Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relationship between MHC class I antigen expression on PBLs from leukemia patients and their susceptibility to lysis by LAK cells was investigated. LAK cells induced small yet significant lysis of leukemic cells. In nine out of 14 cases studied, treatment with Interferon gamma (200 U/ml for 48 hours) resulted in a decrease in the LAK susceptibility of leukemic cells. In six of these cases, there was a concomitant increase in the expression of class I MHC antigen expression. In three samples, the increase in MHC class I antigen expression was not accompanied by a decrease in LAK susceptibility. IFN treatment had no effect on the binding of leukemic cells to LAK effector cells.
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PMID:Effect of gamma interferon on the expression of class I MHC antigens on fresh leukemic cells and their susceptibility to lysis by lymphokine activated killer cells. 792 56

The plasma soluble interleukin 2 receptor (sIL-2R) level and its relationships with haematologic and immunologic data were examined in 40 patients with myelodysplastic syndromes (MDS). The plasma sIL-2R level was significantly higher in the high-risk MDS group (refractory anaemia with excess blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia) than in the low-risk MDS group (refractory anaemia (RA) and RA with ringed sideroblasts) or in normal subjects, although there was considerable variation in the plasma sIL-2R level within each MDS group. The plasma sIL-2R level correlated positively with the bone marrow cellularity and bone marrow blast mass, but not with the absolute number of CD25+ lymphocytes. This may support the idea that plasma sIL-2R is derived from malignant MDS cells in the bone marrow. The plasma sIL-2R level correlated negatively with the absolute numbers of the CD8+, CD3-CD16+, and CD3-CD56+ cell populations in freshly isolated lymphocytes, the percentage of CD3-CD56+ cells in lymphokine (interleukin 2)-activated killer (LAK) cells, and the cytotoxicity of LAK cells. We conclude that MDS patients having a high plasma sIL-2R level often have a defect in natural killer and CD8+ T-cells.
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PMID:Elevated plasma soluble interleukin 2 receptor level correlates with defective natural killer and CD8+ T-cells in myelodysplastic syndromes. 793 36

Human bone marrow transplantation is becoming more common in the treatment of certain forms of cancer despite the scarcity of HLA matched donors. Because human umbilical cord blood (HUCB) has been used as a source for stem cells in bone marrow transplantation, and because NK cells appear to be important in graft versus leukemia response, we investigated the lytic activity of freshly isolated HUCB NK cells (HUCB-NK) against tumor targets and their ability to differentiate into LAK cells following stimulation with various cytokines. Although cytotoxicity mediated by fresh HUCB-NK was low compared to that of adult peripheral blood lymphocyte-derived NK cells (PBL-NK), the ability of HUCB-NK to bind to K562 target cells (TC) was similar to PBL-NK. In addition, the PBL-NK cytotoxicity of postpartum mothers was also low compared to that of normal adult PBL-NK. When we incubated HUCB for 18 hr in either IL-2 or IL-12, we boosted the level of HUCB-NK cytotoxicity to approximately the level observed in PBL-NK and increased the level of perforin, granzyme A, and granzyme B mRNA expression. In addition, when we incubated HUCB in IL-2, IL-4, IL-7, IL-12, TNF-alpha, IFN-alpha, IFN-gamma, or TGF-beta for 5 days, we observed that HUCB was capable of generating LAK cells only when incubated with either IL-2 or IL-12. In contrast, IL-2, IL-7, IL-12, TNF-alpha, and IFN-gamma all generated LAK cells from adult PBL. When we added to the medium low-dose IL-2 and irradiated K562 as feeder cells (mini-LAK), we were unable to generate LAK activity from HUCB-NK, whereas we could generate it with PBL-NK cells under the same conditions. Addition of serum derived from HUCB in a 4-hr 51Cr release assay with PBL-NK as the effector cells (EC) and K562 as the TC resulted in a 42% decrease in PBL-NK-mediated cytotoxicity. Although we detected no TGF-beta in HUCB serum, we did detect high concentrations of soluble class I MHC (sHLA). To our knowledge, sHLA has not previously been shown to inhibit NK cytotoxicity, although the expression of class I HLA on the surface of TC has been shown to inhibit NK cytotoxicity. To study further the effect of sHLA on cell-mediated cytotoxicity, we added various concentrations of sHLA to EC mediating NK, ADCC, and CTL activities. All were inhibited in a dose-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The lack of NK cytotoxicity associated with fresh HUCB may be due to the presence of soluble HLA in the serum. 799 57

One mechanism by which cytotoxic T lymphocytes and natural killer cells inflict target cell death depends upon secreting the contents of their specialized cytoplasmic granules, containing a pore-forming protein, perforin, and a family of homologous serine proteases ("granzymes") with various enzyme activities. We used a granzyme B-specific mouse anti-human monoclonal antibody 2C5 and Western blotting to demonstrate that nuclear extracts of human interleukin-2-stimulated peripheral blood mononuclear cells, the human NK leukemia cell line YT, and the rat NK leukemia cell line RNK-16 contain abundant granzyme B. In interleukin-2-activated peripheral blood mononuclear cells, more than 50% of the total cellular granzyme B was present in the nuclear lysate. Nuclear granzyme B had an apparent molecular mass of approximately 32 kDa in human cells and approximately 30 kDa in RNK-16 and was eluted from immobilized heparin at the same NaCl concentration as granzyme B from cytoplasmic granules. Granzyme B that was affinity-purified with 2C5 from the nuclei of YT or human LAK cells was capable of efficiently cleaving synthetic peptide thiobenzyl ester substrates with the same specificity (peptide cleavage after aspartic acid) as granule-localized granzyme B. By contrast perforin, which colocalizes with granzymes in cytotoxic granules, was not detectable in nuclear lysates. Granzyme B was also demonstrated to be present in the nucleus and cytoplasmic granules of YT by immunohistochemical staining with monospecific anti-granzyme B antisera. Other protease activities (tryptase and peptide cleavage after methionine) were also readily detectable in nuclear and cytoplasmic lysates of YT, RNK-16, and LAK cells, as determined by the cleavage of the synthetic substrates N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester (BLT) and Boc-Ala-Ala-Met-S-benzyl, except that BLT-esterase activity was absent from the nucleus of YT. The localization of serine proteases in the nucleus was restricted to lymphocytes with cytotoxic capacity, as non-cytotoxic cell lines expressed high levels of peptide cleavage after methionine and tryptase activities in their cytoplasm, but possessed no nuclear serine protease activity. Furthermore, non-cytotoxic monkey kidney COS-7 cells transfected with an SV40-driven expression plasmid incorporating full-length human granzyme B cDNA contained abundant cytoplasmic granzyme B, but demonstrated minimal nuclear granzyme B accumulation. We conclude that serine proteases of NK cells are not restricted to cytolytic granules and, further, that their capacity to access the nucleus may have implications for the role of these enzymes in eliciting target cell death.
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PMID:Granule serine proteases are normal nuclear constituents of natural killer cells. 803 81

The transfer of cytotoxic effector cells reduces the risk of relapse after allogeneic BMT. Two murine leukemia cell lines, A20 (B lymphocytic) and WEHI-3 (myelomonocytic), were used to investigate antileukemic effector mechanisms operating independently from graft-versus-host disease (GVHD). Different results were obtained with the two leukemia models. After injection of A20 cells, the majority of Balb/c recipients treated with syngeneic BMT died due to leukemia relapse (89%). The transplantation of MHC-matched DBA marrow resulted in chronic GvHD but did not reduce the risk of relapse (86%). Grafting of MHC-mismatched (but GvH-nonreactive) marrow cells from (C57xBalb)F1 hybrids, however, led to a significantly lower relapse rate (47%, p < 0.05). In vitro testing revealed that F1 cells but not Balb/c or DBA cells exert NK cell activity against A20. The elimination of NK 1.1-positive cells from the graft reduced the antileukemic activity of (C57xBalb)F1 marrow against A20 in vivo. After injection of WEHI-3 leukemia cells, syngeneic BMT cured most of the recipients (62%) and transplantation of (C57xBalb)F1 marrow provided no additional benefit. In contrast to unmanipulated Balb/c and (C57xBalb)F1 cells, which showed no NK activity against WEHI-3 in vitro, IL-2 treated effector cells were highly cytotoxic. Transfer of IL-2 preincubated grafts significantly decreased the relapse rate of WEHI-3 (19 vs. 38%) after syngeneic and allogeneic BMT. Our data indicate that GvL activity can be separated from GvHD. In our murine model, GvL activity appears to depend more on the donors NK/LAK cell activity than on the presence or absence of GvHD.
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PMID:Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model. 812 60

Acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) blasts were studied for their sensitivity to the lytic activity of normal allogeneic interleukin 2 (IL-2) activated killer (LAK) cells, and of autologous LAK effectors generated at the time of complete remission (CR). In 12 of 23 ALL cases (52%), the blasts were susceptible to normal LAK cells (> 15% lysis) and ten of them achieved a CR. Of the remaining 11 LAK-resistant cases, seven obtained a CR. No correlation was found between susceptibility to LAK activity, cytomorphology, immunophenotype, CR duration and survival. Eighteen of the 26 AMLs tested (70%) were susceptible to normal LAK cells, and nine of the 13 cases studied (70%) were also lysed by autologous LAK effectors generated at CR. No clearcut correlation was observed between blast sensitivity to normal LAK cells and morphologic cytotype, though a higher incidence of resistant cases was observed in the M4 subgroup. All AMLs susceptible to normal LAK cells but one achieved a CR, while this occurred only in three of the eight resistant cases (p = 0.004). The median survival and event-free survival duration in the resistant patients were significantly shorter (p = 0.03 and p = 0.02, respectively) compared to those of the susceptible patients. In ten ALL and in six AML, which at presentation displayed less than 10% circulating blasts, the susceptibility of the leukemic population to normal and autologous LAK effectors could be tested, both at diagnosis and at remission. All cases but one were resistant to autologous LAK cells generated at diagnosis, while at CR, seven cases (four ALL and three AML) became susceptible to autologous LAK cells (p = 0.01). The remaining nine were resistant to both allogeneic and autologous LAK effectors. Taken together, these findings suggest that in AML, but not in ALL, the LAK cell compartment may play a role in the clinical course and overall outcome of the disease.
Leukemia 1994 May
PMID:In vitro susceptibility of acute leukemia cells to the cytotoxic activity of allogeneic and autologous lymphokine activated killer (LAK) effectors: correlation with the rate and duration of complete remission and with survival. 818 32

Twenty-two patients with high risk hematologic malignancies (13 c-ALL, two B-ALL/NHL, four T-ALL, two AML M2, one pre-pre B-ALL) entered a phase I/II trial with cyclic administration of low dose natural interleukin-2/recombinant interferon-gamma (nIL-2/rIFN-gamma) following autologous bone marrow transplantation (ABMT), in order to induce a cytotoxic antileukemic effect. Eighteen patients subsequently relapsed, corresponding to a Kaplan-Meier estimate of disease-free survival (DFS) of 18%. Compared with a historical group of autologous bone marrow recipients who have not received immunotherapy, there is no significant difference according to DFS. Immunophenotyping of peripheral lymphocytes at the onset and end of therapy cycles revealed the most significant mean increase among the NK cell population (262/microliters +/- 51 vs. 354/microliters +/- 36, p = 0.004). However, even CD3 positive T cells rose significantly (591/microliters vs. 689/microliters, p = 0.04). In vitro NK cell activity tested against the NK sensitive myeloid leukemic cell line K562, and LAK cell activity tested against the LAK sensitive Burkitt lymphoma cell line Raji, was only low. An additional in vitro stimulus with nIL2, however, led to a therapy-dependent increase of cytotoxicity which was significant against Raji cells (25% +/- 4 vs. 41% +/- 5, p = 0.0124) indicating that low dose nIL2/rIFN-gamma enhances precursors of potentially cytotoxic cells in vivo.
Leukemia 1994 May
PMID:Low-dose natural interleukin-2 and recombinant interferon-gamma following autologous bone marrow grafts in pediatric patients with high-risk acute leukemia. 818 41

The mechanism by which GVHD augments the graft-versus-leukemia (GVL) effect of marrow transplants has not been ascertained. One possibility involves the secondary activation of natural killer (NK) cells by cytokines released during the GVHD process. To evaluate this possibility we have compared NK activity and lymphokine-activated killer cell precursor (LAKp) frequencies in serially sampled PBMC from recipients of unmanipulated autologous or allogeneic marrow with and without active GVHD. NK activity recovered rapidly after BMT and was elevated during episodes of acute GVHD. However, NK activity did not differ between recipients of autologous or allogeneic marrow without GVHD nor was NK activity increased in association with chronic GVHD. Endogenously-activated NK cells were detected only in recipients of allogeneic marrow but this did not correlate with GVHD status. In contrast to NK activity, LAKp frequencies fell below the control range during the first 8 weeks after BMT. By 9-14 weeks the median LAKp frequency was normal and did not differ between the three groups then or later after transplant. We conclude that acute GVHD may serve to increase the lytic activity of NK cells but does not result in increased LAKp. LAKp frequencies are below normal during the first two months after BMT, a finding not previously recognized from bulk culture LAK studies. The role of LAK effectors in GVL may involve more the degree of cellular activation rather than the number of cells activated.
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PMID:Effect of GVHD on the recovery of NK cell activity and LAK precursors following BMT. 824 89

We studied the anti-tumor effect of control human lymphocytes and interleukin-2 (IL-2) activated lymphocytes (lymphokine activated killer cells, LAK-cells), on two different cell lines: SW742 human colon adenocarcinoma and K562 human myeloid leukaemia cell line. Our results indicate that IL-2 augment the anti-tumor activity of human lymphocytes and these LAK-cells lyse the tumor cells very efficiently. Furthermore, we treated the target cells (SW742 and K562) with different cytokines in order to establish whether these cytokines have any effect on susceptibility to lysis by LAK-cells. Anti-tumor activity of human lymphocytes and IL-2 is discussed in this study.
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PMID:Anti-tumor effect of human lymphocytes and interleukin-2. 832 67

The Mitoxantrone-resistant murine leukemia P388/Mitox, expressing the multidrug-resistant phenotype, has a higher immunogenicity than the parent sensitive P388. This could be shown in vivo by immunization with lethally-irradiated tumor cells. If the P388/Mitox was used for immunization before subsequent challenge with viable tumor cells of the same line, this resulted in a partial rejection of tumors and production of a substantial number of tumor-free survivors. For an effective immunization at least two primings s.c., i.v. or i.p. with at least 10(6) irradiated cells were necessary. This protected the recipient mice from a challenge of up to 10(8) viable cells over a period of at least 75 days. Treatment of BDF1 mice with the T-cell suppressor Cyclosporin A prevents immunization. In nude mice no immunization effect could be obtained. It was possible to transfer immunity adoptively with spleen cells from mice, which were treated with irradiated tumor cells of the P388/Mitox line. Treatment of tumor-bearing mice with IL-2 resulted in a prolongation of survival both when it was administered prophylactically before transplantation of P388/Mitox and at an advanced stage (day 7-11). Also the alkyl-phosphocholine hexadecylphosphocholine was significantly effective in the resistant but not in the parent P388 leukemia. The data presented demonstrate that by development of a multidrug-resistance, concomitantly a xenogenization must have taken place which leads to a recognition of cells by immune mechanisms. In our model, T-lymphocytes and NK-/LAK-cells probably play a role in the immunologically conditioned rejection of tumor cells of the P388/Mitox leukemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo characterization of immunogenicity of a mitoxantrone-resistant murine P388 leukemia. 850 10


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