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)

Several murine tumors were used to determine whether the phenomenon of tumor inhibition in athymic "nude" mice reported previously could be extended to other tumor systems in nude as well as conventional mice. The results with the L5MF-22 tumor line were confirmed, and similar data were obtained with the K36 leukemia of AKR mice and the LAF-17 leukemia of B10.A origin. This phenomenon of tumor inhibition has been called, tentatively, radioresistant inhibition of tumor and may be explained by one of several possibilities. The immunological origin of such tumor inhibition is supported by various observations. The data on tumor cell proliferation in spleens and liver of lethally irradiated mice were similar to previous findings on hemopoietic histocompatibility-incompatible lymphomas. Additionally, the nude mice were stronger responders against lymphoma cells than were conventional hosts. Another explanation is that the tumor inhibition is due to natural cytotoxicity.
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PMID:Radioresistant inhibition of lymphoma growth in congenitally athymic (nude) mice. 83 64

The Rfv-2 gene that influences the rate of spontaneous recovery from erythroleukemia induced by a low dose of Friend retrovirus complex was mapped to the Q/TL region of mouse MHC. Rfv-2 was physically and functionally distinct from the I-A-linked Ir gene that has been shown to control the responsiveness of Th cells to the envelope glycoprotein of Friend murine leukemia helper virus. The negative effect of the Rfv-2s allele was overcome by the B10.D2-H-2dm1 mutation of the D-L genes of H-2, suggesting functional similarities between the D-L and Q/TL genes in influencing resistance against Friend murine leukemia retrovirus complex infection or possible modification of Q/TL expression by genes in the D-L region.
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PMID:Spontaneous recovery from Friend retrovirus-induced leukemia. Mapping of the Rfv-2 gene in the Q/TL region of mouse MHC. 154 33

It is thought that natural killer cells may play a role in graft-vs.-host reactions after allogeneic bone marrow transplantation, but the use of NK cell-specific reagents has been limited. In this report, an NK allele-specific monoclonal antibody, anti-NK 1.1, was used to study the impact of in vivo donor NK cell depletion on GVH disease, graft-vs.-leukemia (GVL) reactivity and donor T cell chimerism after allogeneic murine BMT. AKR/J (H-2k) recipient mice were preconditioned with suboptimal irradiation (9 Gy = LD50) and transplanted with major histocompatibility complex-matched B10.BR (H-2k) BM cells with or without added spleen cells as a source of T cells. The addition of increasing numbers of spleen cells to the BM inoculum produced GVHD of varying intensities. The beneficial effect of NK depletion on GVHD was dependent on the intensity of the GVH reaction. Donor NK cell depletion had no effect on the survival of mice with severe GVHD after MHC-matched BMT (B10.BR into AKR) or after MHC-mismatched BMT (B10.BR into DBA/2; H-2k into H-2d). However, donor NK depletion increased survival of AKR hosts given sufficient B10.BR splenic T cells to induce mild-to-moderate GVHD. Ex vivo depletion of donor CD8+ T cells also reduced GVH-associated mortality, but the use of both CD8 and NK depletion offered no improvement over either alone, suggesting an interaction between CD8+ and NK 1.1+ cells. In contrast to CD8 depletion, donor NK depletion did not compromise the rapid and complete establishment of donor T cell chimerism nor the ability of chimeras to mount an effective GVL reaction. Thus, elimination of donor NK cells provides an alternate strategy for reducing GVHD without loss of GVL reactivity following MHC-matched allogeneic BMT.
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PMID:A decrease in graft-vs.-host disease without loss of graft-vs.-leukemia reactivity after MHC-matched bone marrow transplantation by selective depletion of donor NK cells in vivo. 163 18

Mice of certain strains are highly sensitive to development of a severe immunodeficiency disease following inoculation as adults with LP-BM5 murine leukemia viruses (MuLV) whereas others are extremely resistant. These strain-dependent differences in response to infection have been shown to be genetically determined with resistance to disease being, in general, associated with homozygosity for Fv-1n and H-2 haplotypes a and d and sensitivity with homozygosity for Fv-1b and other H-2 haplotypes including b, s, and q. The Fv-1b, H-2r strain RIIIS/J (RIIIS) was found to be highly resistant to disease even though B10.RIII(71NS)/J (B10.RIII), also H-2r, was very sensitive, thus excluding a role for H-2 in the resistance of RIIIS. The characteristics of RIIIS resistance were evaluated in studies of infected (B10.RIII x RIIIS) F1, F2 and reciprocal backcross mice. Resistance to disease was shown to be semidominant and determined by more than one gene, although a preponderant influence of a single gene was suggested. Studies of segregating populations showed that resistance was not associated with or linked to polymorphisms of the V beta complex or genes in proximity to the Emv-2 locus on chromosome 8. However, there was almost complete concordance between absence of disease in infected mice and inhibition of ecotropic virus spread. These results demonstrate that genes other than Fv-1 or H-2 can profoundly influence the development of retrovirus-induced immunodeficiency and replication of ecotropic viruses.
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PMID:Effects of non-MHC loci on resistance to retrovirus-induced immunodeficiency in mice. 164 65

Using a mouse model for MHC-matched unrelated donor transplantation, the relative influences of the CD4 and CD8 T cell subtypes on graft-versus-leukemia (GVL) were examined in a murine erythroleukemia induced in SJL/J mice by the injection of Rauscher virus. Following leukemia induction, the mice were given 9.5 Gy of total body irradiation (TBI) and injected with mixed marrow and spleen cells from normal MHC-matched--but minor histocompatibility mismatched--B10.S donors. Prior to their injection these donor cells were selectively depleted ex vivo for either CD4, CD8 or Thy-1 by exposure to the appropriate monoclonal antibody (MoAb) plus complement. Following transplant the recipients were observed for 20 weeks, along with parallel control groups, for survival, leukemia relapse, graft failure and graft-versus-host disease; 98% of the controls receiving no transplantation therapy died of leukemia. Among the controls that received TBI plus undepleted B10.S cells 30.9% died of leukemia relapse, but another 34.2% survived free of any clinical evidence of their leukemia. Donor cell depletion for Thy-1 increased the relapse to 68.8%, while survival fell to 10.4%. CD8 depletion resulted in a relapse of 55.6%, with a survival of 19.4%. By contrast, CD4 depletion had no effect on relapse, but did significantly increase the incidence of graft failure. At the end of the 20 weeks additional tests were run to determine whether those transplant survivors that had remained leukemia-free were also free of any residual Rauscher virus. Those tests showed that they were not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of CD4 and CD8 T cells in the graft-versus-leukemia response in Rauscher murine leukemia. 168 16

Early studies showed that resistance to RadLV-induced leukaemia is mediated by gene(s) in the H-2D region of the MHC. Furthermore, these experiments correlated disease resistance with changes in H-2 expression occurring very early after virus inoculation. In the present study, we have begun to study at the molecular level this stimulation of H-2Dd class I expression in thymocytes of resistant mouse strains following infection by RadLV. The resistant strain of B10.T(6R) mice is used in these studies. When these infected thymocytes are assayed by fluorescence-activated cell sorting analysis, we can detect increased levels of H-2Dd expression on the surface of the thymocytes as early as 12 days following intrathymic injection of RadLV. RNA was prepared and examined by Northern blot analysis; H-2 mRNA levels are shown to be elevated on the order of four-fold. Nuclei were prepared from normal and infected thymocytes and the run-off transcripts were analysed by slot-blot hybridization. The rate of H-2 mRNA transcription is shown to be two- to three-fold higher in RadLV-infected thymocytes at 14 days post-infection when compared to that of normal thymocytes. These data demonstrate that elevation of H-2 surface expression following RadLV infection is the result of transcriptional activation. Extracts have been prepared from both normal and infected B10.T(6R) thymocytes and have been used in gel mobility assays in order to detect the interaction of potential trans-acting regulatory factors with sequences 5' of the H-2Dd gene. Specific binding occurs in both extracts, but the assay shows that the extracts differ both quantitatively and qualitatively; the extracts from infected thymocytes bind to additional sequences and to a higher degree than that from normal thymocytes. DNase I protection analysis locates a number of protein-binding sites, some of which are protected by extracts of either origin and some of which are only protected by extracts from infected cells. Two of these sequences are similar to the previously recognized consensus recognition sequences for the binding of AP-1 and NF-chi B. Oligonucleotides have been synthesized for both the genomic sequences being protected from DNase I digestion as well the published consensus sequences. While the DNA-binding activity in infected thymocytes for both AP-1 and NF-chi B-binding sites is increased, the binding to the genomic "AP-1 like" binding site is activated to a considerably greater level.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo stimulation of H-2Dd expression following RadLV infection of thymocytes: increased transcription and DNA-binding activity to sequences 5' of the Dd gene. 175 16

An intrathymic (i.t.) injection assay on B10.Thy-1 congenic mice was used to demonstrate that thymic prelymphoma cells developed first within mouse thymus 4 to 8 days after split-dose irradiation and were present in more than 63% of the test donor mice thymuses examined 21 and 31 days after irradiation. For the characterization of these thymic prelymphoma cells, thymocytes from B10.Thy-1.1 mice sampled 1 mo after irradiation were stained with J11d mAb and mAb against TL-2 (thymus-leukemia) antigen which is not expressed on normal thymocytes of the B10.Thy 1.2 and B10.Thy 1.1 strains but does appear on thymocytes of split-dose irradiated mice. These cells were sorted into subpopulations, samples of which were injected into recipient thymuses to determine which subpopulations contained thymic prelymphoma cells. Results showed that the prelymphoma cells were located in the J11d+TL-2+ cells. These prelymphoma cells were further characterized phenotypically as to their expression of the CD4 and CD8 antigens, which demonstrated that the thymic prelymphoma cells were present in the CD4-CD8- and CD4-CD8+ thymocyte subpopulations mainly and in the CD4+CD8+ subpopulation. The experiments on i.t. injection of a graded quantity of TL-2+ thymocytes from individual mice suggest that not all TL-2+ cells undergo neoplastic initiation and that prelymphoma cells may develop infrequently from one or more TL-2+ cells by genetic or epigenetic changes.
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PMID:Characterization of thymic prelymphoma cells that develop during radiation-induced lymphomagenesis in B10 mice. 182 52

DBA/2 (H-2d) mice bearing a transplanted highly metastatic lymphoma (ESb) in a state of widely disseminated disease could be successfully treated by a combination of surgery (removal of the local tumour), irradiation (5 Gy) and adoptive immunotherapy. The immunotherapy was achieved by transfer of anti-ESb-immune spleen cells from B10.D2 mice, which express the same major histocompatibility complex (MHC) molecules as DBA/2. In contrast, anti-ESb-immune cells from MHC-disparate C57BL/6 mice did not confer protective immunity. The B10.D2 anti-ESb-immune T cells contain two types of cytolytic specificity as detected by limiting-dilution analysis: (1) clones with specificity for the ESb-tumour-associated transplantation antigen (TATA) (at low frequency), and (b) clones with specificity for minor DBA/2 histocompatibility (H) antigens (at high frequency). Immune B10.D2 cells raised against different tumour lines or against TATA-ESb tumour variants did not confer the 100% protection seen with immune cells against ESb TATA+ cells. Finally we demonstrate that the allogeneic immune cells are more potent in terms of protective immunity than corresponding syngeneic immune cells. The data suggest that the strong graft-versus-leukemia effect with immune T cells from allogeneic MHC-identical but not from MHC-disparate mice was due to T cells with MHC-restricted specificity for an ESb-associated TATA. A graft-versus-host reactivity that developed much later and could not be prevented was most likely due to T cells sensitized against normal minor H antigens of the host. Our results are of potential relevance for allogeneic bone marrow transplantation and adoptive immunotherapy protocols.
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PMID:Specific eradication of micrometastases by transfer of tumour-immune T cells from major-histocompatibility-complex congenic mice. 182 94

A murine model of allogeneic bone marrow (BM) transplantation was used to determine the relative importance of CD4+ and CD8+ T cells in establishing donor T cell chimerism and in the development of graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity. Mature donor T cells were essential for complete chimerism when host mice (AKR, H-2k) were conditioned with suboptimal irradiation (9 Gy = LD50). Transplantation of donor BM (B10.BR, H-2k) resulted in mixed chimerism, whereas mice given BM containing additional T cells developed into complete and stable chimeras. Depletion of T cell subsets was associated with an increase in the frequency of mixed chimerism. The incidence of lethal GVHD was dependent on the number of T cells added to the BM inoculum. Ex vivo depletion of CD4+ T cells eliminated GVH-associated mortality. Removal of CD8+ T cells had no effect on overall survival. In contrast to the GVH results, removal of either CD4+ or CD8+ T cells compromised GVL reactivity, indicating that an optimal GVL response required both CD4+ and CD8+ T cells. T cell-subset depletion did not interfere with the induction of donor-host tolerance in these chimeras and may have facilitated its development. The loss of GVH/GVL effector cells as a result of T cell depletion and the development of donor-host tolerance may act synergistically to prevent or suppress GVH and GVL reactivity.
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PMID:Contribution of CD4+ and CD8+ T cells to graft-versus-host disease and graft-versus-leukemia reactivity after transplantation of MHC-compatible bone marrow. 183 16

Manifestation of graft-versus-leukemia (GVL) effect in MHC-compatible and -incompatible, allogeneic bone marrow transplantation and the roles of T cell subsets contaminated in the donor bone marrow were studied using radiation-induced leukemia-bearing C3H mice maintained under specific-pathogen-free (SPF) condition. The results indicated that BMT from MHC-incompatible allogeneic (B10) donor significantly improved the survival of the treated mice as compared with that from syngeneic (C3H) donor. When donor (B10) bone marrow cells were treated with either anti-Thy 1.2 or anti-Lyt 2.2 antibody plus complement prior to BMT, a beneficial GVL effect was completely abolished. On the other hand, BMT from MHC-compatible allogeneic donors (B10.BR, CBA, AKR) failed to show an improvement in survival. However, intentional enhancement of GVH reaction by preimmunization of B10.BR donor mice with a relatively small number (10(4) approximately 10(5] of C3H spleen cells or by an addition of B10.BR lymph node cells to the donor bone marrow resulted in a significant improvement in survival. The depletion of all T cells completely abrogated the GVL effect, while the depletion of either Lyt 2+ or L3T4+ T cells from donor (B10.BR) bone marrow resulted in only partial, if any, abrogation of GVL effect. The results indicate that GVL effect observed in leukemic mice treated with allogeneic BMT from MHC-compatible (B10.BR) and -incompatible (B10) donors was totally dependent on T cells contaminated in the donor bone marrow, and suggest that the roles of T cell subsets in the induction of GVL effect were different between MHC-compatible (B10.BR) and -incompatible (B10), allogeneic BMT.
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PMID:Graft-versus-leukemia effect in MHC-compatible and -incompatible allogeneic bone marrow transplantation of radiation-induced, leukemia-bearing mice. 194 75


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