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)

Infection of certain strains of mice, such as C57BL/6 and C57BL/10 [B10], with LP-BM5 murine leukemia virus (MuLV) rapidly causes a profound and lethal immune suppression. The H2d congenic strain of B10, B10.D2, is resistant to disease, but B10 x B10.D2 F1 mice are susceptible, indicating that disease sensitivity is dominant. To determine whether disease resistance could be adoptively transferred to a sensitive host, radiation chimeras (B10.D2 --> B10 x B10.D2 F1 and F1 --> F1) were challenged with LP-BM5 virus. Infected B10.D2 --> F1 chimeras showed no loss of immune function, whereas F1 --> F1 chimeras infected with LP-BM5 MuLV developed MAIDS and became completely immune suppressed. These results, coupled with previous studies, indicate resistance or sensitivity to disease is an inherent property of the hematopoietic system that can be transferred by bone marrow grafts.
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PMID:Adoptive transfer of resistance to murine retrovirus-induced immune suppression. 861 90

Since the T cell receptor rearrangement is a sequential process and unique to the progeny of each clone, we investigated the early initiating events in radiation-induced thymic lymphomagenesis by comparing the oncogenic alterations with the pattern of gamma T cell receptor (TCR) rearrangements. We reported previously that after leukemogenic irradiation, preneoplastic cells developed, albeit infrequently, from thymic leukemia antigen-2+ (TL-2+) thymocytes. Limited numbers of TL-2+ cells from individual irradiated B10.Thy 1.1 mice were injected into B10.Thy 1.2 mice intrathymically, and the common genetic changes among the donor-type T cell lymphomas were investigated with regard to p53 gene and chromosome aberrations. The results indicated that some mutations in the p53 gene had taken place in these lymphomas, but there was no common mutation among the donor-type lymphomas from individual irradiated mice, suggesting that these mutations were late-occurring events in the process of oncogenesis. On the other hand, there were common chromosome aberrations or translocations such as trisomy 15, t(7F;10C), t(1A;13D) or t(6A;XB) among the donor-type lymphomas derived from half of the individual irradiated mice. This indicated that the aberrations/translocations, which occurred in single progenitor cells at the early T cell differentiation either just before or after gamma T cell receptor rearrangements, might be important candidates for initiating events. In the donor-type lymphomas from the other half of the individual irradiated mice, microgenetic changes were suggested to be initial events and also might take place in single progenitor cells just before or right after gamma TCR rearrangements.
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PMID:Analysis of early initiating event(s) in radiation-induced thymic lymphomagenesis. 861 26

Murine AIDS (MAIDS) is caused by a defective retrovirus present in the LP-BM5 murine leukemia virus mixture. Strains of inbred mice differ in resistance to MAIDS development; some are susceptible (e.g., C57BL/6), while others are resistant (e.g., CBA and B10.BR). As an early block to viral replication in resistant mice has been demonstrated previously by PCR studies, we postulated that alpha/beta interferons (IFN-alpha/beta) may be involved in resistance to MAIDS. Susceptible C57BL/6 mice infected with LP-BM5 were treated with IFN-alpha/beta or Newcastle disease virus. Newcastle disease virus induces high endogenous IFN-alpha/beta production in mice. Both treatments delayed the development of MAIDS, as assessed by splenomegaly and T- and B-cell proliferation. In addition, an IFN-alpha/beta response was detected by reverse transcription-PCR and dot blotting 3, 6, and 9 h after LP-BM5 infection in resistant mice but not in susceptible mice. These results suggest that the ability to produce IFN-alpha/beta in response to LP-BM5 infection may contribute to host resistance to MAIDS.
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PMID:Alpha/beta interferons increase host resistance to murine AIDS. 867 77

The effect of 15-deoxyspergualin (DSG) on bone marrow (BM) engraftment and graft-versus-host disease (GVHD) was studied in mice across both major (MHC) and minor (MiHC) histocompatibility barriers. (BALB/c x C57BL/6)F1 mice were inoculated with C57BL/6 cells, CBA mice were given B10.BR cells and BALB/c mice were transplanted with B10.D2 cells. All recipient mice were irradiated lethally or sublethally prior to transplantation. DSG had no effect on engraftment of parental cells in F1 mice at both 2.5 mg/kg and 10 mg/kg given daily for 10 days after treatment. Survival of F1 recipients of C57BL/6 cells increased significantly with 2.5 mg/kg DSG (p < 0.05). Across MiHC, 75% of DSG-treated CBA mice survived transplant for more than 150 days. No effect on GVHD was observed in the B10.D2 --> BALB/c setting. DSG abolished graft-versus-leukemia (GVL) effects in F1 mice transplanted with both BM and spleen cells (20%) of C57BL/6 mice and additionally inoculated with B cell leukemia (BCL1). In summary, in the semi-allogeneic murine models presented here DSG prevented GVHD but at the same time suppressed GVL effects induced by the allograft. For clinical use, DSG might therefore be very useful for prevention of GVHD post-allogeneic bone marrow transplantation for non-malignant diseases or for leukemia.
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PMID:Effect of deoxyspergualin on graft-versus-host disease and graft- versus-leukemia in mice. 873 99

CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.
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PMID:Control of immunodeficiency and lymphoproliferation in mouse AIDS: studies of mice deficient in CD8+ T cells or perforin. 903 10

Graft-versus-leukemia (GVL) and Graft-versus-host (GVH) reactions were compared after systemic transfer of allogeneic antitumor immune T lymphocytes from B10.D2 (H-2d; Mls(b)) into DBA/2 (H-2d; Mis(a)) mice. Before immune cell transfer, recipient DBA/2 mice were sublethally irradiated with 5 Gy to prevent host-versus-graft reactivity. Recipients were either bearing syngeneic metastatic ESb lymphomas (GVL system) or were normal, non-tumor-bearing mice (GVH system). We previously reported that this adoptive immunotherapy protocol (ADI) had pronounced GVL activity and led to immune rejection of even advanced metastasized cancer. In this study, monoclonal antibodies were used for immunohistochemical analysis of native frozen tissue sections from either spleen or liver to distinguish donor from host cells, to differentiate between CD4 and CD8 T lymphocytes, and to stain sialoadhesin-positive macrophages at different time points after cell transfer. The kinetics of donor cell infiltration in spleen and liver differed in that the lymphoid organ was infiltrated earlier (days 1 to 5 after transfer) than the nonlymphoid organ (days 5 to 20). After reaching a peak, donor cell infiltration decreased gradually and was not detectable in the spleen after day 20 and in the liver after day 30. The organ-infiltrating donor immune cells were mostly T lymphocytes and stained positive for CD4 or CD8 T-cell markers. A remarkable GVL-associated observation was made with regard to a subset of macrophages bearing the adhesion molecule sialoadhesin (SER+ macrophages). In the livers of tumor-bearing mice, their numbers increased between days 1 and 12 after ADI by a factor greater than 30. Double-staining for donor cell marker and SER showed that the sialoadhesin-expressing macrophages were of host origin. The SER+ host macrophages from GVL livers were isolated by enzyme perfusion and rosetting 12 days after ADI, when they reached peak values of about 60 cells per liver lobule, and were tested, without further antigen addition, for their capacity to stimulate an antitumor CD8 T-cell response. The results of this immunologic analysis suggest that these cells in the liver function as scavengers of the destroyed metastases and as antigen-processing and -presenting cells for antitumor immune T cells.
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PMID:Differences between graft-versus-leukemia and graft-versus-host reactivity. I. Interaction of donor immune T cells with tumor and/or host cells. 905 44

Graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation is associated with significant morbidity and mortality. T cell depletion of the marrow graft, which is currently used to prevent GVHD, has been shown to result in increased graft failure and leukemia relapse. To explore the feasibility of controlling GVHD, transgenic mice with the herpes simplex virus thymidine kinase suicide gene linked to the IL-2 promoter were used as a source of T cells to induce GVHD, which would be modulated with ganciclovir. Injection of herpes simplex virus thymidine kinase transgenic B10.A(5R) spleen cells into lethally irradiated DBA/2 mice resulted in severe acute GVHD. Treatment of the recipient mice with ganciclovir significantly inhibited GVHD-mediated weight loss and mortality and reduced the severity of inflammation in the target organs of GVHD.
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PMID:Inhibition of graft-versus-host disease. Use of a T cell-controlled suicide gene. 916 20

The biological consequences of radiation leukaemia virus (RadLV) infection include the stimulation of H-2 antigen expression soon after injection of the virus. Early studies demonstrated that resistance to RadLV-induced leukaemia in certain mouse strains is mediated by genes in the H-2D region of the major histocompatibility complex (MHC). Recent studies have shown that elevated H-2Dd expression on the thymocyte cell surface of resistance mouse strains results from increased mRNA transcription and is correlated with elevated levels of a DNA-binding activity that recognizes a short DNA sequence 5' of the start of transcription for the H-2Dd gene. This binding activity has been termed H-2 binding factor 1 (H-2 BF1) and is found exclusively in the thymus. In an effort to examine the H-2 genes of RadLV-susceptible mice for the presence of the H-2 BF1 binding target, we have cloned class I genes from the highly susceptible B10.S mouse strain and have identified both the Ds and the Ks genes. The entire genomic sequence for the Ds gene has been determined and is reported here. In addition, the 5' regulatory region of the previously cloned Dq gene has been sequenced; mice of the Dq haplotype are also susceptible to RadLV-induced leukaemia. In this report, we show that the H-2 BF1 DNA binding sequence is present 5' of each of these three class I genes.
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PMID:Conservation of the H-2 BF1 binding motif 5' of the H-2Ds, Ks and Dq genes. 930 93

Graft-vs-leukemia (GVL) can reduce relapse rates after bone marrow transplantation (BMT). Delayed lymphocyte infusion (DLI) post-BMT can mediate a potent GVL effect with less graft-vs-host disease (GVHD) than would be observed if given early post-BMT. In vivo CD28/B7 blockade can reduce GVHD lethality, and B7 ligand expression can augment an antitumor immune response in mice. To examine the role of CD28/B7 interactions in DLI-mediated GVL, we established murine allogeneic BMT models in C57BL/6 (B6) recipients of C1498 (B6 acute myeloid leukemia) or EL4 (B6 acute T cell leukemia) that closely mimic human GVL. Recipients of C1498 and DLI had a marked reduction in relapse. GVL was blocked by anti-B7 mAb infusion. In contrast, recipients of EL4 cells and B10.BR DLI had a more modest GVL effect. The forced expression of B7-1 on EL4 cells markedly augmented the GVL effect of DLI, in contrast to the forced expression of B7-2 on EL4 cells. Relapse rates observed in recipients of C1498-B7-1 and DLI were significantly lower than in recipients of parental C1498 cells. We conclude that the administration of anti-B7 mAbs may impair the GVL effect of DLI and that the forced expression of B7-1 ligands stimulates a GVL effect without adversely affecting the GVHD lethality effect of DLI.
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PMID:CD28/B7 interactions are required for sustaining the graft-versus-leukemia effect of delayed post-bone marrow transplantation splenocyte infusion in murine recipients of myeloid or lymphoid leukemia cells. 931 45

We have recently demonstrated that a single injection of 4,900 IU of interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully major histocompatibility complex plus minor antigen-mismatched BMT model (A/J --> B10, H-2(a) --> H-2(b)), in which donor CD4(+) T cells are required for the induction of acute GVHD. We show here that donor CD8-dependent graft-versus-leukemia (GVL) effects against EL4 (H-2(b)) leukemia/lymphoma can be preserved while GVHD is inhibited by IL-12 in this model. In mice in which IL-12 mediated a significant protective effect against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated alloreactivity, protection was not observed in recipients of either syngeneic (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analyzed IL-12-treated recipients of EL4 and A/J spleen cells which survived for more than 100 days. No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or histologic examination. Both GVL effects and the inhibitory effect of IL-12 on GVHD were diminished by neutralizing anti-interferon-gamma (IFN-gamma) monoclonal antibody. This study demonstrates that IL-12-induced IFN-gamma production plays a role in the protective effect of IL-12 against GVHD. Furthermore, IFN-gamma is involved in the GVL effect against EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single cytokine, IFN-gamma. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreactivity.
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PMID:Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice. 937 79


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