UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
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We studied the presence of HLA class I antigens in 115 samples of bronchogenic carcinomas (66 frozen and 49 formalin-fixed and paraffin-embedded specimens) by the immunophosphatase alkaline and immunoperoxidase methods with antibodies against major histocompatibility complex antigens. We also studied HLA class II antigens on the 66 frozen tumor samples. Nonneoplastic lung tissue was also analyzed for purposes of comparison. Pneumocytes and epithelial respiratory cells expressed HLA class I and II antigens. The expression of class I antigens was totally lost in 29 tumors (25%). The defect in HLA gene expression affected both heavy chain and beta 2-microglobulin, as demonstrated by the null reactivity with specific antibodies. In 2 cases of 66 studied in cryostatic section, the selective loss of A locus was observed, and in three cases selective loss of B locus was detected. The expression of class I antigens was compared with clinical-pathological parameters such as histological type, degree of differentiation, and tumor stage, as well as tumoral ploidy. The absence of expression of HLA class I molecules was significantly associated with poorly differentiated and undifferentiated tumors (P less than 0.0001) and with aneuploid tumors (P less than 0.001), suggesting that some lung tumors may escape immune surveillance and become biologically more aggressive. Class II antigens were expressed in 13 cases of 66 studied (18%) in frozen specimens, and a clear relationship was observed with well-differentiated tumors (P less than 0.05).
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PMID:Expression of HLA class I and II antigens in bronchogenic carcinomas: its relationship to cellular DNA content and clinical-pathological parameters. 165 7

Tumor-infiltrating lymphocytes (TIL) were obtained from a biopsy of a patient with a Ki-1-positive large cell lymphoma of the skin. Immunohistologic studies of the large anaplastic tumor cells showed an "aberrant" T "helper/inducer" phenotype (CD30 + CD3-CD4+ CD8-IL-2R + HLA-DR+). Using cDNA probe for the constant region of the T-cell receptor (TCR) beta gene, the cells were identified by their distinct monoclonal rearrangement of T-cell receptor (TCR)-beta DNA. Tumor cells isolated from biopsies were cultured in the presence of interleukin-2 (IL-2). Outgrowing lymphocytes were cloned, expanded in vitro, and 11 clones were subjected to phenotypic analysis: ten clones showed a predominantly CD4-positive T "helper/inducer" phenotype whereas one clone expressed CD8 T "cytotoxic/suppressor" antigens. In contrast to the tumor cells, cells of all clones grown in vitro expressed the TCR-associated CD3 complex. Furthermore, cells from all clones analyzed expressed CD5, CD7, CD45RO (UCHL1), CD11a (LFA-1), CD25, and HLA-DR antigens. Cells of two of ten CD4-positive clones expressed CD45RA (2H4) in addition to UCHL1. T-cell clones isolated from the tumor and grown in vitro exhibited individual DNA restriction band patterns different from that of a DNA tumor biopsy specimen. Therefore, the authors conclude that these T-cell clones represent presumably nonmalignant TIL. All clones tested secreted interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha in vitro. Nine of 11 clones were found to secrete additionally IL-2 and IL-4 upon stimulation with phytohemagglutinin (PHA) whereas two clones did not secrete detectable amounts of IL-4. Selective growth of TIL in the presence of IL-2 opens the possibility to use these cells in adoptive immunotherapy of cutaneous T-cell lymphoma (CTCL). Cytokines secreted by TIL cells in vitro (IL-2, IL-4, IFN-gamma, TNF-alpha) may be involved in their antitumorigenic activity. Moreover, these data implicate that CD4-positive TIL derived from CTCL cannot be grouped into different subsets based on the production of IL-2, IL-4, IFN-gamma, and TNF-alpha.
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PMID:Tumor-infiltrating lymphocytes isolated from a Ki-1-positive large cell lymphoma of the skin. Phenotypic characterization and analysis of cytokine secretion. 165 3

The studies on the T cell response against EBV carrying B cells demonstrated its high power in vivo. Malignancies with phenotypes similar to the in vitro transformed B cells occur only in severely immunosuppressed patients. Presently the goal of the studies is the identification of the antigens recognised by T lymphocytes and their association with the various HLA alleles. The studies on human sarcomas and carcinomas still struggle with the demonstration of specific T cell responses and the characterisation of the target molecules on the tumor cells. The main goals are the possibilities to readminister tumor reactive T cells for therapeutic purposes and the use of in vitro assays for guidance of the design and schedule for immunotherapy protocols.
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PMID:Recognition of transformed cells by autologous lymphocytes: a review. 166 69

Autologous melanoma-specific CTL recognize a common tumor-associated Ag (TAA) in the context of HLA class I antigens. We have demonstrated that HLA-A2 can be a restricting Ag and, in T cell lines homozygous for HLA-A2, that CTL can be generated by stimulation with HLA-A2 allogeneic melanomas. In the current study, we have investigated T cell lines from patients who are heterozygous at HLA-A region locus, to determine the relative importance of each A-region allele in this MHC-restricted recognition of tumor. We have shown that HLA-A1 can be a restricting Ag, and that allogeneic melanomas expressing HLA-A1 can substitute for the autologous tumor in the generation of HLA-A1-restricted CTL. However, when T cell lines express both HLA-A1 and HLA-A2, the HLA-A2 allele governed restriction of the melanoma TAA. Three autologous-stimulated HLA-A1, A2 CTL lines all demonstrated restriction by the HLA-A2 allele, when examined in cytotoxicity assays, cold-competition assays, and proliferation assays. There was no evidence of restriction by the second HLA-allele, HLA-A1. Although the autologous-stimulated CTL use a single A-region allele for tumor recognition, the autologous HLA-A1, A2 tumors are lysed by both HLA-A1-restricted and HLA-A2-restricted CTL. The dominance of restricting alleles was further demonstrated when HLA-matched allogeneic melanomas were used as the stimulating tumor to generate tumor-specific CTL. Stimulation of the heterozygous (HLA-A1, A2) lymphocytes with HLA-A2-matched allogeneic melanomas resulted in CTL specific for the autologous tumor, and restricted by the HLA-A2 Ag. However, stimulation with an HLA-A1-matched allogeneic melanoma failed to induce tumor-specific CTL restricted by the HLA-A1 Ag. The data suggest there is a dominance of HLA-A region Ag at the level of the T cell, such that only one is restricting in the recognition of the autologous melanoma. At the level of the tumor, however, the TAA is expressed in the context of both HLA-A region alleles. We can generate specific CTL from lymph node cells or PBL and HLA-A region matched allogeneic melanomas; however, because most patients are heterozygous at the HLA-A region locus, an understanding of the dominant restricting alleles must be obtained so that an appropriately matched allogeneic melanoma can be selected.
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PMID:MHC-restricted recognition of autologous melanoma by tumor-specific cytotoxic T cells. Evidence for restriction by a dominant HLA-A allele. 167 80

A total of 31 human peripheral adenocarcinomas (AC) of the lung were subclassified by light and electron microscopy according to their phenotypic characteristics. The expression of HLA-A,B,C and HLA-DR on tumor cells, and the degree of subclassified mononuclear cell infiltration were determined using immunohistologic and morphometric methods. The study shows that pulmonary AC can be subdivided in two main types with different properties. The first type is characterized by mucin production comparable to that of bronchial goblet cells. These mucinous AC of type I show nearly no expression of HLA-DR; the tumor volume fraction with HLA-A,B,C expression is greatest in highly differentiated AC I, and decreases significantly with lower grades of differentiation. The AC of type II, possibly originating from the bronchioloalveolar transitional zone, show properties of Clara cells and of type II-pneumocytes by light and electron microscopy. These features include apically located electron-dense granules and lamellar bodies occurring often simultaneously. Both groups of HLA-antigens, HLA-A,B,C and HLA-DR, are homogeneously distributed in a similar phenotypic fashion to Clara cells and pneumocytes II of the normal lung. The significant differences in mononuclear cell infiltration between the two tumor types are possibly induced by the different HLA-DR expression, which have not been seen in AC from other sites. In AC II with homogeneous HLA-DR expression in the tumor epithelium, the numbers of tumor-infiltrating Langerhans cells, and T- and B-lymphocytes are significantly higher than in AC I, possibly indicating better host immunologic defense mechanisms against these tumors.
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PMID:Special subtypes of pulmonary adenocarcinomas indicated by different tumor cell HLA-expression and stromal infiltrates. A light, electron microscopic and immunohistologic study. 168 66

We have studied restriction fragment length polymorphism (RFLP) in the region 300 kb centromeric to the HLA-B locus. Four probes were used: one was genomic DNA derived from the tumor-necrosis factor (TNF)-beta gene, one was a cDNA for the BAT3 gene, and two single-copy genomic probes, R5A and M20A. The order of these markers from HLA-B towards the centromere is M20A, R5A, TNF and BAT3. The BAT3 and TNF-beta probes each detected two allelic bands with Taq I and Nco I digestion, respectively; the R5A and M20A probes each detected three polymorphic allelic bands with BstEII digestion. To determine if these restriction polymorphisms are preferentially associated with certain HLA-B and -DR haplotypes, a total of 153 HLA haplotypes was analyzed. The haplotypes A1, B8, DR3 and A3, B7, DR2 were each associated with a distinct combination of polymorphisms identified at these four sites, thereby demonstrating that the strong linkage disequilibrium characteristic of these haplotypes extends also to this segment of the class III region. In contrast, haplotypes that are not in positive linkage disequilibrium, such as A1,B8,DR4 and A2,B7,DR3, showed no preferential association with any of these polymorphisms. The antigens HLA-B27 and B35 were also found to be in positive linkage disequilibrium with RFLP patterns at three of these sites, and HLA-B14,B35,B44,Bw57 and Bw62 were found preferentially associated with polymorphisms at one or two of these sites, independent of the DR antigen present. These data further demonstrate that genetic linkage disequilibrium in the HLA class III region is complex and variable among different HLA haplotypes.
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PMID:Association of four HLA class III region genomic markers with HLA haplotypes. 168 63

Nine different human melanomas and 16 clones, isolated from 2 of them, were characterized for susceptibility to rIL1-beta-, rIL4-, rTNF-alpha- and rIFN-gamma-mediated effects on proliferation and surface expression of class-II HLA (DR and DP), ICAM-1 and LFA-3 molecules and of 3 tumor-associated antigens (recognized by MAb 763.74T, 149.53 and R24). In spite of marked inter- and intra-tumor heterogeneity for susceptibility to the effects of each cytokine, the most frequent upregulation was induced on the HLA class-II antigens by rIFN-gamma and on adhesion molecules by rIFN-gamma, rTNF-alpha and rIL1-beta, while tumor-associated antigens were often down-modulated by rIFN-gamma. Tumor heterogeneity was also evident on tumor-cell proliferation with an apparent hierarchy in the frequency and extent of inhibitory effects: rIFN-gamma greater than rTNF-alpha greater than rIL1-beta = rIL4. Combinations of 2 cytokines resulted in rare and limited changes in the antigenic profile in comparison to the effects seen with single factors, while the combination of rTNF-alpha and rIFN-gamma resulted in significant synergistic antiproliferative effects on most tumor cells and clones. Taken together, these results indicate that single cytokines can profoundly affect the antigenic profile of melanoma cells, while strong tumor-growth inhibition is often achieved by combinations of 2 cytokines acting in synergism.
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PMID:Cytokine-mediated modulation of HLA-class II, ICAM-1, LFA-3 and tumor-associated antigen profile of melanoma cells. Comparison with anti-proliferative activity by rIL1-beta, rTNF-alpha, rIFN-gamma, rIL4 and their combinations. 168 76

Transplantation of immunocompetent cells present within allogeneic bone marrow has been associated with the elimination of residual host leukemia, both in animal tumor models and in patients receiving marrow transplants for leukemia. This observation has been called the "graft-versus-leukemia effect." We have attempted to study this phenomenon in vitro by characterizing the cytolytic response of T cells from normal donors after in vitro activation with allogeneic leukemic cells. As expected, most T cells that react against an allogeneic patient's leukemic cells recognize their foreign HLA antigens and lyse the patient's nonleukemic remission lymphoid cells. In addition, we have shown that a small fraction of the T cells recognize and lyse foreign leukemic targets without lysis of nonmalignant remission targets from the same leukemic patient. These T cells have been isolated and characterized as CD3+, CD4+ cells expressing the alpha/beta T cell receptor (TCR). Their lysis appears to reflect specific antigen recognition mediated via the CD3-TCR complex and interactions involving the CD4 receptor. Some of these "leukemic specific" T cell lines, which are restricted by HLA class II molecules, can also lyse occasional nonleukemic cells from certain unrelated donors. This recognition appears to involve crossreactive determinants shared by the leukemic cells and the unrelated allogeneic nonleukemic cells. These specific interactions may represent an in vitro model of the graft-versus-leukemia effect.
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PMID:Specific recognition of human leukemic cells by allogeneic T cells: II. Evidence for HLA-D restricted determinants on leukemic cells that are crossreactive with determinants present on unrelated nonleukemic cells. 169 92

A monoclonal antibody, 1D10, was derived that identifies a new antigenic epitope on the surface of malignant B lymphocytes. Normal resting and stimulated lymphocytes do not express the antigen. The majority of individuals with acute Epstein-Barr virus infection express the antigen on their lymphocytes, and in these patients, the T lymphocyte may also be antigen positive. The antigen was found on B-lymphoid neoplasia from the early pre-B cell stage through terminally differentiated plasma cells, a characteristic not reported for other B cell-associated antigens. Studies on homozygous typing cells and cells from individuals with known HLA phenotypes indicate that the antigen does not segregate in a pattern characteristic for major histocompatibility antigens. The molecule is a heterodimeric polypeptide with the molecular weight and isoelectric points of the alpha and beta chains being 32,000 d/4 and 28,000 d/6, respectively. Evidence is presented that the 1D10 molecule is not HLA-DR, -DP, or -DQ. By extrapolation, we suggest that this novel molecule may represent HLA D-region gene expression of a gene(s) not normally expressed. Potential candidates are D-region pseudogenes. We conclude that the antigenic epitope identified by the 1D10 monoclonal antibody is unique among previously described B-lymphocyte antigens. Further studies of the factors controlling the expression of this molecule, as well as studies designed to look at the possible cellular function, may provide insights for understanding crucial events in the malignant transformation of lymphocytes.
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PMID:Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes. 169 29

Peripheral blood mononuclear cells were enriched for gamma delta T cells by immunomagnetic separation, stimulated with cells from an allogeneic donor, and cloned. T-lymphocyte clones (TLC) of the two major gamma delta T-cell subsets, BB3+ (i.e. V delta 2+) and delta TCS1+ (i.e. V delta 1/(D)/J delta 1), were obtained. In addition, one gamma delta TLC was BB3- delta TCS1-. All of the BB3+ TLC showed strong cytotoxicity against various allogeneic tumor cell lines, such as Daudi and K562. The cytotoxicity against the tumour cell lines was modulated by MoAb against the gamma delta TcR. The BB3+ TLC were not cytotoxic against B-lymphoblastoid cell lines (B-LCL). In contrast, the delta TCS1+ TLC showed much lower cytotoxic activity against the tumour cell lines, but many were strongly cytotoxic against allogeneic B-LCL. Some of the delta TCS1+ TLC demonstrated HLA-specific cytotoxicity, while other delta TCS1+ TLC had a more broad cytolytic activity against B-LCL. Thus, the two major subtypes of gamma delta T cells from this donor, as defined by MoAb BB3 and delta TCS1, were distinct with respect to recognition specificity.
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PMID:Specificity of two subsets of cytotoxic human gamma delta T-cell clones. 169 96

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