Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.69 (BMT)
2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antigen receptors of the majority of peripheral blood T lymphocytes are constituted of alpha- and beta-chains in association with CD3. The phenotype of those T cell receptor-alpha, beta cells is CD3+, 4+ and/or 8+. The small subset of CD3+, 4-, 8- T cells includes TCR-gamma, delta cells. These two T cell subsets have different TCR gene rearrangement patterns, tissue distributions and mechanisms of antigen recognition. We studied the repopulation of both T cell subsets in 20 allogeneic marrow graft recipients in relation to the type of graft (T cell-depleted versus non-depleted) and the occurrence of active cytomegalovirus (CMV) infection, using three-color immunofluorescence and flow cytometry. The CD3+, 4+ and/or 8+ and CD3+, 4-, 8- T cells had clearly different repopulation patterns. At 1 month post-BMT, they had repopulated the blood to similar levels. Thereafter, the CD3+, 4+ and/or 8+ T cells increased further in number, whereas the CD3+, 4-, 8- T cells stabilized on average between 100 and 200 x 10(6)/l. The nine recipients of T cell-depleted marrow grafts showed a relatively delayed repopulation of their CD3+, 4+ and/or 8+ T cells compared with the 11 recipients of non-depleted marrow. In contrast, the repopulation rate of the CD3+, 4-, 8- T cells was similar in both groups. The occurrence of active CMV infection post-BMT was associated with an increased rate of repopulation of the CD3+, 4+ and/or 8+ T cells, particularly those expressing HNK1, but did not affect the repopulation of the CD3+, 4-, 8- T cells.
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PMID:CD3+, 4+ and/or 8+ T cells and CD3+, 4-, 8- T cells repopulate at different rates after allogeneic bone marrow transplantation. 254 71

Clinical and experimental data suggest a role for the immune response in preventing leukemic relapses following allogeneic bone marrow transplantation the graft-versus-leukemia (GVL) effect. In the context of an allogeneic BMT, a number of different immune mechanisms mediated by donor cells may be responsible for the GVL effect. We have approached this question by using limiting dilution cultures of alloactivated human lymphocytes to analyze the in vitro allogeneic cytolytic response against fresh allogeneic leukemia. Initial results in the limiting dilution assays with split culture analyses demonstrated frequent alloreactive cytolytic T lymphocyte precursors that destroyed remission peripheral blood lymphocytes and leukemic cells from the allogeneic leukemic patient. These assays also demonstrated frequent lymphokine-activated killer (LAK) cell precursors that lysed both the LAK sensitive Daudi line and the allogeneic leukemia. In these experiments, isolated cultures also showed cytolytic activity directed against the allogeneic leukemic blasts without activity against remission PBL, or the LAK-sensitive Daudi cell line. Two T cell lines (ABL1 and ABL2) isolated from an LDA, demonstrated this form of specificity, mediating destruction specifically against the allogeneic acute lymphoblastic leukemic cells. Both cell lines ABL1 and ABL2 were CD3+, TCR alpha beta +, and CD4+. These 2 cell lines mediated little or no cytotoxicity against a large panel of other targets tested (natural killer sensitive and resistant cell lines, allogeneic PBL, and allogeneic fresh leukemic blasts). Antibody-blocking experiments revealed a role for the CD3-TCR receptor of both cell lines in lysis of leukemic cells; the CD4 and MHC class II molecules were clearly involved in the lysis by the ABL1 cell line. Specificity of recognition for the allogeneic leukemic blasts was further confirmed by unlabeled target competitive inhibition studies. The mechanism of the preferential lysis of leukemia by the alloactivated T cell lines described in this paper remains uncertain. Nevertheless, these leukemic-specific populations provide a means by which the human GVL effect may be further studied in vitro.
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PMID:Specific recognition of human leukemic cells by allogeneic T cell lines. 257 Dec 6

Conditioning regimens for BMT are important in determining transplant outcome. A radiation-free protocol containing Mitobronitol (DBM), Cytarabine (Ara-C) and Cyclophosphamide (Cy) was used for conditioning of patients with chronic granulocytic leukemia (CGL). Using this conditioning treatment, fewer transplant related complications, including acute GVHD, VOD and severe infections, were observed. Acute GVHD did not develop, but chronic GVHD, accompanied with graft-versus leukemia, was present in half of the cases. To determine the clinical effect of the DBM/Ara-C/Cy conditioning, the recovery of peripheral blood lymphocytes was examined after allogeneic BMT for patients with CGL in comparison with TBI/Cy conditioning. The lymphocyte subsets of 11 DBM patients were followed and analyzed periodically (30-90 days, 4-12 months and > 13 months) using ten monoclonal antibodies and flow cytometry. Decreased percentage of total T cells as well as CD4+ and CD8+ subpopulations, significantly decreased T cell activation and increased proportion of TCR gamma delta + cells were found to be characteristic in the early post-transplant period in the DBM group. Early recovery and consistently higher percentage of B cells were observed for the whole follow-up period of patients receiving DBM conditioning. A high proportion of NK cells was observed in all transplant recipients. These findings suggest that the characteristic pattern of recovering lymphocytes is associated with the lack of severe transplant-related clinical complications following DBM/Ara-C/Cy conditioning.
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PMID:Lymphocyte subset reconstitution after allogeneic bone marrow transplantation using radiation-free conditioning regimen for patients with chronic granulocytic leukemia. 767 5

Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC-specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta-TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.
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PMID:Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells. 791 63

A severely alloimmunized boy with aplastic anemia received an HLA-identical BMT from his brother. Despite intensive immunosuppression and large marrow dose, peripheral signs of engraftment occurred only late under G-CSF treatment. With leukocyte counts of < 0.5 x 10(9)/l, chimerism could be proven not only by oligonucleotide fingerprinting but also within 48 h by analysis of polymorphism in the TCR gene family. This rapid and sensitive method to detect engraftment before it became quantitatively evident was important for the clinical management of the patient, obviating the need to search for an alternative marrow donor.
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PMID:Rapid detection of engraftment using T cell receptor gene polymorphism after allogeneic bone marrow transplantation in an alloimmunized child with severe aplastic anemia. 813 51

TCR V alpha 3 and V alpha 5 transcripts in PBLs from healthy individuals of multiple age groups and from BMT recipients were analyzed. PCR, cloning, and sequencing studies revealed significant V-J junctional diversity among TCR transcripts from all tested blood samples, as provided both by N/P-region addition and exonuclease activity. However, results illustrated restrictions in TCR alpha diversity at several additional levels. First, V alpha 5 and V alpha 3 gene families, which were expected to be composed of multiple members, were dominated in each case by a single sequence at the transcript level. Second, restrictions existed in V-J pairing in that J alpha genes, which were encoded toward the 5' region of the locus, were rearranged frequently with V alpha 3 and rarely with V alpha 5. Conversely, J alpha genes encoded toward the 3' region of the locus preferentially rearranged with V alpha 5. Healthy individuals showed few differences with regard to V-J pairing patterns, while one of three BMT recipients demonstrated a skewed usage of 3' J alpha genes. In total, results demonstrated qualitative restrictions that may limit the working TCR repertoire in human peripheral tissues, both among BMT recipients and their healthy donors.
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PMID:Restricted usage of T-cell receptor V alpha sequence and variable-joining pairs after normal T-cell development and bone marrow transplantation. 824 80

Secretion of the potentially antileukaemic cytokines IFN-gamma and TNF-alpha was investigated for CD4+ and CD8+ TCR alpha beta + T-cell clones derived from 4 leukaemia patients 3-6 weeks after allogeneic BMT. We investigated cytokine secretion in response to the activation signal accessory cells+phytohaemagglutinin+Interleukin 2. All clones derived after BMT were capable of IFN-gamma and TNF-alpha secretion, and both for CD4+ (n = 96) and CD8+ (n = 8) T cells quantities of IFN-gamma and TNF-alpha were significantly correlated with one another. When comparing the overall results for posttransplant and normal T-cell clones derived from 2 bone marrow donors (n = 65), both CD4+ and CD8+ TCR alpha beta + T-cell clones showed increased IFN-gamma production, and CD4+ but not CD8+ clones showed a decreased TNF-alpha secretion. The results suggest that noncytotoxic T cells derived after allogeneic BMT can produce IFN-gamma and TNF-alpha and may thus be capable of mediating antileukaemic effects.
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PMID:IFN-gamma and TNF-alpha secretion by CD4+ and CD8+ TCR alpha beta + T-cell clones derived early after allogeneic bone marrow transplantation. 837 Apr 21

After lymphocyte-depleted BMT, CD8+ T cells have been expanded to or above normal levels in 45% of the recipients within 3 months. The mechanisms underlying proliferation of donor-derived CD8+ T cells after BMT are still unclear. We investigated whether these CD8+ T cells proliferate in response to specific antigens by determination of TCR clonality and whether these cells exert specific cytotoxicity. PCR analysis of TCR-gamma gene rearrangements showed a marked clonal predominance in CD8+ T cells of recipients with a high number of these cells. Strong association between expansion of CD8+ T cells and CMV infection suggests involvement of CMV antigens. Therefore, we examined CMV-specific cytotoxicity of freshly isolated CD8+ T cells of two BMT recipients with clonal expansion after the onset of CMV infection. CD8+ T cells exerted HLA-restricted cytotoxicity directed against CMV-infected fibroblasts indicating that CMV stimulates proliferation. The majority of CD8+ T cells in these recipients expressed CD57. We demonstrated that TCR clonality was irrespective of CD57 expression. Both CD8+CD57+ and CD8+CD57- T cells showed significant HLA-restricted CMV-specific cytotoxicity. These studies strongly suggest that CMV antigens can induce expansion of clonal CD8+ T cells after BMT.
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PMID:Clonal predominance of cytomegalovirus-specific CD8+ cytotoxic T lymphocytes in bone marrow recipients. 886 44

The frequency of CTL precursors (CTLp) directed towards recipient-derived pre-transplant leukaemic blasts (LB) was measured in the peripheral blood of nine children with acute leukaemia and given BMT from either an HLA-identical sibling or a matched unrelated donor (MUD). Patients were evaluated at various time points between 1 month and more than 2 years after transplantation. A high frequency of donor-derived LB-reactive CTLp was detectable 2-6 months after BMT in all children and persisted for at least up to 18 months in the eight patients in haematological remission, while it rapidly declined in the only patient who relapsed. Generation of LB-reactive T cell clones obtained from some of these patients demonstrates that various T lymphocyte subsets, either HLA class I-restricted/TCR-dependent or HLA-unrestricted, contribute to this phenomenon. The in vitro GVL effect here described seems to be at least partially separated from GVHR, since no correlation was observed between the emergence of LB-reactive CTLp and the development and/or severity of GVHD. Development of LB-reactive CTL in the patients was independent of the frequency of these cells in the donor. These data suggest that donor-derived CTL activity specifically directed towards leukaemic blasts may develop in patients given allogeneic BMT and contribute to the maintenance of a state of haematological remission.
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PMID:Does the emergence and persistence of donor-derived leukaemia-reactive cytotoxic T lymphocytes protect patients given an allogeneic BMT from recurrence? Results of a preliminary study. 982 70

Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3+ TCR alphabeta+ CD8+ CD57+ cells were compared with oligoclonally CD3+ CD8hi+ CD57- lymphocytes expanded after BMT. Leukemic CD3+ CD8hi+ CD57+ LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3+ CD8+ CD57+ LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhIL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity. However, culture of leukemic LGL with these stimuli allowed either a 2 week persistence (PMA or rhIL-2) of CD8+ CD57+ LGL or their disappearance after 3 days (PHA). Furthermore, leukemic CD8hi+ CD57+ T lymphocytes produced an inhibitor of cytotoxic functions as previously described for BMT recipients' CD8+ CD57+ cells. Thus, despite some phenotypic differences between both cell sources, leukemic CD57+ T-LGL display the same functional characteristics of cytotoxic effector and immunoregulatory T cells as CD8+ CD57+ T cells from BMT recipients which might represent their normal counterpart.
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PMID:Leukemic CD3+ LGL share functional properties with their CD8+ CD57+ cell counterpart expanded after BMT. 1002 97


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