Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Allogeneic lymphocytes administered with an unmanipulated bone marrow transplant provide a strong antileukaemic effect, the so-called graft-versus-leukaemia (GVL) effect. On the other hand, T-cell-mediated graft-versus-host-disease (GVHD) observed after transplantation of unmanipulated BM graft causes substantial morbidity and mortality. The aim of the present study was to determine the antileukaemic potential of enriched IL-2 activated NK cells administered 2 h after BMT. Balb/c (H-2d) mice were given a dose of A20 (H-2d, B-cell leukaemia) cells 2 d prior to lethal total body irradiation (TBI) and transplantation of either syngeneic or allogeneic anti-Thy1.2 (CD90) depleted bone marrow cells. Either syngeneic (Balb/c, H-2d) or allogeneic (C57BL/6, H-2b) enriched and IL-2 (200 U/ml for 24 h) activated NK cells were given 2 h after BMT. Injection of A20 leukaemia into normal Balb/c recipients led to death after a median of 14 d. A lethal dose of TBI followed by either syngeneic or allogeneic Thy1.2-depleted BMT resulted in a modest antileukaemic effect. The adoptive transfer of syngeneic enriched and IL-2 preincubated NK cells given at time of BMT exerted a significantly better GVL effect. However, the infusion of allogeneic enriched NK cells resulted in a stronger GVL effect. These results clearly demonstrate that allogeneic NK cells are superior to syngeneic NK cells in their potential to eradicate residual leukaemia cells after BMT without mediating clinical overt GVHD. This experimental setting may offer a strategy for treatment of haematological malignancies in a phase of minimal residual disease.
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PMID:Allogeneic MHC-mismatched activated natural killer cells administered after bone marrow transplantation provide a strong graft-versus-leukaemia effect in mice. 907 19

Suspension and attachment cultures of Y79 human retinoblastoma cells were treated with all-trans retinoic acid (RA) for up to 10 days to assess its effect on growth and cell-surface expression of immunoglobulin superfamily antigens MHC class I and class II, ICAM-1, NCAM and Thy1. RA up to 10 microM induced growth inhibition, and marked morphological differentiation with extension of prominent processes resembling neurites was seen in attachment cultures. However, above 10 microM RA produced extensive cell death. We also observed increased cell-surface expression of MHC class I, ICAM-1, NCAM and Thy1 on Y79 cells treated with 10 microM over 10 days; constitutive MHC class II expression was not apparent, nor did RA treatment appear to induce Y79 cells to express MHC class immunoreactivity. The up-modulation of cell-adhesion molecules (NCAM, ICAM-1 and Thy1) and immune recognition molecules (NCAM, ICAM-1 and MHC class I), associated with reduced growth and tumour cell differentiation, suggests that RA may have a potential role in regulating the growth and development of retinoblastoma tumours.
Cancer Immunol Immunother 1997 Jun
PMID:Human retinoblastoma: in vitro differentiation and immunoglobulin superfamily antigen modulation by retinoic acid. 922 76

Subset analysis of splenic lymphocytes using flow cytometry showed that the percentages of Thy1.2-(pan T-cells), L3T4-(CD4, helper T-cells), and Lyt2-(CD8, cytotoxic T-cells) positive cell populations were significantly increased in mice orally administered a hot water-soluble fraction from Agaricus blazei as compared with mice treated only with saline. 13C-NMR data indicates that the main component in the active polysaccharide is the complex of alpha-1,6- and alpha-1,4-glucan, which had already been shown to have anti-tumor activity against Sarcoma 180. It seems that the polysaccharide from Agaricus blazei may be an effective prophylactic, protecting humans against cancer by stimulating lymphocytes such as cytotoxic T-cells.
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PMID:Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets in mice. 957 72

The subset of blood cells that expresses both CD34 and Thy1 (CD90) cell surface molecules is enriched in hematopoietic stem cell activity and can be obtained from the peripheral blood of cancer patients after mobilization by chemotherapy and granulocyte colony-stimulating factor (G-CSF). Because transforming growth factor-beta1 (TGF-beta1) is a potent inhibitor of hematopoietic progenitor proliferation and differentiation, in this study we analyzed the impact of neutralizing TGF-beta1 activity during culture and retroviral transduction of CD34+Thy1+ cells. When purified CD34+Thy1+ cells were cultured in the presence of a neutralizing antibody against TGF-beta1, the percentage of cycling cells, proliferation, and absolute number of clonogenic progenitors were increased in comparison to the cultures performed without the addition of antibody. Antibody-mediated neutralization of TGF-beta1 during retroviral transduction performed by coculture of CD34+Thy1+ cells with a MFG-S-nlsLacZ retroviral vector-producing cell line did not affect the percentage of transduced progenitors as assessed by direct X-Gal staining of colonies in clonogenic assays. However, due to the better expansion of CD34+Thy1+ cells in the presence of anti-TGF-beta1, the absolute number of transduced progenitors recovered at the end of the culture was increased.
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PMID:A neutralizing anti-TGF-beta1 antibody promotes proliferation of CD34+Thy-1+ peripheral blood progenitors and increases the number of transduced progenitors. 959 Jun 53

The aim of this study was to activate, in mixed leukocyte/tumor cell cultures (MLTC), cytotoxic lymphocytes exhibiting preferential activity in vitro and in vivo towards allogeneic mouse lymphoma cells. Whereas the lymphoma target cells were readily lysed by the MLTC-derived lymphocytes, the cytotoxicity against the corresponding allogeneic concanavalin-A(ConA)-induced lymphoblasts was more than tenfold lower. Both activities were mediated by CD3+, TCR+, CD8+, CD4- cytotoxic T cells (CTL). ConA-induced lymphoblasts were readily lysed by anti-Thy1.2 antibodies and complement, by CTL derived from mixed leukocyte cultures (MLC) and by the MLTC-derived CTL in the presence of ConA, indicating that the lymphoblasts are not merely less lysable than the lymphoma cells but that the latter are specifically recognized by the CTL. Lymphoblasts poorly competed with 51Cr-labeled lymphoma cells in a "cold"-target competition assay, suggesting that the MLTC-derived CTL largely recognize epitopes expressed only by the lymphoma cells. Furthermore, analysis of the cytotoxic activity of more than 500 MLTC-derived CTL oligoclones and over 30 clones revealed that one-third of them were cytotoxic only against the allogeneic lymphoma cells, one-third were reactive against both the lymphoma and the allogeneic lymphoblast target cells and the remainder were not cytotoxic at all. Upon injection into sublethally irradiated, lymphoma-bearing allogeneic mice, the MLTC-derived CTL cured 56% of the recipients and caused graft versus host disease (GVHD) is only 22%, whereas CTL activated in MLC against allogeneic splenocytes were therapeutically ineffective and caused lethal GVHD in 89% of the recipients. Although the therapeutic efficacy of the in vitro-generated antitumor CTL was demonstrated against experimental lymphoma lines, this strategy might prove effective in tumor immunotherapy in conjunction with other modalities.
Cancer Immunol Immunother 1999 Jul
PMID:Induction of preferential cytotoxicity against allogeneic mouse lymphoma cells: in vitro and in vivo studies. 1043 87

In murine models, therapeutic efficacy of adoptive immunotherapy (AIT) of cancer with lymphokine activated killer (LAK) cells is seen only when applied together with substantial doses of interleukin-2 (IL-2), probably because this cytokine is imperative for both motility and viability of the LAK cells. We wanted to investigate whether IL-2 in addition mediates an immunostimulatory activation and expansion of endogenous effector cells contributing to tumor regression. Using an immunoperoxidase technique, we have been able to longitudinally analyze the accumulation of tumor infiltrating lymphocytes expressing the pan-T cell/activated lymphocyte phenotype (Thy1.2), the natural killer (NK) cell phenotype (AsGM,) as well as the cytotoxic T (CD8) cell phenotype within experimental established B16 pulmonary melanoma metastases in C57BL/6 mice during the first 48 h after high dose IL-2 monotherapy. Whereas a substantial and selective infiltration of AsGM1+ lymphocytes in tumor tissue was seen (262 and 937 cells per sq.mm malignant tissue at 0 and 48 h, respectively), only a minor increase in accumulation of CD8+ cells was seen (106 and 171 cells per sq.mm tumor tissue at 0 and 48 h, respectively). The addition of adoptive transfer with lymphokine-activated adherent NK (A-NK) cells to the high-dose IL-2 treatment resulted in more than a 1.5 fold increase in infiltrating AsGM1+ cells compared to IL-2 therapy alone (1520 compared to 937 AsGM1+ cells per sq.mm malignant tissue). No substantial accumulation of CD8+ cells was observed in this setting either. In contrast, the treatment with high dose IL-2 together with adoptive transfer of mitogen-stimulated, lymphokine-activated T killer (T-LAK) cells increased the infiltration of CD8+ cells 10-fold compared to IL-2 monotherapy (2078 compared to 171 CD8+ cells per sq.mm malignant tissue, respectively). Interestingly, infiltration of both endogenous and exogenous cells continued over time, since the effector-to-tumor cell ratio in metastatic tissue dramatically increased from 1:8 and 1:6 at 16 h to 1:3 and 1:2 at 48 h after adoptive transfer of A-NK and T-LAK cells, respectively. These data underline the longevity of LAK cells in vivo and highlight the importance of IL-2 treatment in recruiting endogenous immune cells to tumor areas.
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PMID:Endogenous and adoptively transferred A-NK and T-LAK cells continuously accumulate within murine metastases up to 48 h after inoculation. 1045 91

Delayed lymphocyte infusions (DLIs) are used to treat relapse occurring post bone marrow transplantation (BMT) and to increase the donor chimerism in recipients receiving nonmyeloablative conditioning. As compared with donor lymphocytes given early post-BMT, DLIs are associated with a reduced risk of graft-vs-host disease (GVHD). The mechanism(s) responsible for such resistance have remained incompletely defined. We now have observed that host T cells present 3 wk after lethal total body irradiation, at the time of DLI, contribute to DLI-GVHD resistance. The infusion of donor splenocytes on day 0, a time when host bone marrow (BM)-derived T cells are absent, results in greater expansion than later post-BMT when host and donor BM-derived T cells coexist. Selective depletion of host T cells with anti-Thy1 allelic mAb increased the GVHD risk of DLI, indicating that a Thy1(+) host T cell regulated DLI-GVHD lethality. The conditions by which host T cells are required for optimal DLI resistance were determined. Recipients unable to express CD28 or 4-1BB were as susceptible to DLI-GVHD as anti-Thy1 allelic mAb-treated recipients, indicating that CD28 and 4-1BB are critical to DLI-GVHD resistance. Recipients deficient in both perforin and Fas ligand but not individually were highly susceptible to DLI-GVHD. Recipients that cannot produce IFN-gamma were more susceptible to DLI-GVHD, whereas those deficient in IL-12 or p55 TNFRI were not. Collectively, these data indicate that host T cells, which are capable of generating antidonor CTL effector cells, are responsible for the impaired ability of DLI to induce GVHD. These same mechanisms may limit the efficacy of DLI in cancer therapy under some conditions.
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PMID:Host T cells resist graft-versus-host disease mediated by donor leukocyte infusions. 1104 15

A deranged expression of MHC class I glycoproteins, characteristic of a variety of malignancies, contributes to the ability of cancer to avoid destruction by T cell-mediated immunity. An abrogation of the metastatic capacity of B16 melanoma cells has been achieved by transfecting an MHC class I-encoding vector into class I-deficient B16 melanoma clones [Gorelik, E., Kim, M., Duty, L. & Galili, U. (1993) Clin. Exp. Metastasis 11, 439-452]. We report here that the deranged expression of class I molecules by B16 melanoma cells is more than a mere acquisition of the capacity to escape immune recognition. Namely, cells of the B16 melanoma prompted splenic lymphocytes to commit death after coculture. However, a class I-expressing and nonmetastatic CL8-2 clone was found to be less potent as an inducer of apoptosis than class I-deficient and metastatic BL9 and BL12 clones. Both Thy1.2(+) and Thy1.2(-) splenocytes underwent cell death when exposed to the class I-deficient BL9 clone. A proportion of CD4(+) and CD8(+) cells among splenocytes exposed to the BL9 clone was lower than that observed in a coculture with cells of the CL8-2 clone. Consistently, none of the melanoma clones studied produced a ligand to the FAS receptor (FAS-L). Thus, our results provide evidence that (i) the production of FAS-L may not be the sole mechanism by which malignant cells induce apoptosis in immunocytes, and (ii) absence of MHC class I glycoproteins plays an important role in preventing the elimination of potential effector immunocytes by tumor cells.
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PMID:The role of MHC class I glycoproteins in the regulation of induction of cell death in immunocytes by malignant melanoma cells. 1117 21

Interferon alpha/beta plays an important role in the first-line defense against viral infections and can modulate cytokine responses by T-helper cells. Type 1 interferons (IFNs) are clinically important in infectious diseases and in the treatment of leukemia and lymphomas. Many different cell types have the capacity to produce IFN-alpha after encounter with virus and bacteria. The major, natural type 1 IFN-producing cell in humans was recently described as the plasmacytoid T cell, or pDC2, and it can differentiate into dendritic cells (DCs) on culture. This study describes the murine natural IFN-alpha-producing cell, or pDC2, that shares morphologic features with its human counterpart but has some distinct phenotypical characteristics. Murine plasmacytoid DCs can be differentially isolated based on their expression of CD11c, B220 (CD45R), and Thy1.2 (CD90). They lack expression of myeloid (eg, CD11b) antigens and CD8 alpha, a marker used to isolate lymphoid DCs. Like human pDC2, murine plasmacytoid DCs exhibit their maximal type 1 IFN-producing capacity at a precursor stage; pDCs isolated from bone marrow responded to viral stimulation with higher IFN-alpha production than cells of the same phenotype isolated from spleen. Mobilization of mice with Flt3 ligand (Flt3L) or Flt3L and granulocyte-macrophage colony-stimulating factor, hematopoietic factors that specifically enhance DC growth, resulted in strikingly increased numbers of pDC in bone marrow and spleen. The isolation of this novel murine DC subset may serve as a useful tool in the study of viral immunobiology and for the design of treatments for murine malignancies.
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PMID:Isolation and characterization of plasmacytoid dendritic cells from Flt3 ligand and granulocyte-macrophage colony-stimulating factor-treated mice. 1173 52

Internalization and subcellular fate of free doxorubicin or its polymeric conjugates based on poly N-(2-hydroxypropyl)methacrylamide (pHPMA), either non-targeted or targeted with anti-Thy1.2 or anti-CD71 monoclonal antibody was tested on EL-4 mouse T-cell lymphoma, SW620 human colorectal carcinoma and OVCAR-3 human ovarian adenocarcinoma. Doxorubicin fluorescence allowed us to follow the internalization and intracellular distribution of tested conjugates by laser scanning confocal microscopy and/or by fluorescent microscopy. Whereas free doxorubicin was always detectable only in the nuclei of treated cells, detectable fluorescence of doxorubicin bound to a polymeric carrier, targeted or non-targeted, was detectable up to 3 days of incubation only in the cytoplasmatic structures. While free doxorubicin causes apoptosis in the populations of tested cancer cell lines, significant number of apoptotic cells was never found in cell cultures exposed to targeted or non-targeted polymeric conjugates. In contrast to free doxorubicin, which is a strong inducer of p53 expression, increased p53 expression was never observed after the treatment with the polymeric drug. High-performance liquid chromatographic analysis shows that the percentage of cleaved doxorubicin is very low even after 48 h of incubation of tested cells with the polymeric conjugate, and cannot be the only reason for the toxicity of the conjugate. We suggest that: (a) after the treatment with pHPMA-bound drug, the cells die by necrosis and (b) the toxicity of pHPMA-based conjugates is a combination of the toxic effect of released doxorubicin and the toxic effect of doxorubicin in polymer-bound form directed against cell membranes.
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PMID:Differences in the intracellular fate of free and polymer-bound doxorubicin. 1194 91


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