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)

We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)-promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4-2. BALB/c mice receiving 2.5 x 10(5) 2B-4-2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5-day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.
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PMID:Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. 790 57

We report the establishment of a leukemia cell line (UoC-B10) from a patient who developed leukemia several months after the diagnosis of a mediastinal yolk sac tumor. The patient's yolk sac tumor responded to combination chemotherapy, and a mature teratoma with focal areas of hematopoiesis was subsequently resected. However, 5 months after the initial diagnosis, the patient developed an acute lymphoblastic leukemia with a precursor B-cell phenotype. Cytogenetic analysis showed an i(12p) abnormality in the patient's leukemia cells and in the UoC-B10 cell line. The i(12p) was also identified retrospectively in the mediastinal tumor cells by fluorescent in situ hybridization analysis. The UoC-B10 cell line, which has been growing continuously for > 24 months in culture, was Epstein-Barr virus negative and was generally concordant with the patient's leukemia cells by analysis of immunophenotype, karyotype, and genotype. The UoC-B10 cell line possesses receptors for granulocyte-colony-stimulating factor, a cytokine which the patient received as part of his treatment protocol. This cell line may be useful in studying the relationship between i(12p) and hematological differentiation of human mediastinal germ cell tumors.
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PMID:Establishment of a leukemia cell line with i(12p) from a patient with a mediastinal germ cell tumor and acute lymphoblastic leukemia. 806 67

We have recently demonstrated, in a fully MHC-mismatched murine bone marrow transplantation model, that administration of a short course of high dose IL-2 markedly diminishes graft-vs-host disease (GVHD) without compromising alloengraftment or the graft-vs-leukemia (GVL) effect of allogeneic T cells. We have now evaluated the mechanism of the dissociation of GVL and GVHD observed in this model. We demonstrate that CD4+ T cells were required to produce severe, acute GVHD in the fully MHC-mismatched plus minor histocompatibility Ag-mismatched A/J-->B10 strain combination. The GVHD-producing activity of A/J CD4+ T cells administered without CD8+ T cells was inhibited by IL-2 treatment. In contrast, CD8+ T cells alone mediated the GVL effect observed in the EL4 leukemia/lymphoma model, and CD4+ cells did not contribute to this effect. This CD8-mediated GVL activity was not inhibited by IL-2 treatment. Because naive A/J CD8+ T cells administered without CD4+ T cells did not produce acute GVHD, we were unable to evaluate the effect of IL-2 in this model. However, when A/J donors were presensitized with B10 skin grafts, CD4-depleted A/J spleen cells were capable of causing acute GVHD in B10 recipients. This CD8-mediated GVHD was not inhibited by treatment with IL-2. However, IL-2 did partially inhibit the GVHD produced by nondepleted presensitized A/J spleen cells, probably due to selective inhibition of the function of presensitized A/J CD4+ T cells. The dissociation of GVHD and GVL against the EL4 leukemia/lymphoma in IL-2-treated mice can therefore be explained by selective inhibition by IL-2 of CD4 activity.
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PMID:IL-2 reduces graft-versus-host disease and preserves a graft-versus-leukemia effect by selectively inhibiting CD4+ T cell activity. 809 57

Treatment of lethally irradiated mice with a short course of high-dose interleukin (IL)-2 markedly inhibits acute and chronic graft-versus-host disease (GVHD), while preserving a graft-versus-leukemia (GVL) effect of allogeneic T-cells. We recently demonstrated that this GVL effect, observed with the EL4 leukemia/lymphoma in the A/J-->B10 strain combination, was mediated by CD8+ A/J T-cells in a CD4-independent fashion. IL-2 inhibited only the activity of CD4+ cells, and not that of CD4-independent CD8+ T-cells in A/J spleen cell inocula. This inhibition of CD4 function was sufficient to markedly inhibit GVHD, thus explaining the dissociation of GVHD and GVL in IL-2-treated mice. We have now performed studies to determine the capacity of IL-2 to inhibit GVHD induced across a variety of different histocompatibility barriers. IL-2 significantly delayed GVHD mortality in three of four additional fully major histocompatibility complex (MHC) plus minor-disparate strain combinations when CD4+ T-cells were given. Numbers of CD8+ T-cells comparable to those that might contaminate human marrow demonstrated a relatively poor capacity to produce acute GVHD when given without CD4+ cells in all of three additional strain combinations evaluated. In one of these strain combinations (B10-->BALB/c), IL-2 protected against acute but not chronic GVHD mortality when CD4+ cells were given with or without CD8+ cells. In one fully allogenic strain combination, B10-->A/J, IL-2 did not inhibit the GVHD produced by CD4+ cells given with or without CD8+ cells. IL-2 was unable to inhibit CD8-mediated GVHD in strain combinations differing at isolated class I MHC loci. In a strain combination differing only at multiple minor histocompatibility antigen (HA) loci, B10-->C3H.SW, GVHD was largely CD8-dependent, but IL-2 did not inhibit the small CD4-mediated component of GVHD. Together, these results suggest that IL-2 inhibits a restricted subset of CD4 cells or functions, and that the type of CD4 activities mediating GVHD is determined by the particular histoincompatibilities between donor and host.
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PMID:Strain dependence of interleukin-2-induced graft-versus-host disease protection: evidence that interleukin-2 inhibits selected CD4 functions. 811 Jul 26

The intensity of graft-versus-leukemia (GVL) effect was studied using several radiation-induced leukemia cell lines (designated 8027, 8313, 9107, 7929) in MHC-compatible and -incompatible allogeneic bone marrow transplantation (BMT) of leukemia-bearing C3H mice. The results indicated that BMT from MHC-incompatible allogeneic (B10, B10.D2) donors consistently improved the survival of the treated mice compared with that in syngeneic (C3H) donors. However, BMT from MHC-compatible allogeneic (B10.BR, CBA, AKR) donors failed to improve the survival of 8027-bearing recipients. On the other hand, a remarkable improvement in survival of 8313, 9107 or 7929-bearing recipients was observed in MHC-compatible allogeneic (B10.BR, AKR) BMT but there was only a marginal GVL effect in MHC-compatible BMT from CBA donors. There was no clear correlation between the intensity of GVL effect and the amount of class I MHC molecules expressed on leukemic cell lines. The activity of donor lymph node cells for the induction of lethal graft-versus-host disease (GVHD) correlated with the intensity of GVL effect induced by intact donor bone marrow. The results indicate that GVL effect against radiation-induced leukemias could be consistently induced in MHC-incompatible allogeneic BMT whereas the intensity of GVL effect induced in MHC-compatible allogeneic BMT varied among different leukemias and the donor-host strain combinations used.
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PMID:Graft-versus-leukemia effect in allogeneic bone marrow transplantation in mice against several radiation-induced leukemias. 820 78

H-2b mice are immunologic responders to the tumorigenic MCF1233 murine leukemia virus (MuLV), an AKV-related virus derived from endogenous C57BL MuLV. We have identified an immunodominant CTL epitope that is expressed on MCF1233 MuLV-induced lymphomas of H-2b mice. C57BL/10 (B10) mice were immunized with an MCF1233-induced B10 B cell lymphoma, and tumor-specific CTL cultures were generated in vitro. These were tested for recognition of synthetic class I-binding MuLV peptides, selected for class I allele-specific motifs. One of 28 candidate peptides sensitized target cells for CTL recognition. This peptide seems to be an immuno-dominant epitope, because it was recognized by all independent CTL clones, isolated from the tumor-specific bulk culture. The epitope (KSPWFTTL) is derived from the MCF1233 MuLV envelope (env)-p15E region and is shared by all endogenous AKV types of MuLV. It has an optimal length of eight amino acids and is presented by the Kb H-2 class I molecule. Interestingly, Friend, Moloney, and Rauscher (FMR) types of MuLV are not recognized by MCF MuLV-directed CTL. The FMR env-p15E proteins have a single amino acid difference at the first position of the MCF1233 MuLV epitope (RSPWFTTL instead of KSPWFTTL). The corresponding FMR-encoded peptide bound class I H-2 Kb equally well as the MCF peptide, but it was poorly recognized by MCF1233 MuLV-specific CTL. Moreover, in the Rauscher MuLV-induced cell line RMA the FMr peptide seems not to be processed for recognition by CTL, which was illustrated by experiments with CTL elicited against this peptide. Altered TCR interaction as well as lack of processing thus may explain the type specificity of MCF1233 MuLV-directed CTL.
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PMID:Immunodominant mink cell focus-inducing murine leukemia virus (MuLV)-encoded CTL epitope, identified by its MHC class I-binding motif, explains MuLV-type specificity of MCF-directed cytotoxic T lymphocytes. 825 84

A 428-base pair region of the gag gene of a molecular clone of the SL3-3 murine leukemia virus (MuLV) was replaced with allelic sequences that contain the NB-tropic determinants of the Moloney MuLV. SL3-3NB, the ecotropic virus derived from this modified clone, rapidly induced T-cell lymphoblastic lymphomas in the Fv-1n mouse strains CWD and NIH Swiss and the Fv-1b strain, B10.Br. By Southern blot assay, each of the CWD tumors and all but one of the B10.Br tumors that were tested contained recombinant proviruses. The envelope genes of the B10.Br recombinant viruses retained the SL3-3NB 5' p15E (TM) gene sequences (type I env), whereas the CWD recombinants did not (type II env). The production of type I env recombinants by B10.Br mice is a characteristic that is shared with other mouse strains that express the H-2k haplotype. The results indicate that the inserted Moloney virus gag sequences conferred NB-tropism to SL3-3NB and did not interfere with the expression of SL3-3 pathogenic determinants or the formation of recombinant viruses.
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PMID:Generation and pathogenicity of an NB-tropic SL3-3 murine leukemia virus. 838 41

When allogeneic BMT is used for the treatment of leukemia, depletion of T cells from the donor BM to avoid GVHD may be accompanied by persistence of host cells and post-transplant relapse. In this report, a murine model of MHC-compatible BMT was used to show that delayed infusion of immunocompetent donor cells early after T cell-deficient BMT eliminated residual host cells and provided an antileukemic effect without causing lethal GVHD. AKR (H-2k) recipient mice were pre-conditioned with 9 Gy total body irradiation (LD50) and transplanted with 10(7) BM cells from MHC-matched B10.BR donors. These mice did not develop GVHD and became stable, long-term mixed (donor-host) T cell chimeras. In this model, mixed or incomplete donor T cell chimerism was associated with decreased GVL reactivity. AKR hosts that were transplanted with B10.BR bone marrow admixed with 3 x 10(7) B10.BR spleen cells (as a source of T cells) became complete donor T cell chimeras, but they developed severe and lethal GVHD. However, when the infusion of donor spleen cells was delayed until 21 days after BMT, few mice exhibited any clinical signs of GVHD, and > 95% of the mice became long-term survivors. The infused spleen cells eliminated residual host T cells by 21 days after infusion, and most chimeras were able to resist a supralethal challenge with AKR leukemia/lymphoma cells. Thus, post-transplant adoptive immunotherapy with normal mononuclear cells from the marrow donor may be an effective way to eliminate residual disease or treat leukemia relapse after BMT without causing significant GVHD.
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PMID:Delayed infusion of normal donor cells after MHC-matched bone marrow transplantation provides an antileukemia reaction without graft-versus-host disease. 848 80

Our previous results in a murine model indicated that the GVL effect against radiation-induced leukemias could be induced in not only MHC-incompatible but also MHC-compatible allogeneic BMT, and that the intensity of the GVL effect induced in MHC-compatible allogeneic BMT varied among different leukemias and the donor/host strain combinations used. With the use of a radiation-induced T cell leukemia which followed the induction of the GVL effect in both MHC-compatible and -incompatible, allogeneic BMT, the role of T cell subsets in the development of the GVL effect and GVHD was studied. The results indicated that Lyt2+ T cells contaminating donor BM were consistently critical for the induction of the GVL effect in MHC-incompatible (B10) and -compatible (B10.BR and AKR) allogeneic BMT of leukemia-bearing C3H mice, but the depletion of L3T4+ T cells had no effect. In contrast, lethal GVHD induced by AKR donor lymph node cells was totally dependent on L3T4+ T cells, but the depletion of Lyt2+ T cells had no effect. On the other hand, both T cell subsets could cause lethal GVHD induced by MHC-incompatible (B10) and -compatible (B10.BR) allogeneic donors. The distinct roles of T cell subsets of AKR donors were confirmed by the preferential induction of the GVL effect with the AKR donor bone marrow mixed with lymph node cells which had been depleted of L3T4+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An MHC-compatible allogeneic bone marrow donor with a distinct role of T cell subsets in graft-versus-leukemia effect and lethal graft-versus-host disease. 852 79

Studies were performed to examine whether, in addition to T cells, there might be other immune cells also capable of exerting a graft-versus-leukemia (GVL) response following allogeneic marrow transplant. Using an MHC-matched mouse model, consisting of normal B10.S donors and SJL/J Rauscher-retroviral-leukemic recipients, the donor cells were selectively depleted of their Asialo-GM1+ component prior to being infused into the leukemic recipients. The incidence of relapse was then compared against that for matched leukemic control recipients of undepleted cells from the same donors. FCM analysis of the depletion protocol indicated that exposure to anti-Asialo-GM1 antibody eliminated more than half of the donor NK1.1+ cells, but caused no significant losses among the Thy-1+, CD3+, or CD8+ cells. Nevertheless, fatal relapse among the leukemic recipients of the depleted cells was nearly double that found among the leukemic control recipients of undepleted cells, 47.5 vs 25.4% (P = 0.01). In a parallel study, using normal SJL/J recipients, this same depletion protocol was found to have no significant effect on the incidence of graft-versus-host disease (GVHD). These results therefore suggest that Asialo-GM1+ NK cells may be capable of contributing to the suppression of relapse in this type of leukemic recipient of allogeneic marrow, and that this suppression may occur independently of GVHD.
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PMID:Evidence for a possible role of Asialo-GM1-positive cells in the graft-versus-leukemia repression of a murine type-C retroviral leukemia. 853 19


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