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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an effort to develop an experimental system suitable for immunological studies in which Bcr-Abl-positive cells are to be used as antigens, we examined the properties of two mouse (Balb/c) established cell lines that express the Bcr-Abl protein and are oncogenic for syngeneic animals. Under standard conditions the two cell lines, viz. Ba-p210 (B210) and 12B1, expressed comparable amounts of the Bcr-Abl protein. However, they differed in a number of characteristics. From the morphological point of view, B210 cells were the more homogeneous, being mainly represented by leukaemic blastic cells with a large number of AgNORs as markers indicating a high proliferative activity. 12B1 cells were more polymorphic and giant cells were detected within their populations. Many 12B1 cells exhibited nuclear segmentation and "band-like" structures. Markers of proliferation were less frequent in 12B1 and the tendency for aging was more pronounced in these cells. The 12B1 cells were slightly more sensitive to imatinib mesylate than B210 cells. In B210 cells, the expression of MHC class I was downregulated, which was not the case with 12B1 cells. Both cell lines induced leukaemia-like disease in mice after intravenous application but, as compared with B210, 12B1 cells were about 100 times more oncogenic and the disease they induced was more aggressive. Moreover, 12B1, but not B210, induced tumours after subcutaneous or intraperitoneal inoculation.
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PMID:Characteristic of two mouse bcr-abl-transformed cell lines: I. General properties of the cells. 1578 87

Tumor vaccine development aimed at stimulating the cellular immune response focuses mainly on MHC class I molecules. This is not surprising since most tumors do not express MHC class II or CD1 molecules. Nevertheless, the most successful targets for cancer immunotherapy, leukemia and melanoma, often do express MHC class II molecules, which leaves no obvious reason to ignore MHC class II molecules as a mediator in anticancer immune therapy. We review the current state of knowledge on the process of MHC class II-restricted antigen presentation and subsequently discuss the consequences of MHC class II expression on tumor surveillance and the induction of an efficient MHC class II mediated antitumor response in vivo and after vaccination.
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PMID:Chaperoning antigen presentation by MHC class II molecules and their role in oncogenesis. 1579 46

A large number of human malignancies are associated with decreased numbers of circulating T cells. B-CLL, in this regard, represents an anomaly since there is not only high numbers of circulating B cells, characteristic of the malignancy, but also a massive expansion of both CD4 and CD8 T cells. These T cells for the most part may probably not represent a leukaemia-specific TCR-dependent expansion. On the contrary, these T cells, especially the CD4 subset, might support a "microenvironment" sustaining the growth of the leukaemic B cell clone. Conversely, the leukaemic B cells may produce membrane-bound as well as soluble factors that stimulate the proliferation of these T cells in an antigen independent manner. In addition to these T cells lacking anti-leukaemic reactivity, there exist spontaneously occurring leukaemia-specific T cells recognizing several leukaemia-associated antigens, e.g. the tumour derived idiotype, survivin and telomerase. Both CD4 and CD8 leukaemia-specific T cells have been identified using proliferation and gamma-IFN assays. These reactive T cells can lyse autologous tumour cells in an MHC class I and II restricted manner. Spontaneously occurring leukaemia-specific T cells are more frequently noted at an indolent stage rather than in progressive disease. Preliminary results from vaccination trials using whole tumour cell preparations as vaccine have demonstrated that vaccination may induce a leukaemia-specific T cell response, which might be associated with clinical benefits. Extended clinical trials are required to establish the therapeutic effects of vaccination in B-CLL. Studies in our laboratory as well as those of others indicate that whole tumour cell antigen in the form of apoptotic bodies or RNA loaded on to dendritic cells may be a suitable vaccine candidate. Patients with low stage disease may maximally benefit from this form of therapy.
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PMID:T and B cells in B-chronic lymphocytic leukaemia: Faust, Mephistopheles and the pact with the Devil. 1590 26

We have identified human monocytic (THP-1) and myelogenous CD34+ (KG-1) leukemia cell lines that can be differentiated rapidly into mature dendritic cells (DCs) when cultured in serum-free medium containing GM-CSF, TNF-alpha, and ionomycin. These hematopoietic cell line-derived DCs are highly pure and monotypic, and display the morphologic, phenotypic, molecular, and functional properties of DCs generated from human donor-derived monocytes or CD34+ hematopoietic progenitor cells. During differentiation into mature DCs, the cells exhibit de novo cell-surface expression of CD83, CD80, CD86, CD40, CD206, CD209, CD120a, CD120b, and intracellular synthesis of IL-10, increase their endocytotic capacity, and acquire characteristic stellate morphology. To further define the cells as DCs, cytosolic induction and upregulation of RelB and RelA (p65), transcription factors of the NF-kappaB/Rel family essential for differentiation and maturation of DCs, as well as upregulation of the immunoproteasome subunits LMP2, LMP7, and MECL-1, and the proteasome activator PA28alpha, components essential for efficient MHC class I peptide antigen processing, were demonstrated during differentiation of the cells. In contrast to the cell lines, the cell line-derived mature DCs are capable of stimulating allogeneic CD4+ and CD8+ T cells, ultimately defining them as potent antigen-presenting cells. The approach to differentiate THP-1 and KG-1 cells into immature and mature DCs may serve as an experimental model to study molecular events and pathways that govern the differentiation of human malignant myeloid precursors, monocytes, and CD34+ hematopoietic progenitor cells into DCs.
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PMID:A cell line model for the differentiation of human dendritic cells. 1596 58

More than 70% of patients survive childhood leukemia, but chemotherapy and radiation therapy cause irreversible impairment of spermatogenesis. Although autotransplantation of germ cells holds promise for restoring fertility, contamination by leukemic cells may induce relapse. In this study, we isolated germ cells from leukemic mice by FACS sorting. The cell population in the high forward-scatter and low side-scatter regions of dissociated testicular cells from leukemic mice were analyzed by staining for MHC class I heavy chain (H-2K/H-2D) and for CD45. Cells that did not stain positively for H-2K/H-2D and CD45 were sorted as the germ cell-enriched fraction. The sorted germ cell-enriched fractions were transplanted into the testes of recipient mice exposed to alkylating agents. Transplanted germ cells colonized, and recipient mice survived. Normal progeny were produced by intracytoplasmic injection of sperm obtained from recipient testes. When unsorted germ cells from leukemic mice were transplanted into recipient testes, all recipient mice developed leukemia. The successful birth of offspring from recipient mice without transmission of leukemia to the recipients indicates the potential of autotransplantation of germ cells sorted by FACS to treat infertility secondary to anticancer treatment for childhood leukemia.
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PMID:Transplantation of spermatogonial stem cells isolated from leukemic mice restores fertility without inducing leukemia. 1596 2

N(2)-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N(6)-trans-(m-nitrocinnamoyl)-L-lysine (muramyl dipeptide C, or MDP-C) has been synthesized as a novel, nonspecific immunomodulator. The present study shows that MDP-C induces strong cytolytic activity by macrophages on P388 leukemia cells and cytotoxic activity by cytotoxic T lymphocytes (CTLs) on P815 mastocytoma cells. Our results also indicate that MDP-C is an effective stimulator for production of interleukin-2 and interleukin-12 by murine bone marrow derived dendritic cells (BMDCs) and production of interferon-gamma by CTLs. Additionally, MDP-C increases the expression levels of several surface molecules, including CD11c, MHC class I, and intercellular adhesion molecule-1 in BMDCs. Moreover, MDP-C remarkably enhances the immune system's responsiveness to hepatitis B surface antigen (HBsAg) in hepatitis B virus transgenic mice for both antibody production and specific HBsAg T-cell responses ex vivo. Our results indicate that MDP-C is an apyrogenic, nonallergenic, and low-toxicity immunostimulator with great potential for diagnostic, immunotherapeutic, and prophylactic applications in diseases such as hepatitis B and cancers.
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PMID:A novel immunostimulator, N-[alpha-O-benzyl-N-(acetylmuramyl)-L-alanyl-D-isoglutaminyl]-N6-trans-(m-nitrocinnamoyl)-L-lysine, and its adjuvancy on the hepatitis B surface antigen. 1607 31

The product of Wilms' tumor gene 1 (WT1) is overexpressed in diverse human tumors, including leukemia, lung and breast cancer, and is often recognized by antibodies in the sera of patients with leukemia. Since WT1 encodes MHC class I-restricted peptides recognized by cytotoxic T lymphocytes (CTL), WT1 has been considered as a promising tumor-associated antigen (TAA) for developing anticancer immunotherapy. In order to carry out an effective peptide-based cancer immunotherapy, MHC class II-restricted epitope peptides that elicit anti-tumor CD4(+) helper T lymphocytes (HTL) will be needed. In this study, we analyzed HTL responses against WT1 antigen using HTL lines elicited by in vitro immunization of human lymphocytes with synthetic peptides predicted to serve as HTL epitopes derived from the sequence of WT1. Two peptides, WT1(124-138) and WT1(247-261), were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles. Here, we also demonstrate that both peptides-reactive HTL lines were capable of recognizing naturally processed antigens presented by dendritic cells pulsed with tumor lysates or directly by WT1+ tumor cells that express MHC class II molecules. Interestingly, the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine. Because HTL responses to TAA are known to be important for promoting long-lasting anti-tumor CTL responses, the newly described WT1 T-helper epitopes could provide a useful tool for designing powerful vaccines against WT1-expressing tumors.
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PMID:Defining MHC class II T helper epitopes for WT1 tumor antigen. 1622 Mar 25

T cells responsive to minor histocompatibility (H) antigens are extremely effective in curing leukemia but it remains unknown whether they can eradicate solid tumors. We report that injection of CD8(+) T cells primed against the immunodominant H7(a) minor H antigen can cure established melanomas in mice. Tumor rejection was initiated by preferential extravasation at the tumor site of interferon (IFN)-gamma-producing H7(a)-specific T cells. Intratumoral release of IFN-gamma had two crucial effects: inhibition of tumor angiogenesis and upregulation of major histocompatibility complex (MHC) class I expression on tumor cells. Despite ubiquitous expression of H7(a), dissemination of a few H7(a)-specific T cells in extralymphoid organs caused neither graft-versus-host disease (GVHD) nor vitiligo because host nonhematopoietic cells were protected by their low expression of MHC class I. Our preclinical model yields unique insights into how minor H antigen-based immunotherapy could be used to treat human solid tumors.
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PMID:T cells targeted against a single minor histocompatibility antigen can cure solid tumors. 1622 89

B-cell chronic lymphocytic leukaemia (B-CLL) is a slowly progressing malignancy of CD5(+) B cells, for which at present no curative treatment is available. In our current study, we apply a novel bridging reagent to redirect cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTL) to target B-CLL. A streptavidin-fused anti-CD20 single-chain variable fragment (scFv) is used in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CTL with similar efficiency as B-CLL cells directly loaded with CMV peptide. Killing is HLA restricted and occurs at scFv CD20 concentrations of >/=100 ng ml(-1) and HLA/CMV concentrations of >/=20 ng ml(-1). Furthermore, complex-coated B-CLL cells induce both proliferation and cytokine production (interferon gamma, tumour necrosis factor alpha and macrophage inflammatory protein-1 beta) in CMV-specific CD8(+) T cells. Hereby, a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B-cell malignancies is constituted.
Leukemia 2006 Jun
PMID:Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes. 1655 40

The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graft-versus-host disease. To increase efficacy, expansion of HA-1- or HA-2-specific CTL before transplantation is desirable. However, primary HA-1- or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4(+) T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8(+) T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFNgamma-producing CD8(+) T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1- or HA-2-specific CTL in transplant donors before adoptive transfer.
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PMID:DNA fusion vaccines induce epitope-specific cytotoxic CD8(+) T cells against human leukemia-associated minor histocompatibility antigens. 1670 72


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