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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-gamma affected the expression of the products of the immunoassociated antigen complex by a differential modulation of DR- and DC-locus-controlled molecules. In melanoma M14 cells treated with interferon-gamma, levels of DR molecules were increased two- to threefold, whereas levels of DC molecules were increased six- to sevenfold. Similar effects were induced on the two allelic products of each locus.
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PMID:Differential effects of gamma interferon on expression of HLA class II molecules controlled by the DR and DC loci. 641 9

The ability of recombinant interferon-gamma (IFN-gamma) to activate mouse macrophages was investigated. The use of recombinant IFN-gamma has the advantage of being devoid of contaminating lymphokines. Two preparations of IFN-gamma were utilized, one which was not glycosylated and which was highly purified from Escherichia coli another which was glycosylated and which was from transfected COS-7 monkey cells. Both preparations of recombinant IFN-gamma activated murine macrophages to kill lymphoma and melanoma tumor targets, suggesting that glycosylation of the protein or the presence of other mammalian proteins is not essential for activation. Significant levels of cytolytic activity were induced from IFN-gamma (1 to 10 units/ml). This activity was undiminished by treatment of the IFN-gamma preparations with polymixin B at doses which neutralized endotoxin (50 micrograms/ml). Similarly, IFN-gamma, at low concentrations, induced an inhibition of migration by macrophages. Based on antiviral activity, IFN-gamma was shown to be 100 to 1000 times more potent than was IFN-beta as a macrophage-activating agent. Taken together, these results demonstrate that murine IFN-gamma is a macrophage-activating factor which is effective at physiological concentrations. Of particular interest is the observation that the nonglycosylated E. coli-derived IFN-gamma is active and therefore may be of value for therapeutic studies, since it can be easily produced in large amounts.
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PMID:Potent activation of mouse macrophages by recombinant interferon-gamma. 643 14

Intraocular melanomas, especially those of the anterior segment, reside within an immunologically privileged milieu. Aqueous humour contains a variety of immunomodulatory factors that are believed to contribute to ocular immune privilege. Among these is transforming growth factor-beta (TGF-beta), which has been shown to down-regulate major histocompatibility complex (MHC) class I antigens on normal cells. Since the susceptibility of tumour cells to natural killer (NK) cell-mediated lysis is inversely correlated with the expression of MHC class I antigens, tumour cells exposed to TGF-beta might be expected to experience enhanced susceptibility to NK-mediated killing. This was examined by incubating two human uveal melanoma cell lines in the presence of TGF-beta and evaluating the expression of MHC class I antigen and susceptibility to NK cell-mediated lysis. OCM1 and OCM8 melanoma cells constitutively express high levels of class I antigen (85-90% positive) and low susceptibility to NK-mediated lysis in vitro (3-8%). Incubation with TGF-beta produced a significant reduction in class I antigen expression (52-62%) and a proportional increased susceptibility to NK cell-mediated cytolysis (17%). Analogous effects were found using a human uveal melanoma cell line (OCM3) that constitutively expresses low amounts of class I (< 5% positive) and high NK susceptibility (35% lysis). Stimulation of class I antigen expression by incubation with interferon-gamma resulted in a sharp increase in class I expression (80% positive) and a comparable diminution in susceptibility to NK cell-mediated lysis (< 10%). The results indicate that TGF-beta, at concentrations found in the aqueous humour, can significantly alter MHC class I antigen expression and the susceptibility of ocular melanoma cells to NK cell-mediated cytolysis.
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PMID:Transforming growth factor-beta down-regulates major histocompatibility complex class I antigen expression and increases the susceptibility of uveal melanoma cells to natural killer cell-mediated cytolysis. 749 Jan 28

LM mouse fibroblasts (H-2k) were modified for the expression of (antibody-defined) melanoma-associated antigens (MAA) and the secretion of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) (RLBA-IL-2/IFN-gamma cells). The cell construct was tested for its immunogenic properties in C57BL/6 mice (H-2b) with B16 melanoma. The results indicated that the survival of mice injected with a mixture of B16 cells and the modified, double cytokine-secreting fibroblasts was significantly longer than that of mice injected with B16 cells and LM cells modified for the expression of MAA and the secretion of IL-2 or IFN-gamma alone (RLBA-IL-2 or RLBA-IFN-gamma cells). Both natural killer/lymphokine-activated killer (NK/LAK) cells and Lyt-2.2 + CTLs with anti-melanoma cytotoxic activities were predominant in mice immunized with the double cytokine-secreting cells. B16 melanoma cells persisted in mice treated with RLBA-IL-2 cells (B16-R3). The B16-R3 cells were resistant to anti-melanoma effector cells from mice immunized with RLBA-IL-2 cells. The recurrent melanoma cells were deficient in the expression of MHC class I determinants. Class I expression by B16-R3 cells was increased if they were incubated in medium conditioned by the growth of IFN-gamma-secreting RLBA-IL-2/IFN-gamma or RLBA-IFN-gamma cells. After incubation, the sensitivity of B16-R3 melanoma cells to immune-effector cells from mice immunized with RLBA-IL-2 cells was restored. The survival of mice bearing low MHC class I-expressing B16-R3 cells, treated RLBA-IL-2/IFN-gamma cells, was determined. The treated animals survived significantly longer than mice with B16-R3 melanoma treated with RLBA-IL-2 cells. Similar results were obtained for mice with B16-R3 melanoma treated with RLBA-IFN-gamma cells. We postulate that immunization of mice with IL-2/IFN-gamma double cytokine-secreting cells stimulated multiple anti-melanoma effector mechanisms. Analogous to the enhanced therapeutic anti-tumour effects of combination chemotherapy, it was likely that treatment with a cellular immunogen engineered to stimulate more than one effector mechanism resulted in the elimination of larger numbers of tumour cells than treatment with an immunogen that stimulated a single effector mechanism alone.
Melanoma Res 1995 Aug
PMID:Immunization with interleukin-2/interferon-gamma double cytokine-secreting allogeneic fibroblasts prolongs the survival of mice with melanoma. 749 56

Adhesion molecules are likely to play a role in the process of tumour progression. We investigated the expression of integrins, ICAM-1, and CD44 and the influence of interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), and tumour necrosis factor-alpha (TNF-alpha) on expression of these molecules on four uveal melanoma cell lines. The in vitro integrin expression was quite variable. The alpha V and beta 1 subunits were expressed on all cell lines, and none of the cell lines showed any alpha 3, beta 2, or beta 4 expression. Other integrin subunits showed a more variable pattern. ICAM-1 and CD44 were strongly expressed on all cell lines. IFN-alpha, IFN-gamma, and TNF-alpha upregulated alpha 1, alpha 2, and alpha 3 expression, and did not alter alpha 4, alpha 5, alpha 6, beta 2, alpha v beta 3, and beta 4 expression. The effects on alpha V and alpha V beta 5 were variable. ICAM-1 was upregulated by IFN-gamma and TNF-alpha, but not by IFN-alpha. Cytokine treatment hardly changed CD44 expression. In one case a comparison was made between expression on cultured cells and on tissue sections of the tumour of origin. Differences in expression were observed for the integrin subunits alpha 2, alpha 3, and alpha 5. This study shows that integrins and ICAM-1 expression on uveal melanoma cells in vitro are susceptible to cytokine treatment, but that the effects on integrin expression are cytokine and cell line dependent. Furthermore, some differences in integrin expression between cells in vivo and in vitro exist.
Melanoma Res 1995 Aug
PMID:Cytokine-mediated modulation of integrin, ICAM-1 and CD44 expression on human uveal melanoma cells in vitro. 749 58

The combination of chemotherapy and immunotherapy seems to improve response rate in metastatic melanoma. We investigated the effects on toxicity and immunological effects of a single dose of dacarbacin (DTIC; 850 mg/m2) or cisplatin (CDDP; 100 mg/m2) added to subsequent immunotherapy with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). Twelve patients, who did not respond to IFN-alpha/IL-2 alone were studied. Six received DTIC and IFN-alpha/IL-2, and six received CDDP and IFN-alpha/IL-2. DTIC did not add significant toxicity except for nausea. Significant thrombocytopenia was observed in two patients after CDDP. Although CDDP led to grade 3 nephrotoxicity in two patients, the IL-2-induced fluid retention was less severe than with IFN-alpha/IL-2 alone. Pharmacokinetics of IL-2 were not altered by DTIC, but higher IL-2 serum levels were found in patients with grade 3 nephrotoxicity after CDDP. The IL-2-related induction of secondary mediators (interferon-gamma, tumour necrosis factor-alpha, soluble CD25) was not impaired by chemotherapy and the induction of neopterin was significantly higher after addition of CDDP. One partial response was observed after addition of DTIC to IFN-alpha/IL-2, and one after addition of CDDP. The addition of a single dose of DTIC or CDDP to IFN-alpha/IL-2 is fairly well tolerated and does not abolish induction of secondary mediators. Randomized trials are necessary to test the clinical efficacy.
Melanoma Res 1995 Aug
PMID:Addition of dacarbazine or cisplatin to interferon-alpha/interleukin-2 in metastatic melanoma: toxicity and immunological effects. 749 66

Human melanomas are infiltrated by tumor-reactive T lymphocytes. However, the ability of these cells to elicit a specific anti-tumor response in vivo remains to be established. Because lymphokine production is critical for T cell functions, we have analyzed the capacity of melanoma-specific tumor-infiltrating lymphocyte (TIL) clones to produce major lymphokines: interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and interleukin-4 (IL-4), as well as tumor necrosis factor (TNF), in response to direct antigen presentation by autologous and allogeneic tumor cells. We report here that, upon stimulation by autologous melanoma cells, all TIL clones secreted TNF but only a few of them produced significant amounts of IL-2, IL-4 or IFN-gamma. Nonetheless, all these clones consistently produced two or three of these last lymphokines upon stimulation with phorbol myristate acetate and calcium ionophore, as well as IL-2 upon CD3 stimulation, showing the existence of three lymphokine profiles among them: Th1, Th0 and a profile characterized by IL-2 and IL-4, but not IFN-gamma secretion. Stimulation of TIL clones by allogeneic melanoma lines sharing the appropriate HLA-peptide complexes revealed that defective IL-2 production seemed to be a constant feature for some clones, while it was, for other clones, dependent on the antigen-presenting tumor cells. For this last type of clone, we further showed that defective IL-2 induction resulted from an LFA-3 defect of some melanoma cells or from distinct yet undefined defects of other melanoma lines. Our data suggest that defective lymphokine secretion may be an essential component of the in vivo failure of melanoma-reactive TIL to control tumor development. Interestingly both CD4+ and CD8+ TIL clones from one patient were fully activated by the autologous melanoma cells in vitro, supporting a potential role of such TIL in spontaneous or induced tumor rejection.
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PMID:Defective lymphokine production by most CD8+ and CD4+ tumor-specific T cell clones derived from human melanoma-infiltrating lymphocytes in response to autologous tumor cells in vitro. 752 55

B7 co-stimulation is necessary to activate resting T cells upon antigen recognition by the T cell receptor. To see whether expression of B7 may render human melanoma cells able to stimulate T cells, a cloned melanoma line (Me1B6), which did not express B7-1, was transfected with the human B7-1 gene. In proliferation assays, B7-1 transfected cells (Me1B6/B7) showed greater stimulatory activity of allogeneic and autologous peripheral blood lymphocytes (PBL) compared to parental, non-transfected tumor cells. This effect was also seen when allogeneic CD8+ and CD4+ subpopulations were used as effectors. In these studies, activation of lymphocytes was B7-1-dependent and HLA classes I and II mediated. The higher proliferation correlated with an increased lytic activity by PBL stimulated with B7-1+ tumor cells against the untransfected Me1B6. Furthermore, PBL from a metastatic melanoma patient stimulated by Me1B6/B7 developed an higher lytic activity not only against Me1B6 but also against their autologous, B7-1- tumor. Finally, after Me1B6/B7 stimulation, PBL released interleukin (IL)-2 and interferon-gamma, but not IL-4, suggesting a Th1-mediated response. These data support the use of B7-1 transfected melanoma cells in the therapeutic vaccination of melanoma patients.
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PMID:A B7-1-transfected human melanoma line stimulates proliferation and cytotoxicity of autologous and allogeneic lymphocytes. 758 65

THP-1 myelomonocytic leukemia cells cultured with either macrophage colony-stimulating factor (M-CSF) or interferon-gamma (IFN-gamma) alone produce, at best, only low levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha). However, combinations of the two factors resulted in at least 3- to 20-fold greater amounts of IL-1 beta and TNF-alpha than would have been predicted by additive mechanisms. This enhanced cytokine production was observed when M-CSF and IFN-gamma were added simultaneously or when M-CSF was added 24 h after addition of IFN-gamma to the cells. Similar results were obtained with fresh human peripheral blood cells treated with IFN-gamma + M-CSF. Cycloheximide treatment of the cultures containing M-CSF and IFN-gamma inhibited the production of IL-1 beta and TNF-alpha. Northern blotting studies revealed no effect of IFN-gamma alone on IL-1 beta or TNF-alpha mRNA production. IL-1 beta and TNF-alpha mRNA expression was observed at 2 and 6 h after treatment with M-CSF or IFN-gamma + M-CSF. Higher TNF-alpha mRNA expression was observed at 2 and 6 h after treatment with IFN-gamma + M-CSF, and higher IL-1 beta mRNA expression was observed at 2 h after treatment with IFN-gamma + M-CSF compared with mRNA levels observed for cells cultured only with M-CSF. These results suggest that the augmented cytokine production resulting from treatments with combinations of M-CSF and IFN-gamma occurs due to increased cytokine mRNA and increased cytokine protein synthesis. In addition to up-regulating cytokines, combinations of IFN-gamma and M-CSF resulted in augmented cell surface expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. This was accompanied by morphological and functional changes that included plastic adherence, extensive homotypic aggregation, and a macrophage-like appearance. These phenotypic changes and enhancements in cytokine expression and cell surface molecule expression may be related to activation of monocytic cells to become cytotoxic effectors by M-CSF and IFN-gamma combinations. In vitro cytotoxicity against A-375 melanoma cells was greatest for cultures that contained M-CSF and IFN-gamma in combination.
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PMID:Activation of cytokine production and adhesion molecule expression on THP-1 myelomonocytic cells by macrophage colony-stimulating factor in combination with interferon-gamma. 759 61

We have previously shown that administration of cyclosporine A (CsA) plus interferon-gamma (IFN) after chemotherapy to mice bearing B16 melanoma results in the generation of cells with major histocompatibility complex (MHC)-unrestricted cytotoxicity in vitro and in vivo; the antitumor effect of these cells could be attenuated by normal spleen cells. This study shows that antitumor effect after treatment with CsA plus IFN after chemotherapy was mediated by T and natural killer (NK) cells, both in vitro and in vivo. Infusion of purified T or NK cells into secondary recipients after chemotherapy resulted in a significant control in the dissemination of tumor as compared to chemotherapy alone. The antitumor potential of NK cells was at least 10 times greater than that of T cells. The effector cells could inhibit the proliferation of tumor cells in vitro without a contact between the effector and tumor cells, suggesting that antitumor effect in this system was partly related to the secretion of cytotoxic factors by the effector cells. Infusion of normal spleen cells inhibited the antitumor effect of adoptively transferred effector cells. This study defines the nature of effector cells involved in mediating the antitumor effect in this model; the optimal efficacy of these cells in the recipient is possibly related to the abolition of a suppressor system by chemotherapy.
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PMID:Induction of antitumor effect by treatment with cyclosporine A plus interferon-gamma after chemotherapy: role of cytotoxic cells. 761 40


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