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

To examine whether donor T cells can grow and survive long term in hosts without previous immunosuppression, cultured T cells (B6/Thy 1.1) specific to FBL-3 tumor were adoptively transferred into normal B6/Thy 1.2 mice and induced to proliferate in vivo by specific stimulation with irradiated FBL-3. Donor T cells residing in the spleen and ascites of hosts were identified and quantified by use of Ab to the Thy-1 allele. The results demonstrated that on day 7 after transfer, donor T cells in greater numbers than input (1.2-fold) could be recovered. By day 35, donor T cells had decreased to approximately 10% of T cells input. Administration of IL-2 at doses of 2,500 or 25,000 U/day for 7 days preferentially increased the growth of Ag-activated donor T cells rather than host lymphocytes, and increased both the short term growth on day 7 (6.6-fold and 14.5-fold greater than input, respectively) and the long term survival on day 35 (0.75-fold and 3.15-fold of input, respectively) of donor T cells. The combination of CY pretreatment plus low dose IL-2 (2,500 U/day) increased donor T cell growth over and above that of either manipulation alone. However, with higher dose IL-2 to 25,000 U/day, donor T cell growth was equivalent in CY-pretreated and normal hosts (18-fold vs 16-fold increase, respectively; p > 0.05). With either dose of IL-2 there was no significant difference in the survival of donor T cells on day 35 in CY-pretreated vs normal hosts. Functional assay confirmed that specific cytolytic function of donor T cells could be maintained in hosts without previous immunosuppression. Accordingly, established disseminated FBL-3 leukemia could be cured without CY treatment, in a regimen using 10(7) cultured immune T cells plus IL-2 (25,000 U/day x 7 days). Thus, adoptively transferred donor T cells can be grown to large numbers and survive long term in vivo with maintenance of substantial function without the necessity of previous host immunosuppression.
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PMID:Donor T cells can be induced to grow and survive long term in vivo without previous host immunosuppression. 817 2

Resistance and/or susceptibility for Friend leukemia virus (FLV)-induced leukemogenesis was examined in the fully H-2 incompatible C57BL/6 (B6)-->C3H radiation bone marrow chimeras (RBMC). The results indicated that B6-->C3H chimeras never developed FLV-induced leukemias when infected with FLV 4 months after bone marrow transplantation (BMT). Spleen cells from B6-->C3H chimeras that were preimmunized with 100 Gy-irradiated FBL-3 cells (FLV-induced leukemic cell line originated from B6 mice) were shown to generate anti-FBL-3 specific T-cell proliferation as well as cytotoxic T cells. We also found that when bone marrow cells from B6 mice were mixed with those from C3H mice and then grafted into supralethally irradiated C3H mice, resulting chimeras whose peripheral blood contained less than 30% C3H-derived (susceptible) cells were refractory to FLV-induced leukemogenesis. On the other hand, when C3H mice were infected with FLV and then supralethally irradiated 5 days later and grafted with bone marrow from B6 donors, they developed leukemias which were of B6 origin. Athymic nu/nu mice of B6 background were again shown to develop leukemia following infection with FLV. Possible implication of these findings on the role of T cell-mediated immune response in resistance to FLV-induced leukemogenesis and the immunocompetent nature of fully H-2 incompatible RBMC were discussed.
Leukemia 1993 Jul
PMID:Friend leukemia virus-induced leukemogenesis in fully H-2 incompatible C57BL/6-->C3H radiation bone marrow chimeras. 832 Oct 19

FBL-3N is an MHC class II Ag+ variant line that was obtained spontaneously during maintenance of Friend virus-induced leukemia FBL-3 in an athymic C57BL/6 (B6) mouse. Inocula of FBL-3N, but not the parental FBL-3 tumor, regressed after initial growth in CD8-depleted, syngeneic B6 mice. The cellular mechanisms by which FBL-3N was rejected in these mice were investigated in this study. We demonstrated that CTL with both CD4+ and CD4-CD8-TCR-alpha beta phenotypes were generated in mixed lymphocyte tumor cell culture spleen cells obtained from CD8-depleted B6 mice that had rejected FBL-3N by in vitro stimulation with mitomycin C-treated FBL-3N. After adoptive transfer of these CTL that were generated in vitro into athymic B6 mice, challenge with the FBL-3N tumor resulted in tumor regression after its initial growth. Thus, CD4+ and CD4-CD8-TCR-alpha beta CTL mediated rejection of the FBL-3N tumor in CD8-depleted B6 mice. Furthermore, the findings that depletion of B6 mice of CD4+ cells in addition to CD8+ cells abrogated the rejection of FBL-3N and generation of CTL in mixed lymphocyte tumor cell culture spleen cells suggest that CD4+ cells were required not only as a source of CD4+ CTL, but also as helper cells for generation of CD4-CD8-TCR-alpha beta CTL. Tumor Ag recognition of CD4-CD8-TCR-alpha beta CTL was restricted to Db, like that of classical CD8+ CTL, but the restriction appeared to be less obligatory than that of CD8+ CTL.
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PMID:Rejection of an IA+ variant line of FBL-3 leukemia by cytotoxic T lymphocytes with CD4+ and CD4-CD8- T cell receptor-alpha beta phenotypes generated in CD8-depleted C57BL/6 mice. 849 92

A major obstacle to the development of T cell therapy for the treatment of human tumors has been the difficulty generating T cells specifically reactive with the tumor. Most of the characterized human tumor antigens have been classified as tumor associated, because of demonstrable expression at low levels in some normal cells, and thus have not been extensively studied as potential targets of a therapeutic immune response. However, the quantitative difference in expression of such antigens between the tumor and normal cells might permit the generation of antigen-specific T cells capable of selective antitumor and not autoimmune activity. To address this issue, transgenic (TG) mice were generated that expressed low levels of Friend murine leukemia virus (FMuLV) envelope protein in lymphoid cells under the control of an immunoglobulin promoter. This protein is expressed at high levels by a Friend virus-induced erythroleukemia of C57BL/6 (B6) origin, FBL, and has been shown to serve as an efficient tumor-specific rejection antigen in B6 mice. The env-TG mice were tolerant to envelope, as reflected by the failure to detect an envelope-specific response after in vivo priming and in vitro stimulation with preparations of FMuLV envelope. However, adoptively transferred envelope-specific T cells from immunized non-TG B6 mice mediated complete eradication of FBL tumor cells in TG mice, and did not induce detectable autoimmune damage to TG lymphoid tissues. The transferred immune cells were not permanently inactivated in the TG mice, since donor T cells responded to envelope after removal from the TG mice. The lack of autoimmune injury did not reflect inadequate expression of envelope by TG lymphocytes for recognition by T cells, since TG lymphocytes functioned effectively in vitro as stimulators for envelope-specific T cells. The results suggest that this and analogous strains of TG mice may prove useful for elucidating principles for the generation and therapeutic use of tumor-reactive T cells specific for tumor-associated antigens.
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PMID:An evaluation of the potential to use tumor-associated antigens as targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues. 849 86

FBL-3 Leukemia cells transfected with IL-6 gene were expanded in vitro and inoculated into C57BL/6 mice subcutaneously. Tumor growth was observed and histologic analyses of the tumors in situ and the liver, spleen and bone marrow were performed at 14, 21, 28 and 35 days after inoculation. The mice inoculated with wild-type FBL-3 leukemia cells were used as the control. We found that the tumor invasiveness in the mice inoculated with FBL-3-IL-6+ occurred later than in the control group. The survival time of experimental mice was longer than in the control mice. The results demonstrated that inoculation of IL-6 high-secreting FBL-3 inhibited invasiveness of the leukemia cells, suggesting that the IL-6 gene transfected FBL-3 cells can be used as a vaccine to treat leukemia. The mechanism of the anti-invasiveness of IL-6 gene transfected leukemia cells needs further study.
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PMID:[Pathological studies on the anti-invasive character of IL-6 gene transfected leukemia cells]. 869 88

FBL-3 is a highly immunogenic murine leukemia of C57BL/6 origin induced by Friend murine leukemia virus (MuLV). Immunization of C57BL/6 mice with FBL-3 readily elicits CD8+ cytotoxic T lymphocytes (CTL) capable of lysing FBL-3 as well as syngeneic leukemias induced by Moloney and Rauscher MuLV. The aim of this current study was to identify the immunogenic epitope(s) recognized by the FBL-3-specific CD8+ CTL. A series of FBL-3-specific CD8+ CTL clones were generated from C57BL/6 mice immunized to FBL-3. The majority of CTL clones (32 of 38) were specific for F-MuLV gag-encoded antigen. By using a series of recombinant vaccinia viruses expressing full-length and truncated F-MuLV gag genes, the antigenic epitope recognized by the FBL-3 gag-specific CTL clones, as well as by bulk-cultured CTL from spleens of mice immune to FBL-3, was localized to the leader sequence of gPr80gag protein. The precise amino acid sequence of the CTL epitope in the leader sequence was identified as CCLCLTVFL (positions 85-93) by examining lysis of targets incubated with a series of synthetic leader sequence peptides. No evidence of other CTL epitopes in the gPr80gag or Pr65gag core virion structural polyproteins was found. The identity of CCLCLTVFL as the target peptide was validated by showing that immunization with the peptide elicited CTL that lysed FBL-3. The CTL elicited by the Gag peptide also specifically lysed syngeneic leukemia cells induced by Moloney and Rauscher MuLV (MBL-2 and RBL-5). The transmembrane peptide was shown to be the major gag-encoded antigenic epitope recognized by bulk-cultured CTL derived from C57BL/6 mice immunized to MBL-2 or RBL-5. Thus, the CTL epitope of FBL-3 is localized to the transmembrane anchor domain of the nonstructural Gag polyprotein and is shared by leukemia/lymphoma cell lines induced by Friend, Moloney, and Rauscher MuLV.
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PMID:Identification of a gag-encoded cytotoxic T-lymphocyte epitope from FBL-3 leukemia shared by Friend, Moloney, and Rauscher murine leukemia virus-induced tumors. 889 98

In the present study, we investigated the effects on hematopoiesis of inactivated vaccines prepared from mouse erythroid leukemia cells (FBL-3) transfected with IL-6 gene. After treatment with IL-6 gene-transfected FBL-3 cells, the platelet count in mice started to increase at day 4, reached its maximum at day 10 and lasted for 25 days. The neutrophil count also increased significantly, but WBC count remained unchanged. The CFU-GM and CFU-MK were elevated to some extent in bone marrow and spleen. These results indicated that in addition to augmentation of antitumor immunity, IL-6 gene-transfected tumor vaccine could promote hematopoietic functions in bone marrow and spleen, and elevate platelet and neutrophil counts in peripheral blood. This approach to gene therapy may be applicable in leukemia treatment, especially for thrombocytopenia related to leukemia or chemotherapy.
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PMID:[Experimental study on in vivo hematopoietic regulation of IL-6 gene-transfected tumor vaccine]. 920 37

The leader signal sequence of the non-structural gag-encoded glycoprotein precursor, Pr75gag, of Friend murine leukemia virus (F-MuLV) contains overlapping epitopes, SIVLCCLCL (p71-79) and CCLCLTVFL (p75 83) that activate Friend virus (FV)-induced tumor (FBL-3)-specific cytotoxic T-lymphocytes (CTL) (Kondo et al., J. Virol., 69, 1995, 6735-6741; Chen et al., J. Virol., 70, 1996, 7773-7782). It was investigated whether these two peptides are recognized by a single CTL clone or by individual clones with different specificities. The results show that both hydrophobic and cysteine-containing peptides are bound to H-2Db class I major histocompatibility complex (MHC) molecules and cross-recognized by a single CTL clone as well as bulk-cultured CTL from the spleens of mice immunized with FBL-3. The peptide p71-79 was effective for sensitizing target cells to lysis by CTL in the concentration of common antigenic peptides. Moreover, peptide p75-83 was 1000-fold more potent than the peptide p71-79. Specific cytotoxicity assays with variant peptides with alanine- and serine-substitutions suggested a highly complex function of the disulfide bond-forming peptides potentially sensitive to small sequence differences. The dominance of CTL responses to the transmembrane region is discussed in light of the high affinity of a novel hydrophobic peptide to compete with other peptides for binding to MHC molecules.
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PMID:Overlapping epitopes of friend murine leukemia virus gag-encoded leader sequence recognized by single cytotoxic T-lymphocyte clones. 967 45

Dendritic cells (DC) are professional antigen-presenting cells (APC) within the immune system and antigen-pulsed DC can be used as an effective vaccine for active immunotherapy of cancer. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the generation of DC. We previously showed that GM-CSF can induce murine erythroleukaemia cells (FBL-3) to differentiate into monocyte-like cells. To develop a new vaccinating method to stimulate the host immune response to leukaemia, we further investigate whether FBL-3 cells induced by GM-CSF can differentiate into DC in the present study. After being treated with GM-CSF, FBL-3 cells expressed high levels of 33D1 and NLDC-145, which are the specific markers of DC. The expression of MHC-II, B7-1, B7-2 and vascular cell adhesion molecule-1 (VCAM-1) was up-regulated markedly; the typical morphology of DC were also observed by electron microscopy. Functionally, the GM-CSF-induced FBL-3 cells could apparently stimulate the proliferation of naive allogeneic and autologous T lymphocytes and induce the generation of specific CTL more efficiently than the wild-type FBL-3 cells. Mice immunized with GM-CSF-induced FBL-3 cells could resist the subsequent challenge with the wild-type FBL-3 cells. Collectively, these data indicate that GM-CSF differentiates murine erythroleukaemia cells into DC phenotypically, morphologically and functionally. FBL-3-derived DC can be used as a new type of vaccine. Our results may have important implications for the immunotherapy of leukaemia.
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PMID:Granulocyte-macrophage colony-stimulating factor induces the differentiation of murine erythroleukaemia cells into dendritic cells. 976 69

Transgenic (TG) mice were generated selectively expressing the gag protein of Friend murine leukemia virus (FMuLV) in the liver. FMuLV(gag) is also expressed by the FBL leukemia, and is the immunodominant tumor Ag of the CD8(+) T cell response in C57BL/6 mice. gag-TG mice expressing FMuLV(gag) in the liver were tolerant to the protein and failed to generate a CTL response to either FBL or FMuLV(gag). This tolerance reflected anergy rather than deletion, as CTL responsiveness could be recovered after four cycles of in vitro stimulation. Adoptively transferred gag-specific T cells were not anergized in gag-TG recipients, as revealed by antitumor activity in vivo. Also, such T cells did not induce detectable autoimmune injury in gag-TG liver cells. These results suggest that the requirements for a tissue Ag to provide a tolerizing stimulus are distinct from those for being the target of a T cell-mediated autoimmune response and that the requirements for induction and maintenance of peripheral tolerance are distinct for naive and primed T cells. That anergic T cells reactive with tumor-associated Ags can be recovered by repetitive in vitro stimulation and can mediate tumor therapy suggests strategies that use such Ags to generate CTL for adoptive immunotherapy should be further developed.
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PMID:Expression of a tolerizing tumor antigen in peripheral tissue does not preclude recovery of high-affinity CD8+ T cells or CTL immunotherapy of tumors expressing the antigen. 1116 Mar 55


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