effects of T3-LAK cells and BsAb on autologous normal CD34+ BM cells in both cytotoxicity and colony formation assays. When T3-LAK cells were incubated with CD34+ BM cells, low levels of cytotoxicity were induced against the CD34+ BM cells and the cytotoxicity was enhanced by the addition of anti-CD3 Fab' x anti-CD 13 Fab' BsAb but not by the addition of anti-CD3 Fab' x anti-CD10 Fab' BsAb. This enhancement appeared to be due to the lysis of CD34+CD13+ BM cells. When T3-LAK cells were preincubated with CD34+ BM cells in the presence or absence of the BsAb and plated for colony assay, neither the T3-LAK cells nor the BsAb affected granulocyte-macrophage or mixed-cell colony formation by CD34+ BM cells. Taken together with our previous finding that T3-LAK cells used in combination with the BsAb markedly inhibited colony formation by leukemic progenitor cells, these results indicate that this combination provides a potential new strategy for CD34+ BM cell purging in autologous BMT.
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PMID:Combination of interleukin-2-stimulated lymphocytes and bispecific antibodies that efficiently lyse leukemic cells does not affect bone marrow CD34-positive stem cell function in vitro. 752 85

The activation of autologous cytotoxic cells by interleukin-2 (IL-2) may be a promising tool for elimination of minimal residual blast populations in patients with acute myelocytic leukemia (AML) to prolong disease-free survival. Here, we report the results of a phase II study using IL-2 for consolidation therapy in patients with second remission of de novo AML. All patients in 1st relapse of AML received a uniform induction therapy consisting of intermediate high-dose AraC (iHDAraC) 2 x 600 mg/m2 d1-4 and VP-16 100 mg/m2 d1-7. Patients achieving 2nd remission were treated with 4 cycles recombinant IL-2 (rIL-2) 9 x 10(6) IU/m2 administered on d1-5 and 8-12/cycle as 1h infusion every six weeks. In 37/66 (56%) evaluable patients, complete remission (CR) was achieved. So far, 21/37 patients (4 after additional autologous bone marrow transplantation (ABMT) received rIL-2 consolidation. Three patients are too early for evaluation, 4 received allogeneic BMT, 6 relapsed before IL-2 was scheduled and 4 refused treatment with rIL-2. The median disease-free survival (DFS) was 11 (4-49+) months. Up to now, in 5/21 (24%) patients the duration of 2nd remission exceeded that of 1st remission 7/21 (33%) are in ongoing 2nd remission (7+ to 49+ months). The side effects of rIL-2 were generally moderate and manageable. Only in two patients, previously treated with ABMT, severe side effects occurred; septicaemia and pneumonia in one patient and desquamative erythrodermia in the second one. In accordance with other studies rebound lymphocytosis with a marked increase of CD56(+)-cells and release of secondary cytokines such as TNF-alpha, IFN-gamma and IL-6 was observed. The schedule is feasible and the data suggest a possible benefit for DFS, which, however has to be confirmed by randomized trials.
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PMID:Interleukin-2 bolus infusion as late consolidation therapy in 2nd remission of acute myeloblastic leukemia. 771 35

Allogeneic T cells are capable of discriminating between leukemia cells and non-malignant hematopoetic cells. This has been concluded from clinical BMT data and demonstrated by in vitro experiments. We analyzed the frequency and specificity of leukemia-reactive T cells from syngeneic and allogeneic blood donors by limiting dilution assays for interleukin-2-producing (TH1) and cytotoxic (CTLp) T cells. Target cells were leukemia blasts obtained from a patient with common ALL. Control targets were generated by EBV transformation. Effector cells were generated from the peripheral blood of the patient in remission, from his syngeneic brother and from eight healthy, HLA-mismatched volunteers. The effector cells were stimulated with leukemia cells and interleukin-2. Neither the patient nor his brother were able to generate anti-leukemic CTLp or TH1. The HLA-mismatched allogeneic donors displayed anti-leukemic CTLp frequencies with a range from 0 to 68 million. TH1 cells with anti-leukemic specificity were not detectable. We conclude that there are great inter-individual differences in the GVL potential of fully allogeneic peripheral T lymphocytes. It is possible to identify T cell lines with reactivity against leukemia blasts and non-reactivity against normal hematological cells from the same individual. These cell lines are potential effector cells for immunotherapy of human leukemia.
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PMID:Leukemia-specific allogeneic donor T cells: quantification by limiting dilution assay. 777 7

Acute and chronic graft-versus-host disease (GVHD) are responsible for a significant fraction of the morbidity and mortality of allogeneic bone marrow transplantation. Attempts to reduce the incidence of GVHD by exhaustive T cell depletion of donor marrow have frequently been associated with an increase in graft failure and disease relapse. For the past 10 years, we have evaluated the use of a monoclonal antibody (T12) that selectively targets the CD6 determinant on mature T cells. 171 patients with hematologic malignancies have received donor marrow depleted of mature T cells with anti-CD6 and rabbit complement. Initial engraftment in recipients of HLA-matched marrow has been > 98% with 96% of patients showing stable hematologic reconstitution. The incidence of acute GVHD in this population was only 15%. Chronic GVHD has developed in 5% of patients. Overall, transplant-related mortality was 17%. Examination of peripheral blood lymphocyte reconstitution in the early post-BMT period has been helpful in predicting which patients will ultimately go on to develop GVHD. Treatment of recipients of CD6 depleted marrow with low doses of interleukin-2 post-BMT can expand the number of circulating NK cells and may be associated with a decrease in disease relapse rate.
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PMID:Selective T cell depletion of donor allogeneic marrow with anti-CD6 monoclonal antibody: rationale and results. 812 62

The efficacy of the rat monoclonal IgG2b antibody LO-Tact-1 specific for the human interleukin-2 (IL-2) receptor was evaluated for prophylaxis of graft-versus-host disease (GVHD) in patients who received transplants of marrow from HLA-matched sibling donors. Fifteen patients received cyclosporine (CsA) + antibody LO-Tact-1, 0.2 mg/kg/day from day +7 to day +28. Twelve additional patients were administered methotrexate (MTX) + CsA+antibody LO-Tact-1, 0.4 mg/kg/day from day -1 to day +28. The antibody was well tolerated. Engraftment was not affected. GVHD grade > or = II occurred in six of 15 and eight of 12 patients receiving CsA+LO-Tact-1 and MTX+CsA+LO-Tact-1, respectively (P = 0.52). GVHD grade > or = II developed in patients at a median of 32 and 34 days with CsA+LO-Tact-1 and MTX+CsA+LO-Tact-1, respectively (log-rank test, P = 0.57). GVHD contributed to death in four patients who were administered CsA+LO-Tact-1 and in one patient who was administered MTX+CsA+LO-Tact-1. Chronic GVHD occurred in two patients who were treated with CsA+LO-Tact-1 and in two patients treated with MTX+CsA+LO-Tact-1. Throughout therapy, serum levels of LO-Tact-1 ranged from 2 to 10 mg/l. There was no correlation between serum levels of LO-Tact-1 and the occurrence of GVHD. GVHD occurred in 10 patients during LO-Tact-1 prophylaxis. There was no significant difference between relapse or survival rates among the patient groups. We conclude that, while free of adverse effects, monoclonal anti-IL-2 receptor antibody LO-Tact-1 does not improve prophylaxis of GVHD in HLA-matched sibling BMT.
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PMID:Prophylaxis of graft-versus-host disease in identical sibling donor bone marrow transplant by anti-IL-2 receptor monoclonal antibody LO-Tact-1. 852 75

Soluble interleukin-2 receptors (sIL-2R) are elevated in various disorders involving the activation of T cells. We measured serial serum concentrations of sIL-2R in 30 patients receiving allogeneic BMT to evaluate the usefulness of sIL-2R as a parameter for acute GVHD. In the 17 patients who developed acute GVHD, the sIL-2R concentration rose significantly on day 3 following transplantation, preceding the occurrence of acute GVHD. This change was not seen in the 13 patients without acute GVHD. The serum concentration of sIL-2R decreased as the acute GVHD subsided. The peak concentration of serum sIL-2R correlated with the severity of the acute GVHD. Simultaneous measurement of tumor necrosis factor alpha (TNF alpha) showed a significant rise in patients with acute GVHD, that became evident earlier than the sIL-2R elevation. TNF alpha concentrations also decreased following treatment of the acute GVHD. However, significant rise in TNF alpha were also seen in the early phase of allogeneic BMT in patients who did not develop acute GVHD. Our data suggest that the serum concentrations of sIL-2R as well as TNF alpha might reflect the severity of acute GVHD, and that the serum sIL-2R concentration might be a sensitive and practical indicator for acute GVHD.
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PMID:Serum concentration of the soluble interleukin-2 receptor for monitoring acute graft-versus-host disease. 864 Jan 64


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