Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Human melanoma-specific, HLA restricted, cytotoxic T-cell lines can be generated by in vitro stimulation and culturing of peripheral lymphocytes, or lymph node cells, with autologous or HLA-A region matched melanomas in the presence of a low concentration (5 U/ml) of IL-2. Stimulation is followed by a period of clonal expansion and differentiation into cytotoxic T-cells specific for melanoma. We investigated the effect of the PKC modulating drug phorbol dibutyrate combined with the calcium ionophore Ionomycin on growth and differentiation of the cell lines. The growth of the T-cell lines was substantially augmented in the presence of the drugs with increases of 10-fold or more in clonal expansion by 3 weeks of culture. The cell lines were IL-2 dependent for growth in the presence or absence of the drugs and the phenotypic distribution remained predominantly CD3+ T-cells of mixed CD4 and CD8 phenotypes. In spite of the increased rate of growth in the presence of the drugs, autologous melanoma-specific cytotoxicity was almost completely abrogated in those cultures. The cells were, however, nonspecifically lytic in the presence of concanavalin A. The melanoma-specific cytotoxic response was completely restored following culture with IL-2 alone. The results suggest that the human tumor-specific cytotoxic T-cell response can be induced and amplified in the presence of immune modulating drugs.
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PMID:Modulation of in vitro autologous melanoma-specific cytotoxic T-cell responses by phorbol dibutyrate and ionomycin. 229 96

Human rIL-4 was studied for its capacity to induce lymphokine-activated killer (LAK) cell activity. In contrast to IL-2, IL-4 was not able to induce LAK cell activity in cell cultures derived from peripheral blood. IL-4 added simultaneously with IL-2 to such cultures suppressed IL-2-induced LAK cell activity measured against Daudi and the melanoma cell line MEWO in a dose-dependent way. IL-4 also inhibited the induction of LAK cell activity in CD2+, CD3-, CD4-, CD8- cells, suggesting that IL-4 acts directly on LAK precursor cells. IL-4 added 24 h after the addition of IL-2 failed to inhibit the generation of LAK cell activity. Cytotoxic activity of various types of NK cell clones was not affected after incubation in IL-4 for 3 days, indicating that IL-4 does not affect the activity of already committed killer cells. No significant differences were observed in the percentages of Tac+, NKH-1+ and CD16+ cells after culturing PBL in IL-2, IL-4 or combinations of IL-2 and IL-4 for 3 days. IL-4 also inhibited the activation of non-specific cytotoxic activity in MLC, as measured against K-562 and MEWO cells. In contrast, the Ag-specific CTL activity against the stimulator cells was augmented by IL-4. Collectively, these data indicate that IL-4 prevents the activation of LAK cell precursors by IL-2, but does not inhibit the generation of Ag-specific CTL.
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PMID:IL-4 inhibits IL-2-mediated induction of human lymphokine-activated killer cells, but not the generation of antigen-specific cytotoxic T lymphocytes in mixed leukocyte cultures. 245 60

T cell-mediated immune response against autologous melanoma cells was analyzed, at population and clonal levels, in 31 patients with recurrent and/or metastatic disease. Fresh PBL and lymph node lymphocytes (LNL) from melanoma-involved nodes were not cytotoxic against the respective melanoma cells. When activated in in vitro coculture (IVC) against the autologous melanoma cells in the presence of IL-2, a majority of the activated PBL and LNL became cytotoxic against the autologous targets. The activated effector cells were cloned in limiting dilution microcultures, and growing clones were phenotypically defined and were functionally characterized for cytotoxicity and for potential regulatory function. Functional T cell clones were obtained from 15 of 31 cases. Of these, CTL responses exhibiting cytotoxicity restricted against the autologous melanoma were seen in four cases. All four CTL clones were CD3+, CD8+, and CD4-. Three of these four CTL clones were studied extensively. All three of these CTL clones expressed MHC class I-restricted cytotoxicity. mAb anti-CD3 blocked cytotoxicity in two and enhanced cytotoxicity in the other. Neither autologous sera nor autologous nonactivated fresh PBL modulated the cytotoxic functions of the CTL clones at the effector phase. T cell lines exhibiting regulatory function were obtained in 11 cases. The regulatory T cell lines were CD3+, CD4+, and CD8-. In three cases CD4+ clones amplified the cytotoxic response in the PBL in coculture, while in eight other cases the T cell lines downregulated the cytotoxic responses. Such T cell-mediated down-regulations were either restricted to the autologous system, induced by D/DR antigens expressed by the autologous or allogeneic melanoma cells, or induced by stimulus other than D/DR antigens. Taken together, these findings clearly demonstrate the existence of T cell-mediated cytotoxic and regulatory responses against human melanoma.
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PMID:Clonal analysis of cytotoxic and regulatory T cell responses against human melanoma. 247 70

We studied the phenotypes of lymphocytes extracted from 22 specimens of human melanoma, 11 s.c. metastases and 11 lymph node metastases, by two-color flow cytometry. Lymphocytes extracted from s.c. metastases were characterized by a significantly reduced ratio of CD4+ to CD8+ T-cells, as compared with peripheral blood lymphocytes from the same patients. Ten of 11 tumor-infiltrating lymphocytes from s.c. metastases, but only 1 of 11 peripheral blood lymphocytes, had a CD4/CD8 ratio of less than 1.0. This alteration was not observed for lymphocytes obtained from nodal metastases. Furthermore, almost all of the CD4+ T-cells in s.c. metastases expressed the antigen CD29w and were negative for the complementary antigen CD45R. In contrast, the CD29w/CD45R ratio of tumor-infiltrating lymphocytes from lymph node metastases was similar to that of matched peripheral blood lymphocytes. Thus tumor-infiltrating lymphocytes from s.c. metastases have the phenotype associated with true helper or antigen-committed T-cells, which could reflect their sensitization to tumor antigens, while tumor-infiltrating lymphocytes from lymph node metastases may represent merely an expanded residua of lymph node lymphocytes. Since tumor-infiltrating lymphocytes expanded in vitro are being tested as therapy for patients with advanced cancer, these observations may have important therapeutic implications.
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PMID:Depletion of T-cells with the CD4+CD45R+ phenotype in lymphocytes that infiltrate subcutaneous metastases of human melanoma. 247 65

In the course of a phase I trial, in which recombinant IL-2 (rIL-2) was infused intraperitoneally (i.p.) in patients with peritoneal carcinomatosis, we evaluated the effect on "tumor-associated lymphocytes" (TAL) isolated from the ascitic fluid. No major changes in the percentages of cells expressing the CD3, CD4, CD8, Leu-7, OKM1 and WT-31 antigens were detected either in TAL or in peripheral blood lymphocytes (PBL) after 7 days of rIL-2 infusion. In contrast the percentages of TAL (but not PBL) expressing surface IL-2 receptor (Tac), or LAK-1 antigen were sharply increased. Analysis of cytolytic functions showed a potentiation of the lytic activity against natural-killer (NK) sensitive K562 target cells and the de novo appearance of lytic activity against fresh melanoma cells. In one patient IFN-gamma was detected in the ascitic fluid following rIL-2 infusion. T-cell clones derived from the patient were analyzed for the IFN-gamma production. While only approximately 40% of PB-derived control clones produced medium to low amounts of IFN-gamma, all of the TAL-derived clones produced medium to high amounts of the lymphokine.
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PMID:Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2). 249 78

To study the CD4+ and CD8+ tumor infiltrating lymphocytes (TIL) in the antitumor response, we propagated these subsets directly from tumor tissues with anti-CD3:anti-CD8 (CD3,8) and anti-CD3:anti-CD4 (CD3,4) bispecific mAb (BSMAB). CD3,8 BSMAB cause selective cytolysis of CD8+ lymphocytes by bridging the CD8 molecules of target lymphocytes to the CD3 molecular complex of cytolytic T lymphocytes with concurrent activation and proliferation of residual CD3+CD4+ T lymphocytes. Similarly, CD3,4 BSMAB cause selective lysis of CD4+ lymphocytes whereas concurrently activating the residual CD3+CD8+ T cells. Small tumor fragments from four malignant melanoma and three renal cell carcinoma patients were cultured in medium containing CD3,8 + IL-2, CD3,4 + IL-2, or IL-2 alone. CD3,8 led to selective propagation of the CD4+ TIL whereas CD3,4 led to selective propagation of the CD8+ TIL from each of the tumors. The phenotypes of the TIL subset cultures were generally stable when assayed over a 1 to 3 months period and after further expansion with anti-CD3 mAb or lectins. Specific 51Cr release of labeled target cells that were bridged to the CD3 molecular complexes of TIL suggested that both CD4+ and CD8+ TIL cultures have the capacity of mediating cytolysis via their Ti/CD3 TCR complexes. In addition, both CD4+ and CD8+ TIL cultures from most patients caused substantial (greater than 20%) lysis of the NK-sensitive K562 cell line. The majority of CD4+ but not CD8+ TIL cultures also produced substantial lysis of the NK-resistant Daudi cell line. Lysis of the autologous tumor by the TIL subsets was assessed in two patients with malignant melanoma. The CD8+ TIL from one tumor demonstrated cytotoxic activity against the autologous tumor but negligible lysis of allogeneic melanoma targets. In conclusion, immunocompetent CD4+ and CD8+ TIL subsets can be isolated and expanded directly from small tumor fragments of malignant melanoma and renal cell carcinoma using BSMAB. The resultant TIL subsets can be further expanded for detailed studies or for adoptive immunotherapy.
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PMID:Characterization of the CD4+ and CD8+ tumor infiltrating lymphocytes propagated with bispecific monoclonal antibodies. 250 57

We attempted to induce anti-melanoma cytotoxic T cells (CTL) and suppressor T cells (Ts) inhibiting CTL generation by using liposomes carrying various densities of GM3 as tumor antigens. We found that liposomes carrying 6-16 mol% of GM3 with normal primary structure successfully generated anti-melanoma CTL and suppressor T cells, while liposomes with GM3 outside this range had little or no such activity. Anti-melanoma CTL induced by GM3(NeuGc)-liposomes belonged to CD4-/CD8- double-negative CD3+ CTL while GM3(NeuAc)-liposomes induced two types of T cells, CD4+ T cells and double-negative I-J positive T cells which mediated inhibition of the induction of anti-melanoma CTL responses. These cell types were the same as those induced by mitomycin C-treated melanoma cells for CTL induction and soluble melanoma antigen for Ts generation. The results clearly demonstrate that even GM3 with normal primary structure can, at a certain density, generate melanoma antigenicity.
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PMID:Density of GM3 with normal primary structure determines mouse melanoma antigenicity; a new concept of tumor antigen. 253 93

Previous studies in vitro have shown that monoclonal antibodies (MAbs) against gangliosides GD3 and GD2 potentiate lymphocyte responses to a variety of stimuli. The purpose of the present study was to determine by immunohistological techniques whether GD3 and GD2 was expressed on lymphoid cells in vivo around melanoma cells. Studies on metastases in lymph nodes indicated that the lymphoid infiltrate around the margins of the metastases was predominantly CD4+ T cells, which were shown by dual labelling techniques to express mainly GD2 and to a lesser extent GD3. CD4+GD3+ T cells were detected more frequently in cortical regions of the lymph nodes. CD8+ T cells were less numerous than CD4+ T cells and expressed both GD3 and GD2. Expression of GD2 was also prominent on CD4+ T cells, B lymphocytes and dendritic reticular cells in germinal centres, whereas GD3 was mainly expressed on T cells in the margins of the follicles. In contrast to the predominance of CD4+ T cells in lymph nodes, CD4+ and CD8+ T cells were in approximately equal proportions about primary melanoma and metastases in skin. GD2 was largely undetectable on lymphocytes at these sites. In contrast, GD3 was detected on both CD8+ and CD4+ lymphocytes but not on B lymphocytes. The absence of GD2 on CD4+ T cells in skin suggested the latter were a different subpopulation to those in lymph nodes. There appeared to be no clear correlation, however, with subsets of CD4 T cells defined by the 2H4 and Leu 8 MAbs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of the gangliosides GD3 and GD2 on lymphocytes in tissue sections of melanoma. 266 66

Thirty-three patients were treated with thymopentin (synthetic thymic-hormone) after complete surgical removal of cutaneous malignant melanoma without clinical evidence of metastases and with evidence of immunocellular deficiency, with the aim of obtaining a normalization of the immunological parameters. The cell-mediated immunity was evaluated by utilizing monoclonal antibodies CD3, CD4, CD8, CD21, NK and the Multitest C.M.I. (Institut Merieux-Lyon-France), before treatment and then every three months. A follow-up at 29 months showed an improvement of the immune parameters: respectively 58%, 67% and 42% of the patients undergoing therapy had an increase of 40% of the CD3, CD4 and NK lymphocytes. Seven patients, with pre-existing hypergy following tests of skin-reactions, present a normalization of this parameter during the treatment. In the follow-up three patients had metastases. The results show the improvement of the considered immunological parameters and low percentage of relapses. It may be considered as a preventive measure for immunological control of relapses.
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PMID:[Thymopentin in the treatment of cutaneous melanoma]. 269 55

Tumor infiltrating lymphocytes (TIL) were grown in IL-2 from single cell tumor suspensions of 14 human melanomas resected from 12 patients. As a function of time in culture, 4 of 14 TIL cultures eventually expressed highly specific cytolytic activity against fresh autologous melanoma targets in short term chromium release assays, failing to lyse multiple allogeneic tumors or autologous normal cells. These highly specific TIL were identified as CTL by phenotype (CD3+/CD4-/CD8+/Leu7-) and by function (lysis inhibited by antibodies directed against CD3 and MHC class I molecules). Cell separation experiments using immunomagnetic beads identified a highly tumor-specific CTL subpopulation within a nonspecific TIL culture, suggesting that the lytic activity of tumor-specific CTL may be diluted by the nonspecific killer activity present in heterogeneous TIL cultures. These studies provide evidence for specific MHC-restricted human immune responses against autologous tumor in cancer-bearing patients, and may be of importance to ongoing clinical trials using TIL in the immunotherapy of advanced malignancies.
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PMID:Tumor-specific cytolysis by lymphocytes infiltrating human melanomas. 278 62


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