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

TCR gamma delta expressing T cell clones are able to exhibit in vitro strong cytolytic activity against cultured tumor cell lines as the myeloid K562 or the Burkitt's lymphoma Daudi cell line. We investigate the possibility of developing TCR gamma delta bearing T cell lines from peripheral blood of 2 leukemic patients in complete remission in order to study their ability to kill autologous leukemic cells. T lymphocyte clones are obtained by limiting dilution of lymphocytes from the blood of patients with an acute lymphoblastic leukemia (ALL). The T cell clones are first selected for their CD8- CD4-phenotype and then for their ability to react with the monoclonal antibody anti-CD3 without presenting reactivity with a monoclonal antibody directed against the TCR alpha beta. Further biochemical studies have indicated that the CD3 associated structure expressed on the cell membrane of these T cell clones is a gamma delta heterodimer. Functional analysis have indicated that these cloned cells are able to kill in a classical cell mediated lysis assay the autologous leukemic cells only when also LAK activity is observed. Thanks to this clonal expansion 10(10) cells/week indefinitely only 1 sample of peripheral blood will be necessary. Would these results be found with other leukemic patients, we propose to use this procedure for a possible application of killer cells for maintenance therapy of leukemia.
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PMID:Human CD3 gamma delta + activated lymphocytes exhibit killer activity in vitro against autologous leukemic cells. 252 19

Activation and expansion in culture with rIL-2 of peripheral blood (PB) and/or bone marrow (BM) specimens derived from children with ALL and ANLL, with active disease (AP) and in remission were studied (RP). Baseline NK cytolytic activity from AP was found to be depressed, whereas RP-derived cells had normal NK activity, as assayed against K562 targets. Culture in rIL-2 significantly enhanced the NK activity of both AP- and RP-derived cells and generated LAK activity, as assayed by 4-hour 51Cr release, against NK-resistant Raji cell line and against fresh, allogeneic, and autologous tumor cells. Lytic activity against fresh, cryopreserved leukemia blasts was of lower than that found against cell lines. In three patients higher lytic activity against autologous than against allogeneic blasts was demonstrated. Expansion in culture with rIL-2 varied from twofold to 120-fold. rIL-2 activation and expansion was better in RP than in AP. The predominant phenotype of activated cells, as determined by flow cytometry, was [mean % (SD)]: CD3- = 54 (12), CD8+ = 55 (17), and NKH1+ = 26 (7). The consistently high level of CD8+ cells was accompanied by very low levels of CD4+ cells: mean = 11% (14). Double-marker analysis showed mean of 33% (10) for CD3+/NKH1+ cells and mean = 32 (11) for CD8+/NKH1+ cells, implying that these populations were overlapping. Kinetics of expression of cell surface markers during 2 to 3 weeks in culture showed that CD8+ and NKH1+ enrichment occurred during the first week and lasted for up to 4 weeks, whereas CD4+ expression decreased after the second week. A significant decrease in the expression of IL-2 receptors (CD25) was observed from the second week of culture. This study shows the feasibility of in vitro generation of killer cells from PB and BM of pediatric leukemia patients.
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PMID:Interleukin-2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients: II. Feasibility of LAK generation in children with active disease and in remission. 279 Jan 93

The present study elucidated that N-CWS augments the cytolytic activity against 3LL tumor cells of LAK cells from N-CWS-immunized mice administered i.p. with rIL-2. This augmentative effect of N-CWS was not seen when the LAK cells were prepared from normal mice. The cytolytic activity was predominantly expressed in the NAPC prepared from the site of injection of rIL-2, and repeated administrations of rIL-2 were required to induce and maintain this potent cytolytic activity in vivo. Serological analysis revealed that the LAK cells were positive for Thy 1.2 and asialo GM1 antigens and that they were not classical CTL or NK cells. The administration of rIL-2 statistically prolonged the MST of mice bearing LAK-sensitive 3LL cells but not the MST of mice bearing LAK-resistant EL-4 leukemia. Furthermore, combination therapy with N-CWS and rIL-2 prolonged the MST of the mice more than the therapy with rIL-2 alone. These results suggest that LAK cells potentiated with N-CWS would be useful for immunotherapy of malignant neoplasms.
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PMID:Augmentative effect of Nocardia rubra cell-wall skeleton (N-CWS) on lymphokine-activated killer (LAK) cell induction. 325 99

Highly purified human recombinant interleukin 2 induced cytotoxicity in mouse spleen cells against mouse sarcoma cells when added during the 51Cr microcytotoxicity assay. It elicited similar levels of killer cell activation as did human lymphoid (Jurkat leukaemia-derived) or mouse lymphoid (EL-4 leukaemia-derived) IL-2 preparations. The susceptibility of six MC-induced mouse sarcomas to the cytolytic effect of lymphokine-activated killer cells was compared. Five (MC11, MC13, MC14, MC15, MC16) of six mouse sarcoma cell lines examined were sensitive in vitro to the LAK cell effect, whereas one cell line (MC12) was resistant. Since the sensitive and resistant target cell lines had been induced with the same carcinogen and in mice of the same genotype, they represent a very useful model for investigation of target cell structures responsible for the sensitivity to the LAK cell effect.
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PMID:Immunotherapy of murine sarcomas with interleukin 2. II. Activation of killer cells by human recombinant IL-2. 349 97

The possibility that the peanut agglutinin (PNA) receptor and/or its co-ordinate structures on the surface of leukaemia cells might be recognized by lectin free crude interleukin-2 (IL-2) activated human peripheral blood lymphocytes (LAK) was investigated. Analysis was undertaken of the correlation between the sensitivity to allogeneic LAK lysis and the proportion of PNA receptor on different fresh malignant cells. The results obtained suggested that PNA receptor detected by rhodamine isothiocyanate labelled PNA binding assay appeared to be well expressed on leukaemia cells which were sensitive targets for LAK. PNA receptor and/or its coordinate structures seemed to provide a 'target' structure for LAK.
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PMID:Interleukin-2 activated peripheral blood lymphocytes and the correlation of lytic activity and peanut agglutinin receptor expression on malignant cells. 633 30

Autologous bone marrow (BM) transplantation after high dose therapy is widely used to treat acute leukemia, lymphoma, and selected solid tumors. In studies of BM purging with chemical agents, monoclonal antibodies (MoAbs), or other agents, the emphasis has been on the efficacy of tumor cell removal and sparing of hematopoietic progenitor cells. Two commonly used methods of BM purging for patients with acute myeloid leukemia have been the drug 4-hydroperoxycyclophosphamide (4-HC) and (MoAbs) directed to myeloid antigens such as CD14, CD15, and CD33. Although both methods of BM purging have potent activity against leukemia cells, 4-HC is also quite toxic to normal hematopoietic progenitor cells in the same concentrations that are used to deplete leukemia cells. To further characterize the cellular composition of BM after purging, we examined the effects of MoAbs plus complement and 4-HC on cells of the lymphoid lineage in the BM. 4-HC exerted a concentration-dependent cytotoxicity on clonogenic T lymphocytes, natural killer (NK) cells, and lymphokine (interleukin-2)-activated killer (LAK) cells, whereas the anti-CD14 and anti-CD15 MoAbs had little effect. At a concentration of 4-HC commonly used for BM purging (60 micrograms/mL), there were 4 to 5 logs of T-cell depletion and almost complete elimination of NK- and LAK-cell activity. In contrast, 4-HC at low concentrations (eg, 3 micrograms/mL) spared the majority of lymphoid cells suggesting that low concentration 4-HC combined with MoAb purging may be a desirable alternative to higher concentration 4-HC. These data indicate that purging with antimyeloid MoAbs, but not with 4-HC, spares the function of mature graft lymphocytes. Infusion of viable lymphocytes may be important for the transfer of immune memory against microbial and neoplastic antigens and may hasten immune reconstitution. In addition, mature graft lymphocytes may also be selectively activated and expanded in conjunction with interleukin-2 administration after BM transplantation.
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PMID:Differential effect of 4-hydroperoxycyclophosphamide and antimyeloid monoclonal antibodies on T and natural killer cells during bone marrow purging. 751 45

The immunoprophylactic and immunotherapeutic effects of LAK cells transferred adoptively on L615-suffering mice were studied. The results showed that adoptive transfer of LAK cells could increase the survival rate of the mice and prolong the mean survival time of mice with advanced L615 leukemia. IL-2 in appropriate concentration was required in the adoptive immunotherapy, and the combined use of LAK cells with 5-FU or IFN-r had no additive immunotherapeutic effects. The results also revealed that the immunotherapeutic activity of the transferred LAK cells maintained a relatively long period of time in the host body.
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PMID:[Immunoprophylactic and immunotherapeutic effects of adoptively transferred LAK cells on L615 leukemia suffering mice]. 751 34

In vitro ultraviolet-B (UVB) irradiation of murine and rodent bone marrow cells prevents GVHD without compromising engraftment while inducing tolerance to donor-type allografts. In anticipation of clinical trials of UVB-modified bone marrow grafts, we studied the in vitro effects of UVB irradiation (50-300 J/m2) on human natural killer and lymphokine activated killer cells since both types of cells influence the development of GVHD and graft-versus-tumor effect. Interleukin-2-activated and untreated human lymphocytes were used as effectors in a 51Cr release cytotoxic assay against various tumor cell lines as targets. NK-mediated lysis of K562 targets was decreased by UVB irradiation of the effector cells in a dose-dependent manner. FACS analysis of CD16+ and CD56+ cells 24 hr after UVB exposure showed a UVB-dose-dependent decrease in the number of cells expressing these surface markers. UVB irradiation of lymphocytes prior to activation with high-dose IL-2 resulted in a range of 20- to 89-fold decrease in LAK precursors as measured by limiting dilution analysis using the LAK-sensitive cell line HL60. In contrast, the LAK activity of lymphocytes that had been stimulated in vitro with high-dose IL-2 prior to UVB irradiation was preserved when assayed immediately after UVB modulation; however, there was a significant decrease in lytic activity (with most samples tested) when the assay was performed 24 hr after UVB exposure. It appears that the lymphocyte response to UVB modification is dose dependent, with some cell types displaying higher sensitivity to UVB irradiation than others. These findings suggest that prevention of GVHD by UVB is due, in part, to inhibition of NK activity, and may offer a new strategy to augment the graft versus leukemia effect of UVB-modified bone marrow grafts in clinical transplantation.
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PMID:Effects of ultraviolet-B irradiation on human LAK and NK cytotoxic activity. 755 80

Expansion of the natural killer (NK) subset of lymphocytes represents a rare leukemia phenotype with variations in clinical presentation, morphology, surface phenotype, and effector function. This paper reports on a 5-year-old male patient who had an unusual presentation of an NK cell leukemia that was initially diagnosed as neuroblastoma. A bone marrow (BM) aspirate showed clumps of undifferentiated cells with the following phenotype: CD56bright+, CD33dim+, CD45-, CD2-, CD19-, CD16-, and CD57-. Cytochemistry was noncontributory. The patient, having failed to respond to conventional neuroblastoma chemotherapy, was subsequently diagnosed as having NK cell leukemia based on functional in vitro assays. The patient responded to acute lymphoblastic leukemia (ALL) chemotherapy but relapsed 4 weeks into treatment and eventually died 25 weeks after initial presentation. The cell surface phenotype observed is consistent with a rare NK cell subset, the biology of which has not been well defined. Freshly isolated BM cells killed K562 cells in a conventional 51Cr-release assay. Both interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) induced LAK activity against the Daudi cell line. IL-2 induced proliferation of the leukemic cells. TNF-alpha, IFN-gamma, IL-6, IL-1ra, and TGF-beta levels were assessed and found to be concentrated in BM, in contrast to plasma samples. TNF-alpha was present at a high concentration in BM (150.9 pg/ml), probably a reflection of the associated disease pathology of severe bone pain and pyrexia. In summary, this paper details clinical and laboratory investigations of a leukemia of a rare NK cell subset.
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PMID:Recognition of unusual presentation of natural killer cell leukemia. 757 92

LAK activity is known to increase following autologous and allogeneic bone marrow transplant and peripheral blood stem cell transplant (PBSCT). The aim of this study was to directly compare the 3 types of transplant and the LAK activity generated. LAK activity following PBSCT is significantly greater than that following autologous bone marrow transplantation and even allogeneic transplantation up to 8 weeks. The type of killer cells generated is similar for the different types of transplants, with most killing activity following PBSCT due to CD56+ cells, though CD3+ cells also contribute. This study would suggest that attempts to augment the graft-versus-leukaemia effect is more likely to be successful following PBSCT than autologous bone marrow transplantation.
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PMID:In vitro LAK (lymphokine activated killer) activity following autologous peripheral blood stem cell is significantly greater than that following autologous bone marrow and allogeneic bone marrow transplantation. 758 Nov 48


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