Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cytokines with human recombinant interleukin-2 (rIL-2) on cytolytic T cell (CTL) generation was studied. Lymphocytes were isolated from involved lymph nodes of melanoma patients and expanded in medium containing rIL-2 alone or in combination with other human cytokines (rIL-1, rIL-4, rIL-6, and recombinant human tumor necrosis factor-alpha (rTNF alpha)). Lymphocytes incubated with rIL-2 alone did not grow, whereas addition of the other cytokines augmented IL-2-mediated lymphocyte proliferation. In all cultures, the majority of expanded lymphocytes were CD3+, CD56- T cells. Lymphocytes cultured with rIL-1, rIL-2, rIL-4, and rIL-6 exhibited cytolytic activity specific for autologous melanoma, which increased during the culture period (24.08 and 58.18% at 16 and 30 days in culture, respectively) without detectable changes in cell surface phenotype and remained high even after 100 days in culture. Moreover, the cytolytic activity was inhibited by monoclonal antibodies (mAbs) against HLA-class I, CD3, and CD8 molecules but not by mAbs against HLA-class II or CD4 molecules. Lymphokine-activated killer (LAK) activity was detected in lymphocytes cultured with rIL-1, rIL-2, and rIL-6 in the presence or absence of rTNF alpha. These data indicate that lymphocytes derived from melanoma-invaded lymph nodes and cultured in the presence of rIL-1, rIL-2, rIL-4, and rIL-6 offers an efficient system to expand CD8+ CTLs with HLA-restricted cytolytic specificity against autologous tumor cells.
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PMID:In vitro expansion of tumor-specific, HLA-restricted human CD8+ cytolytic T lymphocytes. 751 62

As a means to increase the immunogenicity of tumor cells, we have developed a retroviral vector to transfect human B7, a molecule capable of delivering co-stimulatory signals to T cells. Three different tumors, a melanoma, an ovarian carcinoma and a myelomonocytic leukemia, were transfected with high efficiency. When compared for their capacity to stimulate allogeneic T cells, B7+ but not B7- tumor cells were able to stimulate strong proliferative and cytotoxic responses. The effector CTL generated recognised B7+ and B7- cells as well as untransfected tumor cells, indicating that B7 is required in the inductive but not the effector phase of the response. Remarkably, B7+ tumor cells were able to induce cytotoxic responses both by CD4-depleted and by CD8-purified T cells, demonstrating that expression of B7 is at the same time necessary and sufficient to induce a cytotoxic response in the absence of T-helper cells and accessory cells.
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PMID:T-helper- and accessory-cell-independent cytotoxic responses to human tumor cells transfected with a B7 retroviral vector. 751 23

The B16/BL6 melanoma is a relatively nonimmunogenic tumor expressing low levels of MHC class I molecules. BL6 clones expressing transfected H-2Kb class I molecules were, by contrast, highly immunogenic in immunocompetent mice. Tumor-infiltrating lymphocytes (TILs) generated from the H-2Kb+ BL6 lesions (Thy 1.2+, CD8+, CD4-) efficiently lysed H-2Kb+ melanoma (CL8-1 and 2Kb38) and the H-2Kb+ nonrelated 3-methylcholanthrene (MCA)-105 sarcoma, but not the H-2Kb- parental melanoma BL6-8. This strongly suggests that CL8-1, 2Kb38, and MCA-105 express identical or cross-reactive T cell epitopes recognized by CL8-1 TILs in the context of the H-2Kb class I allele. To identify the T cell epitopes, peptides were acid-eluted from various cells, and fractionated by HPLC. Five HPLC fractions (F1mel-F5mel) of 70 tested contained peptides derived from H-2Kb+ CL8-1 melanoma (but not H-2Kb- melanomas) that were capable of conferring susceptibility to CL8-1 TIL lysis on H-2b-expressing target cells (EL4, C1R.Kb), but not on H-2d-expressing P815 target cells. CL8-1 TILs failed to recognize peptides derived from H-2Kb+ nonmelanoma targets such as EL4 or normal B6 splenocytes. Interestingly, CL8-1 TILs appeared to recognize peptide species contained in two HPLC fractions derived from the MCA-105 sarcoma (F1sar and F5sar). Conversely, TILs derived from MCA-105 lesions recognized MCA-105 and CL8-1 tumor cells, as well as F5mel and F5sar peptides presented by EL4 targets. These data support common murine tumor-associated peptide epitopes presented by H-2Kb and recognized by CD8+ CTLs derived from histologically distinct tumors, melanoma and sarcoma.
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PMID:Partial purification of murine tumor-associated peptide epitopes common to histologically distinct tumors, melanoma and sarcoma, that are presented by H-2Kb molecules and recognized by CD8+ tumor-infiltrating lymphocytes. 751 74

Interleukin 15 (IL-15) is a novel cytokine that shares no homology with IL-2, but it requires the use of beta and gamma chains of the IL-2 receptor complex for binding and signaling. In vitro studies have shown induction of CTL and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMCs) from normal donors by IL-15 against known tumor targets. The present study attempts to define the role of IL-15 in generating LAK activity from melanoma patient lymphocytes. PBMCs of patients newly diagnosed with metastatic melanoma were incubated with different doses of recombinant human IL-15 and tested against autologous tumor cells, LAK sensitive cell lines (i.e., FMEX and Daudi), as well as the natural killer-sensitive cell line K562, in a 15-h 51Cr release assay. The effect of IL-15 was found to be both time and dose dependent, with peak activity detected after 2 or 3 days of culture with 100 ng/ml of this cytokine. LAK and not CTL activity in patient PBMCs was detected by the inability of mAbs against CD4, CD8, and MHC class I to effectively block lysis of autologous tumor and FMEX melanoma cells. In addition, interaction via the CD18 adhesion molecule was shown to be critical in IL-15-induced LAK-mediated lysis of autologous tumor cells. Finally, incubation of patient PBMCs with IL-15 for 6 h resulted in the up-regulation of perforin mRNA transcription. These findings suggest that LAK activity can be generated from melanoma patient PBMCs in the presence of IL-15 to lyse autologous tumor cells in a non-MHC-restricted manner. This new cytokine may play an important role in antitumor immunity with a possible use for cancer immunotherapy.
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PMID:Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. 758 40

There exists substantial evidence that the immune system plays an important role in the prevention and control of cancer. This evidence includes 1) the occasional clinical observation of spontaneous tumor regression, 2) the correlation of this phenomenon with the presence of tumor-infiltrating lymphocytes, and 3) the in vitro demonstration of the specificity of tumor-infiltrating lymphocytes for the autologous tumor. Because of the only weak immunogenicity of and the occurrence of active immunosuppression by the cancer, this response often does not suffice to combat the neoplasm successfully. One strategy for amplifying the anti-tumor immune response is vaccination of patients or experimental animals with cancer cells, the immunogenicity of which has been enhanced by the introduction of genes encoding immunostimulatory molecules. Several investigators have shown that transfection of certain types of cancer cells with the interleukin-2 gene reduces their tumorigenicity and that immunization with interleukin-2-transduced cancer cells protects animals from challenge with a tumorigenic dose of wild-type cancer cells. We have recently established a murine melanoma model (M-3) and have used it to elucidate the mechanism by which interleukin-2-transfected cancer cells can induce protective immunity. We will demonstrate the following: 1) that the mechanisms leading to the loss of tumorigenicity of interleukin-2-expressing cancer cells are somewhat different from those leading to the rejection of wild-type cancer cells in immunized animals, 2) that immunity resides within both CD4- and CD8-positive T cells, and 3) that host antigen-presenting cells are probably important in the induction of this protective anti-tumor immunity.
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PMID:Immunologic host defense in melanoma: delineation of effector mechanisms involved and of strategies for the augmentation of their efficacy. 761 88

Interleukin-2 (IL-2)-dependent large granular lymphocytes (LGL) with a distinctive surface phenotype were generated from histologically normal duodenal biopsy tissues. Immunoperoxidase staining of the mucosa with an anti-CD56 monoclonal antibody revealed LGL localized in the lamina propria rather than in the epithelium. Light and electron microscopy demonstrated azurophilic and electron-dense cytoplasmic granules. Flow cytometry analysis revealed that these cells express CD45, CD56, CD2, CD7, CD11a, CD18, CD69 and the intermediate affinity (p70) IL-2 receptor (IL-2R) but not CD57, CD16, CD3, CD4, CD5, CD8, CD45RA, CD25, or the high affinity p55 IL-2R. The LGL proliferated when cultured in the presence of human rIL-2 but not in the presence of human rIL-4. Functional studies demonstrated that the LGL had strong cytotoxicity against natural killer (NK) target cells, K562, but not NK-resistant targets such as Colo 205, Melanoma and Epstein-Barr virus (EBV)-transformed B-cell lines. The LGL expressed genes for IL-5, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha) and the corresponding cytokines were detected in culture supernatant. These results provide evidence for an important role of gut mucosal LGL in the induction and regulation of inflammation and immunity in the gut.
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PMID:Morphological, phenotypic and functional characteristics of a pure population of CD56+ CD16- CD3- large granular lymphocytes generated from human duodenal mucosa. 769 28

It has long been suggested that malignant melanomas, cutaneous as well as uveal, are responsive to human immune-mediated host defenses. We report here 5 consecutive cases of posterior choroidal melanomas which were treated with hyperthermia generated by high-intensity focused ultrasound. Patient immune function was monitored by determination of T-cell helper/suppressor (CD4/CD8) ratios immediately before and approximately 1 week following hyperthermia treatment. All 5 patients had normal total T-cell counts as measured by the pan-T-cell marker CD3. Two patients were noted to have inverted CD4/CD8 ratios (< 1:1) before hyperthermia. In both these cases, the ratio reverted to normal (> 1:1) 1 week following treatment. One patient whose CD4/CD8 ratio was not inverted was noted to have a further increase in his CD4 T cells relative to his CD8 (37% increase). Two patients with initially normal CD4/CD8 demonstrated no significant change following hyperthermia. It appears that ultrasonic hyperthermia may induce a systemic immunomodulatory effect in patients with posterior choroidal melanoma and inverted T-cell helper/suppressor resulting in a normalization of T-cell subset ratios.
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PMID:Immunomodulation in choroidal melanoma: reversal of inverted CD4/CD8 ratios following treatment with ultrasonic hyperthermia. 770 33

Autolymphocyte therapy (ALT) is adoptive cellular therapy of neoplastic disease using ex vivo activation of autologous (human) or syngeneic (murine) lymphocytes from tumor-bearing hosts (TBH) by low doses of anti-CD3 monoclonal antibody (MAb) and a mixture of previously prepared autologous cytokines (T3CS). Ex vivo activation by T3CS without tumor antigen results in expansion of CD44+ (memory) T cells. These memory T cells (ALT cells) mediate in vivo anti-tumor specificity and with cyclophosphamide (CY) are capable of curing metastatic disease in murine TBH. To determine whether CY could enhance the effectiveness of CD4+ or CD8+ subsets of ALT cells, C57BL/6J TBH with B16 melanoma or Lewis lung (3LL) carcinoma were treated with adoptive chemoimmunotherapy (ACIT) using CD4-depleted or CD8-depleted ALT cells and CY. ALT cells were derived from splenocytes of B16 or 3LL-TBH and activated ex vivo with T3CS. Depletion of CD4+ or CD8+ T cells was performed before or after activation with T3CS. B16-TBH or 3LL-TBH that received ACIT using CY with B16-derived or 3LL-derived CD8-depleted ALT cells, respectively, demonstrated cure of metastatic disease regardless of whether CD8+ T cells were depleted before or after T3CS activation. B16 or 3LL-TBH that received ACIT using CY with B16 or 3LL-derived CD4-depleted ALT cells also cured metastatic disease but only if CD4+ T cells were depleted after T3CS activation. Interleukin (IL)-2 added to pre-T3CS CD4-depleted ALT cells cultured with T3CS restored anti-tumor activity when combined with CY. TBH cured by ACIT using CY and ALT-cell subsets derived from syngeneic TBH with the identical tumor displayed tumor-specific immunity in rejecting a lethal challenge of identical but not reciprocal tumor. TBH given ACIT using CY and ALT-cell subsets derived from splenocytes of syngeneic TBH with reciprocal tumors rejected lethal challenges of both tumors. Tumor specificity measured by interferon (IFN)-gamma and 51Cr-release assays was demonstrated in pre- or post-T3CS/CD8-depleted, post-T3CS/CD4-depleted and pre-T3CS + IL-2/CD4-depleted ALT-cell subsets. Our data demonstrate that ACIT using CY combined with ex vivo T3CS-activated CD44+ memory T-cell subsets conveys long-term tumor-specific immunity.
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PMID:Adoptive transfer of ex vivo-activated memory T-cell subsets with cyclophosphamide provides effective tumor-specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma. 775 64

Human autologous tumor-specific T-helper 2 (Th2) cells were investigated in melanoma tumor-infiltrating lymphocytes (TILs). Both a CD4+ T-cell line and its 5 potential T-cell clones established from TILs of a patient with metastatic melanoma produced significant levels of IL-4, IL-6, IL-10 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in response to autologous, but not any of 12 allogeneic, melanoma cell lines. They also produced IL-3 and IL-8 but not IL-2, IFN-gamma, TNF-alpha or TNF-beta in response to autologous tumor cells. Furthermore, they showed autologous melanoma-specific cytotoxicity only in an 18-hr 51Cr-release assay. Specific IL-4, IL-6 or IL-10 production by the CD4+ M73 T-cell line and its clone was inhibited by anti-class II DR (but not anti-class I) MAb, whereas their specific cytotoxicity was inhibited by anti-class I (but not anti-class II) MAb. Anti-CD3 and -CD4 MAb (but not anti-CD8) abrogated both IL-4, IL6 and IL-10 production and cytotoxicity, while anti-IL-4 antibody did not inhibit cytotoxicity. CD4+ potential T-cell clones, but not CD8+ clones, that were established from freshly isolated TILs without in vitro sensitization by autologous tumor cells also produced IL-4, IL-6 and IL-10 but not IFN-gamma or tumor necrosis factor (TNF) alpha in an autologous tumor-specific fashion. These Th2 cells were neither reactive to EBV-B cells nor suppressive against CD8+ T-cell clones. PMA and PHA stimulated these potential T-cell clones, regardless of their specific lymphokine production, to produce IL-3, IL-4, IL-6, IL-8, IL-10, GM-CSF, TNF alpha and IFN-gamma. Our results demonstrate the presence of autologous tumor-specific Th2 cells at the melanoma sites.
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PMID:Characterization of autologous tumor-specific T-helper 2 cells in tumor-infiltrating lymphocytes from a patient with metastatic melanoma. 791 81

We have studied the properties of eosinophils from 26 patients with malignant melanoma and 16 patients with renal cell carcinoma (RCC) who were entered into a phase II clinical trial using various schedules of low-dose rhIL-2 immunotherapy. Eosinophilia was observed in 65% of melanoma patients and 100% of renal patients when receiving rhIL-2 therapy. The eosinophil count increased up to 20-fold approximately 5 d after the appearance of lymphocyte activation markers. This would be consistent with eosinophil kinetics and the release of soluble mediators, for example IL-5, from lymphocytes. Eosinophils from eosinophilic patients became hypodense compared to their pre-treatment levels as demonstrated by sedimentation through a discontinuous metrizamide density gradient; they also showed an increased expression of CD4, CD25 and CD11b cell surface activation markers. Eosinophil count could not be correlated to either patient survival or response to therapy in melanoma patients; however, patients with renal cell carcinoma demonstrated a significant correlation (P < or = 0.05) between eosinophil count and survival but not with clinical response. Therefore the maximum eosinophil count achieved during rhIL-2 therapy is of prognostic significance in patients with renal cell carcinoma.
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PMID:Changes in the phenotypic characteristics of eosinophils from patients receiving recombinant human interleukin-2 (rhIL-2) therapy. 791 67


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