Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis (EBL), which is the most common neoplastic disease of cattle. To clarify the way in which BLV-infected cattle progress from the asymptomatic stage to the lymphoma stage, we produced a monoclonal antibody (MAb) c143 which recognized a tumor-associated antigen (TAA) that is phosphorylated in the transformed state of BLV-infected B-lymphoid cells. Since the nature of c143 TAA was likely to be that of the major histocompatibility complex (MHC) class II antigens, we isolated cDNAs for bovine MHC (BoLA) class II a-chains and b-chains, produced transfectants that expressed a single type of BoLA class II molecules and analyzed them by flow cytometry with c143 MAb. The c143 MAb recognized the transfectant expressing BoLA-DR but not BoLA-DQ. However, the treatment of lymphocytes with c143 or anti-BoLA-DR MAb induced different effects. Although mixed lymphocyte reaction (MLR) was inhibited by the addition of anti-BoLA-DR MAb, the c143 MAb did not inhibit a proliferative response of T cells in MLR. Increased spontaneous proliferation of lymphocytes in healthy donors was obtained in the presence of c143 MAb but not anti-BoLA-DR MAb, and was much in lymphocytes from the carrier. Moreover, the patterns of immunohistological staining for c143 MAb in BLV-infected sheep showed distinguishing differences from those of anti-BoLA-DR MAbs.
Leukemia 1997 Apr
PMID:The role of tumor-associated antigen in bovine leukemia virus-induced lymphosarcoma. 920 45

A monoclonal antibody, (MAb) c143, that recognizes a tumor-associated antigen (TAA) that is upregulated on neoplastic B cells in cattle with enzootic bovine leukosis (EBL), was used as a marker to study disease progression. Immunohistochemical examination of neoplastic tissue and lymph nodes from animals with EBL, revealed three morphologically definable stages of change in the architecture of lymph nodes associated with infiltration and proliferation of neoplastic cells: 1) presence of c143 positive cells at the marginal sinus with no apparent changes in lymph node architecture at the earliest stage of neoplastic cell accumulation, 2) presence of positive cells extending into and distorting the architecture of the lymph node with clear evidence of proliferation, and 3) presence of positive cells throughout the lymph node with total disruption of lymph node architecture. The results indicated that, at the earliest stages of EBL, neoplastic cells in peripheral blood may accumulate at the marginal sinus area and subsequently proliferate and infiltrate pressing follicles leading to the development of clinical signs of lymphosarcoma.
Leukemia 1997 Apr
PMID:Tumor-associated antigen in lymph nodes during the progression of enzootic bovine leukosis. 920 47

Crosslinking of immunoglobulin E molecules that are bound to the Fc epsilon receptors expressed on mast cells or basophils triggers activation of these cells, resulting in the development of a type I hypersensitivity. Targeting this potent immune reaction towards tumors by using IgE that reacts with a tumor-associated antigen, may induce a local inflammation at the tumor site, and may therefore promote tumor regression. We have previously shown that murine IgE bound to tumor cells can activate murine mast cells to release TNF-alpha and histamine. To further investigate the therapeutic potential of IgE-mediated immunotherapy of carcinomas, we have developed human/murine chimeric versions, containing the murine variable regions and human constant regions, of both G250 and 323/A3 IgE. These chimeric IgEs are reactive respectively with the G250 renal cell carcinoma antigen and the Ep-CAM molecule, which is highly expressed by most carcinomas. Transfection of the respective chimeric heavy and light chain genes into recipient Sp2/0 myeloma cells yielded chimeric IgE-producing clones. Chimeric G250 and 323/A3 IgE reacted with tumor cells expressing the G250 antigen or Ep-CAM, respectively. To generate a cell line that expresses Fc receptors for human or chimeric IgE, the rat basophilic leukemia cell line RBL-7 was transfected with the human Fc epsilon RI alpha chain (RBL-7TZ) and subsequently tested for binding of chimeric IgE. Functional assays showed that both chimeric IgEs activated RBL-7TZ cells to release TNF-alpha when cultured with tumor cells that express the respective specific antigen. Furthermore, both chimeric IgEs were able to activate freshly isolated human basophils.
 ...
PMID:Chimeric immunoglobulin E reactive with tumor-associated antigen activates human Fc epsilon RI bearing cells. 939 19

We transduced BALB/c-derived C-26 colon carcinoma cells with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (CD40L) genes to favor interaction of these cells with host dendritic cells (DCs) and, therefore, cross-priming. Cotransduced cells showed reduced tumorigenicity, and tumor take was followed by regression in some mice. In vivo tumors were heavily infiltrated with DCs that were isolated, phenotyped, and tested in vitro for stimulation of tumor-specific cytotoxic T lymphocytes (CTLs). BALB/c C-26 carcinoma cells express the endogenous murine leukemia virus (MuLV) env gene as a tumor-associated antigen. This antigen is shared among solid tumors of BALB/c and C57BL/6 mice and contains two epitopes, AH-1 and KSP, recognized in the context of major histocompatibility complex class I molecules H-2Ld and H-2K(b), respectively. DCs isolated from C-26/GM/CD40L tumors grown in (BALB/c x C57BL/6)F1 mice (H-2d x b) stimulated interferon gamma production by both anti-AH-1 and KSP CTLs, whereas tumor-infiltrating DCs (TIDCs) of BALB/c mice stimulated only anti-AH-1 CTLs. Furthermore, TIDCs primed naive mice for CTL activity as early as 2 d after injection into the footpad, whereas double-transduced tumor cells required at least 5 d for priming; this difference may reflect direct DC priming versus indirect tumor cell priming. Immunohistochemical staining indicated colocalization of DCs and apoptotic bodies in the tumors. These data indicate that DCs infiltrating tumors that produce GM-CSF and CD40L can capture cellular antigens, likely through uptake of apoptotic bodies, and mature in situ to a stage suitable for antigen presentation. Thus, tumor cell-based vaccines engineered to favor the interaction with host DCs can be considered.
 ...
PMID:Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response. 1042 76

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that need to be activated before they can function to initiate primary and secondary immune responses in vivo. DCs are also specialized to maintain peripheral tolerance to self after uptake of apoptotic material, likely corresponding to both apoptotic bodies and whole apoptotic cells. Here, we report that murine bone marrow-derived DCs can be activated in vitro by exogenous signals received from apoptotic leukemia cells expressing on the cell surface a model tumor-associated antigen. Injected in vivo, these exogenously activated DCs can function as adjuvants to protect mice against leukemia by stimulating an antigen-specific cellular-mediated cytotoxic immune response. To our knowledge, this is the first report indicating that DCs loaded with apoptotic leukemia cells protect mice against leukemia development.
 ...
PMID:Protection of mice against leukemia after vaccination with bone marrow-derived dendritic cells loaded with apoptotic leukemia cells. 1128 1

We and other groups have recently reported that CTLs that specifically recognize a peptide derived from WT1 lyse leukemia cells in a HLA class I-restricted manner. Because WT1 is expressed in various solid tumors as well as in leukemic cells, we investigated whether WT1-specific CTLs can also inhibit the growth of lung cancer by examining their cytotoxic activity against lung cancer cell lines in vitro and their inhibitory effect on the growth of human lung cancer cells engrafted into nude mice. The WT1 transcript was detected in most of the lung cancer cell lines examined. A WT1-specific, HLA-A24-restricted CTL clone (designated TAK-1) exhibited cytotoxicity against lung cancer cell lines bearing HLA-A24 but did not lyse cells lacking this HLA. This suggests that the target antigen for TAK-1 on HLA-A24-positive lung cancer cells is the naturally processed WT1 peptide. Adoptive transfer of TAK-1 into nude mice that had been engrafted with a HLA-A24-positive lung cancer cell line resulted in inhibition of cancer cell growth and prolonged survival. These findings strongly suggest that WT1 is a universal tumor-associated antigen and that WT1-targeting immunotherapy offers a potentially effective treatment option for lung cancer as well as leukemia.
 ...
PMID:Antilung cancer effect of WT1-specific cytotoxic T lymphocytes. 1217 94

Although several clinical trials have shown beneficial effects by targeting tumor-associated antigens (TAAs) with monoclonal antibodies, a number of issues, including poor penetration of the tumor mass and human antimouse antibody responses, remain. The use of recombinant single-chain Fv (scFv) fragments has the potential to address these and other issues while allowing the addition of different effector functions. To develop therapeutic strategies that recruit both humoral and cellular arms of the immune response, we have constructed chimeric proteins linking either the human IgG1 Fc domain or the extracellular domain of murine B7.1 to a scFv specific for the oncofetal glycoprotein, 5T4. This TAA is expressed by a wide variety of carcinomas and is associated with metastasis and poorer clinical outcome. We have engineered retroviral constructs that produce fusion proteins able to interact simultaneously with both 5T4-positive cells and with the receptor/ligands of the immune effector moieties. Genetic delivery through a murine leukemia virus vector to 5T4-positive tumor cells results in the secreted scFv fusion protein binding to the cell surface. Furthermore, the scFv-HIgG1 fusion protein is able to direct lysis of 5T4-expressing human tumor cell lines through antibody-dependent cell cytotoxicity, indicating its potential as a gene therapy for human cancers.
 ...
PMID:Targeting immune effector molecules to human tumor cells through genetic delivery of 5T4-specific scFv fusion proteins. 1238 27

The CDM (ced-5 of Caenorhabditis elegans, DOCK180 [downstream of Crk with molecular weight of 180 kDa] of humans, and myoblast city of Drosophila melanogaster) family of proteins has been shown to play a pivotal role in the integrin-mediated signaling pathway under the regulation of an adaptor molecule c-CT10-related kinase II (c-Crk-II) in adherent cells. Recently, hematopoietic cell-specific CDM protein DOCK2 has been shown to be indispensable for lymphocyte migration. However, the regulatory mechanism for DOCK2 is still unknown because DOCK2 lacks a c-Crk-II binding consensus motif. In this study, we demonstrated that DOCK2 bound to CrkL, which is present exclusively in hematopoietic cells both in vivo and in vitro, and we also found that 2 separate regions of DOCK2 contributed to its binding to Src homology 3 (SH3) domain of CrkL. Colocalization of DOCK2 with Crk-like (CrkL) and F-actin was shown by immunocytochemical analysis with the use of Jurkat cells. We also found that CrkL-induced activation of small guanine triphosphatase (GTPase) Rac1 was significantly inhibited by the DOCK2-dCS mutant in 293T cells. Furthermore, the association of DOCK2 and Vav, the guanine-nucleotide exchanging factor (GEF) for Rac1, was demonstrated in Jurkat cells. Finally, the stable expression of DOCK2-dCS mutant in Jurkat cells was shown to reduce cell attachment. These data suggest the presence of a novel protein complex of CrkL, DOCK2, and Vav to regulate Rac1 in leukemia cell lines.
 ...
PMID:DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines. 1239 32

It has long been a matter of debate whether tumors are spontaneously immunogenic in patients. With the availability of sensitive methods, naturally occurring T cells directed against tumor-associated antigens (TAAs) can be frequently detected in cancer patients. In this review, we summarize the current data on T cell responses to TAAs in various malignancies, including melanoma, colorectal cancer, leukemia, and breast cancer. T cell responses against various antigens, including melanoma differentiation antigens, carcinoembryonic antigen, epithelial cell adhesion molecule, her-2/neu, Wilms' tumor protein, proteinase 3, NY-ESO-1, and surviving, have been reported in a substantial number of patients. In contrast, other TAAs, including most antigens of the MAGE family, do not usually elicit spontaneous T cell responses. A distinction between direct ex vivo T cell responses and in vitro-generated T cell responses is provided because in vitro stimulation results in quantitative and functional changes of T cell responses. The possible role of TAA-specific T cells in immunosurveillance and tumor escape and the implications for immunological treatment strategies are discussed. Naturally occurring T cells against TAAs are a common phenomenon in tumor patients. Understanding the mechanisms and behavior of natural TAA-specific T cells could provide crucial information for rational development of more efficient T cell-directed immunotherapy.
 ...
PMID:Natural T cell immunity against cancer. 1455 98

Wilms tumor gene 1 product (WT1) has been recognized as an attractive target antigen of immunotherapy for various malignancies including leukemia. Because tumor-associated antigen-specific CD4+ T lymphocytes undoubtedly play an important role in the induction of an antitumor immune response, we attempted to generate WT1-specific CD4+ T lymphocytes in vitro and examined their antileukemia functions. A CD4+ T-cell line, designated NIK-1, which proliferated and produced Th1 cytokines specifically in response to stimulation with the WT1-derived peptide, WT1(337-347) LSHLQMHSRKH, in an HLA-DP5-restricted manner was established. NIK-1 exhibited cytotoxicity against HLA-DP5-positive, WT1-expressing leukemia cells but did not lyse HLA-DP5-negative, WT1-expressing leukemia cells or HLA-DP5-positive, WT1-negative cells. NIK-1 did not inhibit colony formation by normal bone marrow cells of HLA-DP5-positive individuals. This is the first report to describe WT1-specific and HLA class II-restricted CD4+ T lymphocytes possessing direct cytotoxic activity against leukemia cells.
 ...
PMID:Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner. 1584 94


<< Previous 1 2 3 4 5 6 7 Next >>