GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Society of Hematology  (19)
  • 1
    Online Resource
    Online Resource
    Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation
    American Society of Hematology ; 2000
    In:  Blood Vol. 95, No. 7 ( 2000-04-01), p. 2434-2439
    Details
    In: Blood, American Society of Hematology, Vol. 95, No. 7 ( 2000-04-01), p. 2434-2439
    Abstract: Expression of CD134 (OX40) on activated CD4+ T cells has been observed in acute graft-versus-host disease (GVHD) after human and rat allogeneic bone marrow transplantation (BMT). We investigated the role of interaction between CD134 and CD134 ligand (CD134L) in a murine model of acute GVHD by using a newly established monoclonal antibody (mAb) against murine CD134L. Acute GVHD was induced by transfer of bone marrow cells and spleen cells into lethally irradiated recipients in a parent (C57BL/6) to first filial generation (C57BL/6 crossed with DBA/2) BMT. Administration of anti-CD134L mAb significantly reduced the lethality of acute GVHD and other manifestations of the disease, such as loss of body weight, hunched posture, diarrhea, and patchy alopecia. The survival rate 80 days after BMT in mice treated with the mAb was about 70%, whereas all mice treated with control antibodies died within 43 days. Histologic examinations revealed that inflammatory changes in target organs such as the liver, gut, and skin were also ameliorated in mice treated with the mAb compared with control mice. An in vitro assay of T-cell proliferation showed a marked hyporesponsiveness to host alloantigen in samples from mice treated with anti-CD134L mAb. In addition, low levels of interferon γ and transiently elevated levels of interleukin 4 and IgE in serum samples were found in mice treated with anti-CD134L mAb. These results suggest that CD134-CD134L interactions have an important role in the pathogenesis of acute GVHD.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V95.7.2434.007k11_2434_2439
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2000
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Human Plasmacytoid Dendritic Cell Line (PMDC05) Established from a Patient with CD4+CD56+ Acute Leukemia.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4330-4330
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4330-4330
    Abstract: Human dendritic cell (DCs) precursors are commonly divided into two distinct subsets: myeloid DCs (mDC) and Plasmacytoid DCs (pDCs). The pDCs, which show plasma cell like morphology, have been defined as the population that produce a large amount of type I interferon in response to viruses. The surface phenotypes of human pDCs are defined as CD4+, DC11c−, CD45RA+, IL3Rα (CD123)+ and lineage negative. But the developmental pathways and the regulations of pDCs have not been fully understood. On the other hand, CD4+CD56+ malignant cells in leukemia/lymphoma have been proposed to be of pDC lineage. CD4+CD56+ pDC leukemia/lymphoma are a rare hematological malignancy, totally only about 100 cases in the world by the literatures. In the recent report, these newly described CD4+CD56+ leukemic pDCs share common phenotypic and functional features with their normal counterparts. We encountered a patient with CD4+CD56+ acute leukemia in December 2004. The leukemia cells have been cultured in IMDM with 10 % FBS and a leukemia cell-derived cell line (PMDC05) was established. The effects of various cytokines on the differentiation and the function of PMDC05 were assayed by using IL-3, IL-4, IL-6, GM-CSF and CD40L alone or in combination. To evaluate the effects of CD40L, PMDC05 were cultured over adherent cell layer of 90 Gy irradiated CD40L cDNA-transfected NIH-3T3 cells at cell ration of 5:1 for 2 days. For investigation of the response of PMDC05 against the danger signals through toll like receptors, inactivated influenza viruses (A/H1N1 and A/H3N2) and GpG ODN 2006 were used. Antigen presenting ability of PMDC05 was evaluated by mixed leukocyte culture consisting of 50 Gy irradiated-PMDC05 cultured with various cytokines as stimulator cells and normal peripheral blood non-adherent cells and naïve cells as responder cells. PMDC05 maintained plasma cell like morphology with abundant cytoplasm and some cells showed small dendrites. PMDC05 showed a complex hypoploid chromosomal abnormalities (44, XY) including add(5)(q22), add(15)(q26) and del(15)(q11q15), which are identical to original leukemia cells. Abnormalities including 5q and 15q are reported as the frequent aberrations in CD4+CD56+ pDC leukemia/lymphoma. The surface phenotypes of PMDC05 were negative for CD3, CD14, CD16, CD19 and CD11c and highly positive for CD4, CD45RA, CD56, CD123, CD86, and HLA-DR. Moreover BDCA4 that is specific antigen of human blood pDC is markedly expressed on PMDC05. No TCR or IgH gene rearrangement was detected. Stimulation of PMDC05 with IL-3/CD40L, virus RNA or CpG, which are known as the potent exogenous signals for maturation of normal pDCs, showed to induce the high expression of the maturation markers such as CD83/CD40 and the production of INF-α. PMDC05 were demonstrated to possess a potent antigen presenting ability to allogeneic CD4+ cells in mixed leukocyte culture. The antigen presenting ability was remarkably enhanced in PMDC05 cultured with IL-3/CD40L for 2 days. These data demonstrated that newly established leukemia cell line PMDC05 is involved in pDC lineage and PMDC05 provides invaluable tools not only for the elucidation of pathophysiology and innovation of therapy in CD4+CD56+ leukemia/lymphoma but for the investigation of human pDCs.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4330.4330
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Anti-Tumor Cytotoxicity of Blood γδ T Cells Expanded from Leukemia Patients Against Autologous Leukemia Cells—Enhancement of the Anti-Tumor Cytotoxicity by Type I IFN.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 2385-2385
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 2385-2385
    Abstract: In order to establish an efficient anti-tumor cellular immunotherapy using blood γδ T cells, we investigated the cytotoxic activity of γδ T cells expanded from patients with leukemia against autologous leukemia cells and explored the potent methods for enhancing the anti-tumor cytotoxic activity of γδ T cells. We clarified that γδ T cells generated from leukemia patients possess the cytotoxic activity against autologous leukemia cells. Besides, anti-tumor cytotoxic activity of expanded γδ T cells was enhanced by the short-term culture of γδ T cells with type I IFN (IFN-α and IFN-β). The sensitivity of target leukemia cells to γδ T cells was enhanced by the exposure of the target cells to bisphosphonate such as zoledronate, which is one of the antigens recognized by γδ T cells and elevates the content of potent antigen for γδ T cells, isoprenyl pyrophosphate (IPP), in tumor cells. Blood γδ T cells were expanded from anti-CD3 microbead-separated T cells or anti-γδ TCR microbead-separated γδ T cells in the patients with acute myelogenous leukemia by the culture with zoledronate and a low concentration of IL-2 for 1–2 weeks. For the activation of expanded γδ T cells, cultured γδ T cells were exposed with type I IFN for 1–3 days. The supernatant prepared from the culture of type I IFN-activated γδ T cells was assayed for cytokine (IFN-γ, TNF-α, IL-4, IL-5, IL-10) concentration by cytometric bead array. Anti-tumor cytotoxicity of γδ T cells was evaluated by 51Cr-release assay by using purified γδ T cells as effector cells and autologous leukemia cells as target cells. In most patients with acute leukemia, γδ T cells could be markedly expanded by the culture with zoledronate and IL-2 and almost all the expanded γδ T cells possessed Vδ2 TCR. Expanded and purified γδ T cells derived from the patients with leukemia were demonstrated to be cytotoxic against autologous leukemia cells. By the culture of expanded γδ T cells with type I IFN, the expression of the activation marker CD69 and the apoptosis molecule Trail was enhanced at the concentration dependent of type I IFN especially IFN-β. The expanded γδ T cells were shown to produce a remarkable amount of IFN-γ and a considerable amount of TNF-α and the cytokine production was increased by the addition of type I IFN. In addition, the cytotoxic activity of γδ T cells was enhanced by incubating target leukemia cells with zoledronate for 1–2 days. The present study demonstrated that γδ T cells expanded from patient’s blood are cytotoxic to patient’s leukemia cells. It is also demonstrated that there are two methods practically available for enhancing the cytotoxic activity of expanded γδ T cells against leukemia cells, one of which is activating γδ T cells by using type I IFN, and the other is elevating the sensitivity of target cells by using bisphosphonate. These findings implied the possibility that type I IFN-activated γδ T cells could be efficiently applied for cellular immunotherapy in the patients with hematological malignancies who is being administered with bisphosphonate. Moreover, in vivo administration of bisphosphpnate, a low dose of IL-2 and type I IFN could be effective for tumors as γδ T cell-based cellular immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.2385.2385
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Induction of Recipient Cell-Specific Donor T Cell Anergy by UV-C-Irradiated Recipient Immature Monocyte-Derived Dendritic Cells.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4897-4897
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4897-4897
    Abstract: The induction of donor T cell anergy to recipient cells for reducing GVHD could be one way of expanding donor candidates for HLA-mismatched hematopoietic stem cell transplantation. The present study was designed to clarify whether recipient cell-specific T cell anergy could be induced by priming donor lymphocytes with recipient monocyte-derived dendritic cells (mo-DCs) irradiated with UV-C. By irradiation of mo-DCs with 100 J/m2 or more UV-C, the expression of DC-associated surface phenotypes such as CD1a, CD54, CD40, CD80, CD83 and CD86 was reduced in one day after irradiation and the effects of UV-C irradiation continued for at least 7 days. By irradiation of mo-DCs with 100 J/m2 or more UV-C, the antigen-presenting ability of both immature and mature mo-DCs, which was examined by 3H-thymidine incorporation assay, was clearly decreased at UV-C dose-dependent manner. Proliferation of CSFE-labeled lymphocytes by the stimulation with immature or mature Mo-DCs was suppressed by 300 J/m2 UV-C irradiation to immature or mature mo-DCs. The response of normal donor 1 lymphocytes, which had been co-cultured with 300–3,000 J/m2 UV-C-irradiated donor 2 immature mo-DCs for 7 days, against mature donor 2 mo-DCs in mixed leukocyte culture (MLC) for 7 days was markedly reduced, compared with the response of the donor 1 lymphocytes co-cultured with non-irradiated donor 2 mo-DCs or UV-C-irradiated mo-DCs derived from a different individual donor 3. CFSE-labeling analysis of donor 1 lymphocytes, which were co-cultured with 300 J/m2 UV-C irradiated donor 2 mo-DCs in the first MLC and then stimulated with donor 2 mature mo-DCs in the second MLC, showed that by stimulation with mature mo-DCs in the second MLC, the proliferation of donor 1 lymphocytes co-cultured with UV-C irradiated donor 2 mo-DCs in the first MLC was less than that of the lymphocytes co-cultured with non-irradiated mature mo-DCs. Flow cytometry analysis of the lymphocytes co-cultured with 300 J/m2 UV-C irradiated mo-DCs using surface CD4/CD25 and cytoplasmic Foxp3 monoclonal antibodies revealed that there was no increase of regulatory T cell population in the lymphocytes co-cultured with UV-C-irradiated immature mo-DCs, compared with the lymphocytes co-cultured with non-irradiated immature mo-DCs. Cell proliferation in allogeneic MLC consisting of lymphocytes as responder cells and mature mo-DCs as stimulator cells was not suppressed by the addition of the lymphocytes co-cultured with UV-C-irradiated immature mo-DCs. The present study demonstrated that recipient cell-specific T cell anergy could be induced by priming donor lymphocytes with UV-C-irradiated immature mo-DCs derived from a recipient and the T cell anergy was not associated with regulatory T cells. These data suggest the applicability of donor graft cells, which have been pre-stimulated with UV-C-irradiated recipient immature mo-DCs for expanding donor candidates for HLA-mismatched hematopoietic stem cell transplantation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4897.4897
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    BCL6 Rearrangement Detected by FISH Analysis Is a Poor Prognostic Factor in the “Non-Germinal Center Phenotype” of Diffuse Large B-Cell Lymphoma.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4620-4620
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4620-4620
    Abstract: Background: Diffuse large B-cell lymphoma (DLBCL), which is the most common type of adult non-Hodgkin lymphoma, is considered to be heterogeneous in cytogenetics, immunophenotype and clinical feature. As the results of gene expression profiling, DLBCL can be divided into prognostically significant 3 subgroups of germinal center B-like (GCB), activated B-like and type 3. Chromosomal translocations affecting the BCL6 locus at the 3q27 locus are common in DLBCL, however, the prognostic significance of BCL6 rearrangement is still controversial. Methods: Twenty-six cases of DLBCL were examined with interphase fluorescence in situ hybridization (FISH) on touch preparations of lymph nodes using LSI BCL6 dual color probes (Vysis) for the incidence of BCL6 rearrangement and immunohistochemistry on paraffin section using CD10, BCL6 and MUM1 for subclassfying “GCB phenotype” and “non-GCB phenotype”. The correlation of BCL6 rearrangement with survival was investigated in two subgroups of DLBCL. Results: Of the 26 DLBCL cases, 6 cases (23%) were considered GCB phenotype and 20 cases (77%) non-GCB phenotype. BCL6 rearrangements were detected in 2 of 6 cases (33%) with GCB phenotype and 9 of 20 (45%) with non-GCB phenotype (total 11/26, 42%). ALL 6 cases with the GCB phenotype achieved sustained complete remission after chemotherapy and are alive. On the other hand, complete remission rate was 22% for the cases with BCL6 rearrangement but 73% for the cases without BCL6 rearrangement in the non-GCB phenotype (p=0.069). BCL6 rearrangement had a significant adverse effect on progression free survival within the non-GCB phenotype (P=0.016), but there was no significant correlation between BCL6 rearrangement and overall survival. Conclusion: FISH-based technique of the BCL6 rearrangements using touch preparations of lymph nodes could be developed for the retrospective analysis on survival. BCL6 rearrangement showed a poor prognostic effect particular in the non-GCB subgroup of DLBCL. Overall survival Overall survival Progression free survival Progression free survival
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4620.4620
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Micafungin Is Extremely Effective Against Fungal Infections Complicating Hematological Malignancies: Report of a Multicenter Study by N-FISH (Niigata Fungal Infection Study Group in Hematology).
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 5350-5350
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 5350-5350
    Abstract: [Background]Micafungin (MCFG) is a candin antifungal agent, and was marketed in Dec. 2002 in Japan and in Apr. 2005 in the United States. The Niigata Fungal Infection Study Group in Hematology (N-FISH) performed a multicenter prospective study to clarify the therapeutic effects of MCFG on deep fungal infections complicating hematological malignancies. [Methods]A total of 36 pts. who had been treated in centers belonging to N-FISH between Oct. 2003 and Apr. 2005 were included in this study. They consisted of 14 men and 22 women with a mean age of 53.5 years: 14 pts. with AML, 10 pts. with malignant lymphoma, 6 pts. with ALL, and 6 pts with other diseases. They had a proven fungal infection, or were suspected of having a fungal infection because of fever unresponsive to antimicrobial agents or from laboratory data. Three of them had a proven infection, and 33 were suspected of having a fungal infection. Three of these 33 pts. failed to respond to fluconazole. As a rule, MCFG was administered for more than 14 days until infectious symptoms improved or disappeared. When MCFG was judged ineffective because of the worsening of clinical symptoms despite the administration of MCFG, or when the administration of MCFG was judged difficult because of adverse effects, the drug was discontinued or replaced by other drugs. Two pts. orally received amphotericin B syrup singly. [Results]The mean dose of MCFG was 2.6 mg/kg (1.5–4.2 mg/kg), and the mean duration of administration was 15.9 days (5–85 days). Complete or partial response was achieved in 31 (86.1%) of the 36 pts., who showed improvements in infectious symptoms. In 4 pts, MCFG was discontinued because of insufficient effects. There were no breakthrough fungal infections within 7 days after the completion of MCFG therapy. Of the 36 pts., 31 (86.1%) and 24 (66.7%) survived 1 and 3 months after MCFG therapy, respectively. The cause of death was exacerbation of the primary disease, and not exacerbation or the onset of a fungal infection. Eight adverse events occurred in 7 pts.: hypoglycemia in 1, liver dysfunction in 3, eosinophilia in 1, kidney dysfunction in 2, and hypokalemia in 1. In 1 of the 3 pts. with liver dysfunction (grade 3), MCFG therapy was discontinued, with rapid improvement of the liver dysfunction. All other adverse events were mild, allowing continued MCFG therapy. [Conclusion]This multicenter study demonstrated the effectiveness and safety of MCFG therapy for deep fungal infections complicating hematological malignancies. The results suggest that MCFG should be promptly used for fever associated with a fungal infection complicating hematological malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.5350.5350
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Human Plasmacytoid Dendritic Cell like Leukemia Cell Line (PMDC05) Established from a Patient with CD4+CD56+ Acute Leukemia.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 4456-4456
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4456-4456
    Abstract: Human dendritic cell precursors are commonly divided into two distinct subsets: myeloid DC and Plasmacytoid DC (pDC). The pDC, which show plasma cell like morphology, have been defined as the population that produce a large amount of type I interferon in response to viruses. The surface phenotypes of human pDCs are defined as CD4+, DC11c−, CD45RA+, IL3Rα (CD123)+, CD1c (BDCA-1)−, CD303 ((BDCA-2)+ and lineage negative. On the other hand, leukemia/lymphoma cells in CD4+CD56+ leukemia/lymphoma have been proposed to be of pDC lineage. CD4+CD56+ pDC leukemia/lymphoma are a rare hematological malignancy, totally only about 100 cases in the world by the literatures. We established a pDC like leukemia cell line (PMDC05) from leukemia cells of a patient with CD4+CD56+ acute leukemia. PMDC05 showed a complex hypoploid chromosomal abnormalities (44, XY) including add(5)(q22), add(15)(q26) and del(15)(q11q15), which is identical to original leukemia cells. Abnormalities including 5q and 15q are reported as the frequent aberrations in CD4+CD56+ pDC leukemia/lymphoma. PMDC05, which morphology was similar to plasma cells, was positive for CD4, CD56, CD123, CD33, CD86, HLA-ABC, HLA-DR, CD1a, CD40, and CD83 but negative for linage markers. Cytokine receptors for GM-CSF, IL3Rα and IL-6Rα were positive on PMDC05. The expression of Trail and Flt-3L was positive. By the culture with IL-3, CPG-A/B, GM-CSF, molecules associated with antigen presentation such as CD1a and CD40 were up-regulated. Besides, the addition of LPS increased the expression of CD40, CD80 and CD83 on PMDC05. PMDC05 by itself possessed a potent antigen presenting ability to naïve T cells and the treatment of PMDC05 with IL-3, CPG-A/B, or GM-CSF enhanced the antigen presenting ability to naïve T cells. TLR7, TLR 8 and TLR 9 as well as TLR1, TLR2, TLR4 were demonstrated to be expressed on PMDC05 by RT-PCR and RQ-PCR showed that the expression of TLR7 and TLR9 was most characteristic. λ-like 14.1 and preTα was also demonstrated to be expressed on PMDC05 by RT/RQ-PCR. PMDC05 possessed an ability to uptake the antigens like FITC-dextran and lucifer yellow. Although IFN-α was not identified to be secreted from PMDC05 by the stimulation of influenza virus, IFN-γ and TNF-α was demonstrated to be secreted to the similar level in pDC, which was examined simultaneously with PMDC05 by CBA assay. These data demonstrated that newly established leukemia cell line PMDC05 is involved in pDC lineage and PMDC05 provides invaluable tools not only for the elucidation of pathophysiology of CD4+CD56+ leukemia/lymphoma but also for the investigation of differntiation and regulation of pDC. In addition, PMDC05 could be applied for generating tumor-specific CTL clone, which may be used for anti-tumor cellular immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.4456.4456
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Effectiveness of WT1 Peptide Vaccination Combined with Imatinib in a Patient with CML in Chronic Phase.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4253-4253
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4253-4253
    Abstract: Abstract 4253 Cytotoxic T lymphocytes (CTLs) are presumed to kill the relevant antigen-expressing leukemia cells including leukemic stem cells, which display intrinsic resistance against tyrosine kinase inhibitors such as imatinib in CML patients. In order to clarify the safety and effectiveness of WT1 peptide vaccination for the patients with CML, we started WT1 peptide vaccination in combination with imatinib therapy for a CML patient who could not acquire a major molecular response by the administration of imatinib. In addition, we tried to evaluate the kinetics of WT1-specific CTLs in peripheral blood (PB) during WT1 peptide vaccination. A 51 years-old male with CML in chronic phase had been treated with 400 mg imatinib for 4 years. BCR-ABL transcripts decreased transiently to less than 700 copies in 1 μg RNA (3-log reduction: 300 copies in 1 μg RNA extracted from PB cells; median in our laboratory) but gradually increased to more than 1,000 copies thereafter. Since the patient was HLA-A*2402+ and an informed consent was obtained, HLA-A*2402-restricted 9mer WT1 peptides (CYTWNQMNL; a.a. 235-243), which had been identified to possess an anti-tumor immunogenicity, were administered subcutaneously at the dose of 1 mg/day every 2 weeks in combination with 400 mg imatinib for first 5 months and thereafter every 4 weeks for 12 months. No adverse effects due to WT1 peptide vaccination was observed except for skin induration and redness at the sites of WT1 peptide injection. Although BCR-ABL transcripts increased up to more than 2,000 copies after transient decrease to less than 1,000 copies by the administration of WT1 peptides every 2 weeks, the transcripts have decreased to less than 500 copies by the administration of WT1 peptides every 4 weeks. The appearance of WT1-specific CTLs in PB was confirmed by evaluating the frequency of MHC/WT1 tetramer+CD8+ T cells by using MLPC (mixed lymphocyte peptide culture). MLPC was performed by culturing 1-3 ×105 PB mononuclear cells (MNCs) in 200 l of 5% autologous serum-containing medium with 10 μg WT1 peptides in 96 well plates. Frequency of MHC/WT1 tetramer+ cells in PB-CD8+ cells was calculated by the following formula. Number of wells containing a lump of tetramer+CD8+ cells / [(Number of PB-MNCs seeded in a well of MLPC) x (total number of wells for MLPC) x (ratio of PB-CD8+ cells in PB-MNCs)]. Although WT1-specific CTLs were not detected in PB before WT1 peptide vaccination, the CTLs appeared after the second vaccination and maintained at the level of nearly 15/106 CD8+ cells thereafter. The MHC/WT1 tetramer+ cells showed cytotoxicity against only leukemia cells expressing WT1 and HLA-A*2402. The cytotoxicity was blocked clearly by adding unlabeled cold target cells in cold inhibition test and blocked also by antibodies against MHC class I but not by antibodies against MHC class II. In vitro study demonstrated that the stimulation with WT1 peptides made WT1-specific CTLs, which were generated by MLPC, less reactive to MHC/WT1 tetramers and the unreactivity lasted at least for 2 weeks. The present study showed that WT1 peptide vaccination for an imatinib-pretreated CML patient is feasible and effective, which is due to the generation of WT1-specific CTLs with cytotoxicity against WT1-expressing leukemia cells. In addition, since the CTLs are suggested to get tolerant to WT1 peptides presented by leukemia cells by the exposure with WT1 peptides, the interval of peptide administration has to be considered for the clinical efficacy of peptide vaccination. The present findings including in vivo and in vitro studies revealed that the administration of the peptides every 4 weeks is superior to every 2 weeks. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4253.4253
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    In Vitro Expansion of Blood γδ T Cells in Patients with Myeloma/Lymphoma and Anti-Tumor Cytotoxicity of the Expanded γδ T Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 3895-3895
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 3895-3895
    Abstract: In order to establish an efficient anti-tumor cellular immunotherapy using blood In order to establish an efficient anti-tumor cellular immunotherapy using blood γδ T cells, we investigated the in vitro expansion of γδ T cells in the patients with myeloma and lymphoma by the culture of PB-MNC with bisphosphonate and a low dose of IL-2 and we demonstrated the cytotoxic activity of the expanded γδ T cells against myeloma/lymphoma cells. Simultaneously we explored the potent methods for enhancing the anti-tumor cytotoxic activity of γδ T cells by both directions of activating the expanded γδ T cells and making target tumor cells sensitive to γδ T cells. For the activation of γδ T cells, expanded γδ T cells were exposed with type I IFN, monocyte-derived dendritic cells (mo-DC), or plasmacytoid dendritic cell like cell line PMDC05 (leukemia cell line established from CD4+ CD56+ acute leukemia in our laboratory) for 2 days. For the enhancement of sensitivity of target tumor cell to γδ T cells, we aimed to increase the content of IPP (the potent pyrophosphate antigen for γδ T cells) in tumor cells by decreasing the metabolic downstream of IPP. For decreasing the downstream of IPP, we tried to suppress FPP synthetase, which is involved in downstream metabolism of IPP, by using nitrogen-containing bisphosphonate. In addition, the expression of stress-induced molecules such as MICA/B on target tumor cells was evaluated in association with the level of cytotoxicity of γδ T cells against the tumor cells. Compared with normal control, the patients with myeloma (n=8) demonstrated decreased percentage and counts of PB γδ T cells. Patients with lymphoma (n=7) showed a wide range of values in PB γδ T cells, covering a normal range. Amplification rate of PB γδ T cells by culture with zoledronate and IL-2 varied markedly from patient to patient up to 120 times in myeloma and 90 times in lymphoma. Expanded γδ T cells generated in patients with myeloma/lymphoma were demonstrated to possess the cytotoxic activity against myeloma/lymphoma cells by 51Cr-release assay and CFSE-labeled target cell. The cytotoxic activity of expanded γδ T cells was enhanced by the exposure of γδ T cells with type I IFN (IFN-α and IFN-β). The activation of γδ T cells, which was evaluated by the elevation of CD69 expression, was observed by the exposure of γδ T cells with type I IFN, mo-DC, or PMDC05 for 2 days. The sensitivity of target myeloma/lymphoma cells to γδ T cells was enhanced by the exposure of the target cells to bisphosphonate such as zoledronate. The expression level of MICA/B on target tumor cells was demonstrated to be associated with the potency of cytotoxicity of γδ T cells against the tumor cells. The present study demonstrated that γδ T cells expanded from myeloma/lymphoma patient’s blood are cytotoxic to myeloma/lymphoma cells. There are two methods practically available for enhancing the cytotoxic activity of expanded γδ T cells against myeloma/lymphoma cells, one of which is activating γδ T cells and the other is elevating the sensitivity of target cells by using bisphosphonate.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.3895.3895
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Graft-Versus-Leukemia Effect and Graft-Versus-Host Disease Can Be Differentiated by Cytotoxic Mechanisms in a Murine Model of Allogeneic Bone Marrow Transplantation
    American Society of Hematology ; 1999
    In:  Blood Vol. 93, No. 8 ( 1999-04-15), p. 2738-2747
    Details
    In: Blood, American Society of Hematology, Vol. 93, No. 8 ( 1999-04-15), p. 2738-2747
    Abstract: Allogeneic bone marrow transplantation (allo-BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. In the present study, we examined the contribution of cytotoxic effector mechanisms, which are mediated by tumor necrosis factor- (TNF-), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a murine BMT model. Bone marrow cells plus spleen cells (BMS) from wild-type, FasL-defective, or perforin-deficient donors were transferred into lethally irradiated recipients in the parent (C57BL/6) to F1 (C57BL/6 × DBA/2) BMT model with or without prior inoculation of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of anti–TNF- antibody administration was also examined. Whereas the defect or blockade of each cytotoxic pathway could ameliorate lethal acute GVHD, the GVL effect was differentially affected. The wild-type BMS recipients died of acute GVHD within 50 days without residual leukemia cells. The FasL-defective BMS recipients showed 60% 〈 survival over 80 days without acute GVHD or residual leukemia cells. Administration of anti–TNF- antibody resulted in early leukemia relapse and the recipients died within 25 days with massive leukemia infiltration in the liver. The perforin-deficient BMS recipients died within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD without impairing GVL effect in allo-BMT.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood.V93.8.2738.408k30_2738_2747
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 1999
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...