Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.69 (BMT)
 2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We observed that effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells on BMT-11, a fibrosarcoma in C57BL/6 mice were improved by combination with cyclophosphamide (CY)-chemotherapy corresponding to enhanced accumulation at tumor sites of LAK cells. On the other hand, cytotoxic T lymphocytes (CTLs) which were able to accumulate at tumor sites more densely than LAK cells produced significant therapeutic effects by themselves. We have also found observed that LAK-attractant activity was detected in conditioned medium (CM) of CY-treated tumor tissue but not in the CM of untreated tumor tissue. These findings reveal that CY-chemotherapy facilitates LAK-attractant-production and enhances the accumulation in tumor tissue of LAK cells and that therapeutic effects of adoptive transfer of LAK cells are augmented by cancer chemotherapy through the enhanced accumulation of LAK cells.
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PMID:Augmented accumulation of transferred lymphokine-activated killer (LAK) cells at murine tumor sites through production of LAK-attractant facilitated by chemotherapy. 130 28

We studied the therapeutic effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells combined with chemotherapy on BMT-11 fibrosarcoma in C57BL/6 mice. Compared with the untreated group, no significant therapeutic effect was brought about by CY therapy alone or LAK.rIL-2 alone and all mice belonging to these three groups died with a mean survival time (MST) of 45.3, 51.8 and 45.9 days respectively. CY plus LAK.rIL-2 brought about complete cures in 3 out of 8 mice (37.5%) and a significant prolongation of MST of mice which died (64.4 days) and the accumulation of LAK cells (% Dose/g) at tumor sites was enhanced more than 7-fold by combination with CY. On the other hand, the therapeutic effects of cytotoxic T lymphocytes (CTLs) was sufficiently high even in the CTL.rIL-2 alone and were only slightly enhanced by combination with CY compared with LAK cells. Also, we detected LAK-attractant activity in the conditioned medium (CM) of CY-treated tumor tissues but not in that of untreated tumor tissues, and peak activity was reached 5 days after CY-treatment. This attractant activity was located in two major 10,000-50,000 M. W. fractions of CM. We then observed that LAK-attractant was produced in CM of host reactive cell enriched fractions from CY-treated tumor tissues, but not in that of tumor cell enriched fractions. The above findings imply that the effects of adoptive immunotherapy depend upon the accumulation of transferred effector cells at tumor sites, and we believe that the production of LAK-attractant by tumor tissue, facilitated by chemotherapy, is one of the mechanisms responsible for enhanced LAK-cell-accumulation at tumor sites. We performed a preliminary clinical trial with adriamycin, autologous spleen-LAK cells and rIL-2 on 30 hepatocellular carcinoma patients after radical resection on the basis of the experimental results above. There were no significant therapeutic effects after adoptive immunotherapy during the postoperative course but tendency for temporary inhibition of recurrence. Thus it is shown that this method has probable value as effective adjuvant postoperative therapy.
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PMID:[Studies on lymphokine-activated killer (LAK) cell: accumulation in tumor tissue and the therapeutic effects of adoptive immunotherapy]. 133 Aug 59

Serum levels of interferon-gamma and the IFN-dependent marker molecules neopterin and beta 2-microglobulin were assessed in BMT recipients. Concentrations of the latter two markers were corrected for creatinine levels in order to eliminate the impact of alteration of kidney function. Serum levels were assessed daily using commercially available radioimmunoassays. Twelve patients were studied during the early phase of allogeneic bone marrow transplantation and eleven additional patients during complications of BMT. Results indicated that both the conditioning regimen for BMT as well as major clinical complications such as infection and acute graft-versus-host disease strongly influence the endogenous patterns of the lymphokine and its secondary messages. During allogeneic BMT IFN-gamma and neopterin levels exhibited a biphasic pattern with a first peak during conditioning with high-dose cyclophosphamide and a second still higher peak at the time of hemopoietic regeneration. beta-2-microglobulin ratios increased during conditioning and remained elevated throughout observation. Serious infections of bacterial and viral origin as well as GvHD were accompanied by elevated levels of all three serum parameters studied. The kinetics of enhanced endogenous production, however, differed between infectious complications and GvHD. Increasing concentrations were observed during infections subsequent to clinical manifestation, whereas they preceded disease manifestation in GvHD.
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PMID:Endogenous IFN-gamma during human bone marrow transplantation. Analysis of serum levels of interferon and interferon-dependent secondary messages. 217 Nov 63

We have previously reported that both regressor (QR) and progressor (metastatic, QP) clones were obtained after the in vitro exposure of a mouse fibrosarcoma BMT-11 cl-9 to quercetin. In this study, we investigated possible mechanisms of spontaneous regression of QR clones as compared with tumorigenic QP and BMT-11 cl-9 tumor clones. We observed that BMT-11 cl-9 cells produced relatively high amounts of prostaglandin E2 (PGE2) during in vitro culture. The average production by 11 subclones of BMT-11 cl-9 cells was 9236 +/- 2829 pg/ml whereas that by 9 QR clones was 3411 +/- 2213 pg/ml (P less than 0.02). Indomethacin not only inhibited in vitro PGE2 synthesis by QP clones (high-PGE2 producers) but also the s.c. growth of QP clones in mice. Chronological changes in host immune responses to tumor-associated antigen were measured by cytotoxic T lymphocyte (CTL) activity examined after mixed lymphocyte/tumor cell culture of spleen cells obtained from tumor-bearing mice. The CTL activity disappeared abruptly in the spleen of QP-clone-bearing mice 21 days after the inoculation of tumors, whereas the spleen cells of QR-clone-inoculated mice retained their CTL activity. We determined that the mechanism responsible for the regression of these regressor clones is not due to any qualitative or quantitative increase in pre-existing membrane antigens, nor the emergence of new antigen(s) on the cell surface of the QR clones: nor was it due to enhanced susceptibility of QR clones to natural killer cells, lymphokine-activated killer cells and macrophages. These finding suggest that the regression mechanism of QR clones may be the diminished inhibition of host response to tumor-associated antigen caused by the reduced production of PGE2 by QR clones.
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PMID:Regression mechanisms of mouse fibrosarcoma cells after in vitro exposure to quercetin: diminution of tumorigenicity with a corresponding decrease in the production of prostaglandin E2. 238 81

Clinical and experimental data suggest a role for the immune response in preventing leukemic relapses following allogeneic bone marrow transplantation the graft-versus-leukemia (GVL) effect. In the context of an allogeneic BMT, a number of different immune mechanisms mediated by donor cells may be responsible for the GVL effect. We have approached this question by using limiting dilution cultures of alloactivated human lymphocytes to analyze the in vitro allogeneic cytolytic response against fresh allogeneic leukemia. Initial results in the limiting dilution assays with split culture analyses demonstrated frequent alloreactive cytolytic T lymphocyte precursors that destroyed remission peripheral blood lymphocytes and leukemic cells from the allogeneic leukemic patient. These assays also demonstrated frequent lymphokine-activated killer (LAK) cell precursors that lysed both the LAK sensitive Daudi line and the allogeneic leukemia. In these experiments, isolated cultures also showed cytolytic activity directed against the allogeneic leukemic blasts without activity against remission PBL, or the LAK-sensitive Daudi cell line. Two T cell lines (ABL1 and ABL2) isolated from an LDA, demonstrated this form of specificity, mediating destruction specifically against the allogeneic acute lymphoblastic leukemic cells. Both cell lines ABL1 and ABL2 were CD3+, TCR alpha beta +, and CD4+. These 2 cell lines mediated little or no cytotoxicity against a large panel of other targets tested (natural killer sensitive and resistant cell lines, allogeneic PBL, and allogeneic fresh leukemic blasts). Antibody-blocking experiments revealed a role for the CD3-TCR receptor of both cell lines in lysis of leukemic cells; the CD4 and MHC class II molecules were clearly involved in the lysis by the ABL1 cell line. Specificity of recognition for the allogeneic leukemic blasts was further confirmed by unlabeled target competitive inhibition studies. The mechanism of the preferential lysis of leukemia by the alloactivated T cell lines described in this paper remains uncertain. Nevertheless, these leukemic-specific populations provide a means by which the human GVL effect may be further studied in vitro.
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PMID:Specific recognition of human leukemic cells by allogeneic T cell lines. 257 Dec 6

A boy with combined immunodeficiency having low natural killer (NK)-cell activity received thymopoietin pentapeptide (TP-5) treatment, transplanted with T cell-depleted HLA-haploidentical bone marrow (BMT) cells from his father and with thymus tissue from an infant at different times during the first year of life. He showed a marked increase in large granular lymphocytes (LGL) both during the treatment with TP-5 and after BMT. The LGL generated following TP-5 injection had a T3+Leu11- surface phenotype and low NK activity. In contrast, the LGL appearing after BMT showed T3-, Leu7+, and/or Leu11+ surface phenotypes, had high NK- and K-cell activities, and were lymphokine-activated killer (LAK)-cell precursors. These killer activities were assigned to the Leu7-Leu11+ subset and proved to be of recipient origin. LGL proliferation following BMT was accompanied by neutropenia, which was improved in association with a reduction in the number of LGL and the appearance of T cells of BMT donor origin following thymus transplantation. This suggested the inhibition of granulopoiesis by the LGL and an in vitro study revealed that the Leu7+Leu11- subset of LGL suppressed the growth of granulocyte/macrophage colony-forming units. These results indicated that phenotypically different LGL could be generated by different treatments and that the LGL showing NK activity were distinct from those regulating granulopoiesis. It was also suggested that the generation of LGL was controlled by T cells.
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PMID:Phenotypical and functional heterogeneity of the large granular lymphocytes increased after various treatments in a patient with combined immunodeficiency. 264 8

During the early period following bone marrow transplantation before the immune system has reached full functional maturity, unprimed, nonspecific lytic systems may play a critical role as antiviral or antitumor effectors. The reconstitution of cells with this potential is of particular importance in recipients of bone marrow that has been depleted of mature T lymphocytes to prevent graft v host disease (GVHD). We examined the recovery of natural killer (NK) cells and interleukin 2 (IL 2)-augmented lymphokine-activated killer cells (LAK) in 48 patients at various intervals following transplantation of bone marrow depleted of mature cellular elements by treatment with soybean agglutinin and sheep RBCs (SBA-E- BMT). We found normal levels of both NK and LAK activity as early as 3 weeks following SBA-E- BMT. When compared with cells from controls, NK and LAK precursors from transplant recipients appeared to be activated in vivo in that freshly isolated peripheral blood mononuclear cells (PBMCs) from patients had an elevated cytolytic activity toward NK-insensitive targets and a more rapid response to activation by IL 2. In patients as well as controls, both LAK precursors and LAK effectors lacked antigens present on mature T lymphocytes (CD3, CD4, or CD8) but expressed antigens present on NK cells (CD2, CD16, and NKH1A). The LAK cells did not lyse either donor or host peripheral blood T cell targets. The activity of NK effectors but not LAK precursors survived the in vivo total body irradiation used for pretransplant conditioning in three patients studied. LAK precursors could be demonstrated as early as 18 days following transplant at a time when the bone marrow contained primarily donor-derived cells. Little or no LAK activity could be generated from cells of the SBA-E- BM graft itself, suggesting that LAK precursors differentiate rapidly from more primitive progenitors in the marrow graft. Thus, our data indicate that the NK and LAK lytic systems are among the earliest activities to recover during immune reconstitution following T cell-depleted BMTs.
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PMID:Interleukin 2-activated killer cells in patients following transplants of soybean lectin-separated and E rosette-depleted bone marrow. 311 90

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

Donor leukocyte infusions (DLI) were used to treat 2 patients with AML who relapsed within 4 months of treatment with partially mismatched related donor (PMRD) BMT representing 1-2 HLA-mismatches. No other form of cytoreductive therapy was given to these patients. Both patients developed GVHD (grade II-III) following DLI requiring steroid therapy. One of these patients went into complete remission following development of GVHD and immunophenotypic analysis of peripheral blood showed increased numbers of CD3+/CD8+ T cells, CD56+/CD8+ lymphokine activated killer (LAK) cells and CD16+/CD56+ natural killer (NK) cells expressing intermediate affinity IL-2 receptor P75. Unfortunately, the response was of short duration and the patient relapsed 8 weeks later ultimately resulting in death. The second patient did not show any response to DLI and died of progressive leukemia in conjunction with active GVHD. We conclude that DLI from PMRD carries a high risk for the development of GVHD and may have an anti-leukemia effect for relapsed AML. The anti-leukemic effect from PMRD DLI may be mediated by cytotoxic T lymphocytes, LAK cells and NK cells.
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PMID:Immunotherapy with donor leukocyte infusions for patients with relapsed acute myeloid leukemia following partially mismatched related donor bone marrow transplantation. 758 Nov 1

We have previously reported that cancer chemotherapy prior to lymphokine activated-killer (LAK) cell-transfer gave synergistic increase in therapeutic effects of LAK adoptive immunotherapy on transplanted tumors, BMT-11 fibrosarcoma and 3LL lung carcinoma, in C57 BL/6 mice, and that transferred LAK cell-accumulation into tumor tissues was enhanced by treatment with anti-cancer drugs. The author tried to analyze mechanisms responsible for the enhanced LAK cell-accumulation into tumor tissues after chemotherapy by under agarose migration assay and LAK migration inhibitory assay. The author detected a chemotactic factor for LAK cells (LAK-attractant) and a migration inhibitory factor for LAK cells (LAK-MIF) in the conditioned medium of tumor tissues from mice treated with various anti-cancer drugs, which was not found in that of untreated tumor tissues. Since mRNA expression for transforming growth factor-beta 1 (TGF-beta 1) was found to enhance in tumor tissues after chemotherapy through RT-PCR, the author examined a possible participation of TGF-beta 1 as LAK-attractant in tumor tissues of mice treated with cyclophosphamide. Recombinant human TGF-beta 1 showed LAK-attractant activity, and anti-TGF-beta 1 antibody inhibited LAK-attractant activity in the conditioned medium. These findings indicate that TGF-beta 1 produced in tumor tissues of mice treated with anti-cancer drugs may be one of LAK-attractants. On the other hand, LAK-MIF activity was concentrated in the fraction of less than 3kDa which is a smaller molecule than that of TGF-beta 1. These findings suggest that both TGF-beta 1 and LAK-MIF produced in tumor tissues after chemotherapy contributed to the enhanced accumulation of transferred LAK cells into tumor tissues after the chemotherapy.
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PMID:[Mechanisms of enhanced accumulation of transferred LAK cells into tumor sites after chemotherapy]. 759 Jun 1


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