Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antileukemic effects of lymphokine-activated killer (LAK) cells plus recombinant interleukin-2 (rIL-2) therapy were assessed in mice with Friend virus (FV)-induced erythroleukemia. LAK cells were generated by incubating normal spleen cells for 72 hr in the presence of rIL-2 (1000 units/ml). At the time of injection, the LAK cells were cytotoxic in vitro against FV-infected fibroblasts and NK-sensitive and -resistant tumor targets but not normal controls. To determine in vivo activity, fully leukemic mice (spleen weight greater than 0.75 g) were injected with either PBS or LAK cells (10(8) cells/mouse IV at 14 and 17 days post virus) and rIL-2 (10,000 units/mouse IP every 8 hr on days 14 through 18 post virus). More than 70% of the progressively leukemic mice experienced permanent leukemia regressions (disease-free for greater than 100 days) following LAK cell plus rIL-2 therapy. Regressions were characterized by return of spleen and liver weights to normal and elimination of virus-infected erythroid (CFU-E) and macrophage (CFU-C) progenitor cells from spleen and marrow. Leukemic animals treated with either LAK cells alone or IL-2 alone experienced only transient leukemia regressions. These results demonstrate that LAK cell plus rIL-2 treatment can induce permanent regressions in progressively leukemic mice and provide a responsive and manipulable model system to elucidate the mechanisms involved in this form of immunotherapy.
Leukemia 1989 Feb
PMID:Lymphokine-activated killer cell plus recombinant interleukin-2 therapy of erythroleukemia in mice. 278 72

To improve the biologic evaluation of Hodgkin's disease, we determined serum interleukin-2 receptor (IL2R) levels in 88 children with this tumor. In patients with stage III or IV disease, the median receptor level was significantly higher than in patients with lower stages (3195 vs. 1087 U/ml, p = 0.0001). Similarly, the median level for children with stage B disease was 3262 U/ml, compared with 999 U/ml for those lacking constitutional symptoms (p = 0.0001). Patients with very high soluble IL2R levels (greater than or equal to 5000 U/ml) were significantly more likely to fail treatment (p = 0.01), even when the analysis was restricted to groups with advanced disease: stages III and IV (p = 0.0001). When entered in the Cox-proportional hazards model with other potentially useful prognostic factors, soluble IL2R level was found to be an independent predictor of treatment outcome. The relationship of high serum IL2R levels to an adverse clinical outcome in Hodgkin's disease may be explained by a model in which the soluble receptor competes for the ligand with the cellular receptor on normal lymphocytes, thus blocking antitumor immunity dependent on interleukin-2. Alternatively, high serum levels of IL2R may simply reflect increased release of the receptor from activated malignant cells in patients with advanced disease or an otherwise poor prognosis.
Leukemia 1989 Jul
PMID:High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin's disease. 278 97

Binding of interleukin-2 (IL-2) to high affinity receptors on activated normal T cells was shown to be the essential step in induction of proliferation of such cells. The finding of abundant IL-2 receptors on malignant T cells in adult T cell leukemia suggested a deregulation of the IL-2/IL-2 receptor system and was assumed to account for aberrant growth in malignant disorders of T cells. In this study we use malignant T cells from nine patients with the clinical diagnosis of T-ALL or T-NHL and did not detect IL-2 dependent growth under conditions in which normal T cells responded to IL-2. IL-2 receptors comparable in numbers to activated T cells were found on T-ALL/T-NHL cells stimulated with PHA and PMA. However, binding studies using radiolabeled IL-2 indicated that the receptors present on malignant T cells were not able to bind to IL-2 with high affinity. Therefore, if IL-2 is involved in the proliferation of malignant T cells, its mechanism of growth regulation may be different from the one for normal T cells. Alternatively, IL-2 may not play a role in the regulation of growth of malignant T cells in vitro.
Leukemia 1989 Aug
PMID:Lack of interleukin-2 (IL-2) dependent growth of TAC positive T-ALL/NHL cells is due to the expression of only low affinity receptors for IL-2. 278 51

The cytokine secreted by a human hybrid B cell line (STS 25) obtained by fusion of the B lymphoblastoid cell line WI-L2-729-HF2 with neoplastic B cells from a patient with B cell non-Hodgkin's lymphoma (B-NHL) was characterized as IL-1 alpha. STS 25 cells express the idiotypic (Id+) immunoglobulin (Ig) specific for the neoplastic B cells of the B-NHL patient. STS 25 cells are weakly positive for surface mu delta kappa and in addition express the surface markers CD19, CD20, CD23, HLA class I and II, and the 4F2 activation antigen. STS 25 cells are also Epstein-Barr nuclear antigen positive but do not secrete viral particles. Serum-free culture supernatant from STS 25 cells (STS 25 SUP) does not show activity in assays for interleukin-2 (IL-2), -4 (IL-4), -6 (IL-6), interferon or tumor necrosis factor, but is active in the thymocyte costimulation assay and the D10.G4.1 T helper clone proliferation assay for interleukin-1 (IL-1). The IL-1 character of the STS 25 SUP activity was confirmed in inhibition studies with three different poly- or monoclonal anti-IL-1 antibodies (31, 88, and 94% inhibition in thymocyte costimulation assay, respectively). Furthermore, complete blocking of D10.G4.1 cell proliferation mediated by STS 25 SUP was observed by including anti-IL-1 alpha specific antibody in the assay, whereas anti-IL-1 beta antibody had no effect. These results indicate that this STS 25 SUP activity can be attributed to the presence of IL-1 alpha in the supernatant. Northern blot analysis of total STS 25 cellular RNA using IL-1 alpha or IL-1 beta specific probes revealed the constitutive expression of IL-1 alpha messenger RNA by STS 25 cells. In contrast, no IL-1 beta message was detectable, not even after treatment of the cells with phorbol ester or cycloheximide, which resulted in approximately 5-fold enhancement of IL-1 alpha mRNA expression. Binding studies with radiolabeled recombinant (r) IL-1 alpha indicated the presence of high numbers of IL-1 receptors on STS 25 cells (1,170 per cell, Kd = 392 pM). Although both IL-1 alpha and IL-1 beta bound to these IL-1 receptors, no indication was found for IL-1 mediated regulation of STS 25 cell growth.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1989 Aug
PMID:Functional and molecular characterization of B cell line derived interleukin-1 alpha. 278 53

In this report, a Radiation leukemia virus-transformed murine T cell lymphoma is described which is dependent on the interleukin-2 (IL-2) growth factor for proliferation under single cell conditions of growth. It was isolated from a C57BL mouse which had been primed with the Radiation leukemia virus-induced thymoma, C6VL/1, and has been shown to be phenotypically and karyotypically distinct from C6VL/1. IL-2 dependency has been stable over many in vitro passages, and this property also serves to distinguish this cell line from C6VL/1. 5C2 constitutively expresses a T cell receptor (TCR) and can respond by increased proliferation to external stimulation with anti-TCR antibody. This antibody acts to stimulate 5C2 growth in the absence of added IL-2. Maximum stimulation was achieved in the presence of a 50-ng/ml concentration of purified antibody. 5C2 has also been shown to produce detectable levels of IL-2 which can be increased by 8- to 16-fold after exposure of cells to anti-TCR antibody. The C6VL/1 T cell lymphoma has served as a control cell line in three experiments since it cannot be stimulated either to increased proliferation or to lymphokine release by this same antibody. However, a 10-ng/ml concentration of anti-TCR antibody was found to inhibit proliferation of both T cell lymphomas when they were cultured under optimal conditions, i.e., in the presence of an IL-2 source for 5C2. The proliferation of both T cell lymphomas appears to be regulated, although in different ways, by the binding of antibody in the vicinity of the TCR complex. While 5C2 is dependent on IL-2 production (and TCR triggering) to proliferate, C6VL/1 replicates independently of any growth factors. Signal transduction through the TCR/T3 complex, together with the subsequent production of growth factors, may be important for driving the proliferation of T cells such as 5C2 at an early stage in oncogenic progression following infection with an RNA tumor virus.
Leukemia 1988 Feb
PMID:Interleukin-2 and antibody to the T cell receptor regulate proliferation of a radiation leukemia virus-transformed T cell lymphoma. 283 Apr 40

We have studied the expression and function of interleukin-2 (IL-2) receptors on B cell precursor acute lymphoblastic leukemias (ALL). After incubation of B cell precursor ALL in vitro for 24 hr, 11 out of 17 leukemic bone marrow aspirates expressed the Tac/CD25 protein (greater than 10% positive blasts). Expression of Tac/CD25 on the leukemic cells was confirmed by two color flow cytometric analysis using anti-Tac/CD25 and anti-CALLA/CD10 monoclonal antibodies. The molecular mass of the B cell precursor ALL Tac/CD25 protein was 55 kilodaltons (kD), identical to that on activated T cells. Binding of radiolabeled IL-2 in two leukemic bone marrow aspirates demonstrated the presence of high affinity IL-2 receptors. Cross-linking of 125I-labeled IL-2 to TPA activated B cell precursor ALL revealed the 55 kD Tac/CD25 protein and an additional protein of 75 kD. Recombinant IL-2 in concentrations of 10-1,000 U/ml had essentially no proliferative effect in 10 patients tested, whereas low molecular weight B cell growth factor (L-BCGF) induced proliferation in 8 of 10 patients. L-BCGF also induced expression of CD20 in 3 of 7 CD20 negative B cell precursor ALL. IL-2 did not induce CD20, but enhanced its expression in the 3 patients who responded to L-BCGF. We conclude that IL-2 has essentially no proliferative effect on B cell precursor ALL, despite the presence of high affinity IL-2 receptors and the presence of the IL-2 binding cell surface molecules similar to those on activated T cells. IL-2 may, however, induce a phenotypic change (CD20 acquisition) consonant with differentiation in synergy with L-BCGF.
Leukemia 1987 Sep
PMID:Structure/function analyses of IL-2 binding proteins on human B cell precursor acute lymphoblastic leukemias. 311 14

Tumor cells from 5 human B cell non-Hodgkin's lymphoma (B-NHL) patients were investigated for proliferative activity and idiotypic (Id+) immunoglobulin (Ig) secretion in serum-free medium without deliberate addition of B cell growth or differentiation factors (BCDF). These data were compared with cell surface marker expression, notably of activation antigens such as 4F2 and interleukin-2 (IL-2) receptor. Cells from all patients became 4F2 positive at the end of the 6-day culture period. Freshly drawn cells from 3 out of 5 patients expressed the IL-2 receptor (CD25; Tac antigen) or acquired this marker during culture in vitro and secreted relatively high levels of Id+ Ig in vitro. This correlated with elevated serum Id levels (greater than or equal to 0.5 micrograms/ml in vitro versus greater than or equal to 20 micrograms/ml in vivo). In the 2 CD25 (Tac)- B-NHL patients serum Id levels were below the detection limit and the amount of Id+ Ig secreted in vitro did not surpass 50 ng/ml. Only the B-NHL cells from a single patient were initially CD25 (Tac) positive and only these cells proliferated in serum-free culture. To test whether IL-2 receptor expression in the 3 CD25 (Tac)+ patients was functional, recombinant IL-2 (rIL-2) either alone or in conjunction with BCDF and recombinant IL-4 (rIL-4) was added to the cultures. In 2 out of 3 CD25 (Tac)+ patients rIL-2 was capable of enhancing proliferation or Ig secretion. In addition rIL-2 was found to enhance BCDF-mediated but not rIL-4 mediated responses. The third CD25 (Tac)+ B-NHL population was resistant to any of these lymphokines. Thus, this serum-free culture system may accurately reflect patient serum Id levels. IL-2 appears to regulate not only the in vitro but also the in vivo Ig secretion by neoplastic B cells.
Leukemia 1988 Apr
PMID:Idiotypic immunoglobulin secretion by human B cell non-Hodgkin's lymphomas is related to the expression of the interleukin-2 receptor. 312 22

A murine Radiation leukemia virus-induced T cell lymphoma, 5C2, which is dependent on interleukin-2 (IL-2) for proliferation has been analyzed for interleukin-2 receptor (IL-2R) expression. Using fluorescence-activated cell sorter and electron microscopic analysis together with antibody specific for the known p55 chain of the murine IL-2R, no evidence has been obtained to suggest that these cells express detectable numbers of receptors with high affinity for IL-2. However, two different antibodies with specificity for the p55 chain of the IL-2R have been shown to inhibit 5C2 proliferation. An analysis of 125I-IL-2 binding has precluded a cell surface receptor density of greater than 80 molecules per cell. A temperature-dependent, nonspecific uptake of 125I-IL-2 has been described for 5C2. Uptake is saturated at 8.5 nM 125I-IL-2 with equilibrium being established within 60 min. When incubated at 37 degrees C in the presence of 400 pM 125I-IL-2, a maximum of approximately 2,000 molecules are internalized within 40 min. Uptake of other iodinated proteins by 5C2 was not observed. This property is unique to 5C2 and not to the control C6VL/1 cell line. Intracellular vesicles have also been found in 5C2 cells by electron microscopy which stain positively with gold-conjugated antibody specific for the p55 chain of the IL-2R. 5C2 appears to exhibit unique IL-2 regulatory characteristics.
Leukemia 1988 Jun
PMID:Internalization of IL-2 by an IL-2-dependent murine T cell lymphoma expressing no detectable cell surface receptors for IL-2. 313 97

The susceptibility of human myeloid and lymphoid leukemic blasts to the lytic action of recombinant interleukin-2 (rIL-2)-generated lymphokine activated killer (LAK) cells was analyzed. With the exception of the K562 cell line, all 9 leukemic cell lines tested were resistant to the natural killer activity of freshly isolated peripheral blood lymphocytes (PBL) from healthy donors but were susceptible to the lytic action of PBL cultured for 3 days in the presence of rIL-2. Of the 32 primary myeloid and lymphoid acute leukemia samples investigated, the great majority were natural killer cell-resistant but were variably sensitive to LAK effectors. Variations in LAK activity were observed according to the donor of PBL, while little or no difference was documented in the capacity to elicit LAK activity of PBL cultured with 100 or 1,000 U of rIL-2/ml. Pretreatment of the leukemic target cells with neuraminidase did not increase substantially their sensitivity to LAK activity. LAK cells generated from the PBL of patients at the onset of the disease or in complete clinicohematological remission lysed Raji cells as efficiently as normal LAK effectors. Finally, LAK cells were capable of abrogating the tumor growth in nude mice of a human leukemic T cell line. These findings demonstrate the susceptibility in vitro and in vivo of human leukemic blasts to the lytic effect of LAK cells and point to a possible clinical exploitment of this new form of adoptive immunotherapy in the management of acute leukemia.
Leukemia 1988 Jan
PMID:In vitro and in vivo susceptibility of human leukemic cells to lymphokine activated killer activity. 325 39

Basophils were isolated from the peripheral blood of two patients with Philadelphia positive-chronic myeloid leukemia using monoclonal antibody Bsp-1 and fluorescence activated cell sorting. DNA blot analyses demonstrated rearrangement of the breakpoint cluster region gene in the isolated basophils, which suggests their leukemic origin. Isolated T cells from these patients that were cultured for 14 days in the presence of interleukin-2 lacked rearrangement of the breakpoint cluster region gene and are therefore unlikely to be derived from the chronic myeloid leukemia clone.
Leukemia 1988 Mar
PMID:Basophils exhibit rearrangement of the bcr gene in Philadelphia chromosome-positive chronic myeloid leukemia. 325 49


<< Previous 1 2 3 4 5 6 7 8 9 Next >>