UMLS:C0018133 - FACTA Search

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Query: UMLS:C0018133 (graft-versus-host disease)
18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe a 17-year-old male patient with chronic myelogenous leukemia (CML) in hematologic and cytogenetic relapse 4 months post-non-T cell-depleted allogeneic bone marrow transplantation for accelerated CML. Two sequential buffy coat transfusion with donor peripheral blood cells (8.9 and 4.8 x 10(7) cells/kg), the second transfusion in combination with in vivo activation of donor cells by human recombinant interleukin-2 (rIL-2) 6 x 10(6) IU/m2 subcutaneously for 3 days, failed to induce remission . The patient responded to an infusion of donor peripheral blood lymphocytes (3.4 x 10(7) cells/kg) pre-activated in vivo with rIL-2 and additionally activated in vivo with rIL-2, 6 x 10(6) IU/m2/day subcutaneously for 3 days. Elimination of the Philadelphia (Ph) clone was confirmed by cytogenetic analysis showing a normal male karyotype and by disappearance of the bcr/abl transcript, using the polymerase chain reaction (PCR). At present, the patient is 26 months post-treatment with no evidence of disease, but with chronic graft-versus-host disease. Our data indicate that allogeneic activated cell therapy (allo-ACT) may provide antitumor effector cells that successfully induce graft-versus-leukemia (GVL) effects even when cell therapy with donor buffy coats was insufficient.
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PMID:Activated allogeneic cell therapy (allo-ACT) for relapsed chronic myelogenous leukemia (CML) refractory to buffy coat transfusions post-allogeneic bone marrow transplantation. 897 87

T cells that express the alpha beta T-cell receptor are thought to be the T-cell population primarily responsible for facilitating alloengraftment. The role of gamma delta + T cells that comprise only a minority of mature T cells in promoting allogeneic engraftment, however, has not been extensively studied. The purpose of this study was to determine whether gamma delta T cells were capable of facilitating alloengraftment in murine recipients of major histocompatibility complex-mismatched marrow grafts. We developed a model where engraftment of C57BL/6 x 129/F2(H-2b) marrow in sublethally irradiated (800 cGy) recipients (AKR/J, H-2k) is dependent on the presence of mature donor T cells in the marrow graft. In this model, donor T-cell engraftment was significantly augmented by as few as 1 x 10(5) alpha beta T cells. The role of gamma delta T cells was then investigated using transgenic donors (C57BL/6 x 129 background) in which a portion of the T-cell receptor-beta chain gene was deleted by gene targeting so that these mice lack alpha beta T cells. Addition of 10 x 10(5) naive gamma delta T cells to T-cell depleted marrow grafts was required to significantly increase alloengraftment, although donor T cells averaged < 50% of total splenic T cells. To determine whether higher doses of gamma delta T cells would improve donor engraftment and eradicate residual host T cells, gamma delta T cells were ex vivo expanded with a gamma delta T-cell-specific mono-clonal antibody and interleukin-2 and then transplanted into irradiated recipients. Transplantation of > or = 160 x 10(6) activated gamma delta T cells was necessary to consistently and significantly augment donor cell chimerism and enhance hematopoietic reconstitution when compared to control mice, but host T cells persisted in these chimeras. Addition of 2.5 x 10(4) mature alpha beta T cells, which alone were incapable of facilitating engraftment, to T-cell depleted marrow grafts containing 160 x 10(6) activated gamma delta T cells resulted in long-term (> 100 day) complete donor engraftment, indicating that limiting numbers of alpha beta T cells were required in the marrow graft for the eradication of residual host T cells. Using serial weight curves and B-cell reconstitution as end points, clinically significant graft-versus-host disease was not observed in these chimeras under these experimental conditions. These data show that, whereas less potent than alpha beta T cells, gamma delta T cells are able to promote engraftment and enhance hematopoietic reconstitution in allogeneic marrow transplant recipients.
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PMID:Donor gamma delta T lymphocytes promote allogeneic engraftment across the major histocompatibility barrier in mice. 902 43

A graft-versus-leukemia (GVL) effect has been considered a major factor responsible for cures in patients with hematologic malignancies undergoing allogeneic bone marrow transplantation; however, associated graft-versus-host disease (GVHD) results in significant morbidity and mortality. T-cell depletion reduces the incidence and severity of GVHD but eliminates, at least partially, the GVL effect. Reinfusion of donor T lymphocytes at relapse posttransplantation can induce a potent antitumor response, but GVHD still occurs in the majority of patients. Prior transduction of T lymphocytes with the suicide gene, the viral thymidine kinase (TK), permits specific cell kill on administration of ganciclovir (GCV). Therefore, infusion of TK-transduced T lymphocytes may induce GVL effect and allow for their subsequent selective elimination in case GVHD develops. To evaluate the efficacy and feasibility of this promising approach, anti-CD3-stimulated primary human lymphocytes cultured in interleukin-2 were TK-transduced by a retroviral vector carrying both TK and neomycin-resistance genes. After selection in G418, more than 90% of the cells contained the TK gene as shown by a semiquantitative polymerase chain reaction. In addition, 1 to 5 days of GCV exposure, at clinically achievable concentrations of 20 to 50 micromol/L, induced > or = 90% killing of G418-selected cells without affecting nontransduced cells. Correlation of the extent of T-cell kill and the proportion of TK-gene-transduced cells is consistent with the absence of a bystander effect. Transduced cells were CD3+ and either CD8+ or CD4+ and retained functional properties of untransduced cells. In vivo administration of GCV prevented tumor development after subcutaneous injection of TK-transduced murine myeloma cells (MOPC-11), whereas such an effect was not observed on injection of untransduced cells into the opposite flank. Our studies provide critical information that (1) adequate numbers of TK-transduced lymphocytes can be selected efficiently with > or = 90% purity, (2) selected cells remain functional, (3) 24 hours of exposure to GCV at clinically achievable concentration effects > or = 90% killing of selected cells, and (4) GCV is effective in vivo in killing TK-transduced cells. Based on these data, a clinical study has been initiated in patients with multiple myeloma with persistent or relapsing disease after T-cell-depleted allogeneic transplants.
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PMID:Thymidine kinase (TK) gene-transduced human lymphocytes can be highly purified, remain fully functional, and are killed efficiently with ganciclovir. 902 56

Highly purified CD4+ CD45RA+ cells from cord blood and peripheral blood from healthy adults were studied. The levels of expression of the CD2, CD3, CD4 and CD28 antigens were similar; however, CD45 and CD45RA antigen expression were slightly lower in cord cells. The reduced expression of the CD45RA antigen on cord CD4+ T cells was confirmed in whole blood. Functional assessment revealed deficiencies in cord CD4+ CD45RA+ T cells. Interleukin-2 (IL-2) production in response to specific triggering via CD2 monoclonal antibody (mAb) alone, or CD2 mAb in combination with CD28 mAb showed marked underproduction (about 10% of adult production). When CD25 expression was examined, it was observed that the proportion of activated CD4+ CD45RA+ T cells in cord blood was lower than in adult (about 20% of adult expression). Proliferation to CD2 mAbs or CD2 + 28 mAbs of cord blood native cells was similarly depressed. Investigation of IL-2 mRNA expression under these stimulatory conditions paralleled the results observed for CD25 expression, IL-2 production and proliferation. When phorbol 12-myristate 13-acetate (PMA) was added to the cells triggered with CD2 + 28mAbs, the responses examined were enhanced in both cord and adult blood with no significant differences between the groups. These findings suggest that under identical conditions of stimulation, purified cord blood CD4+ CD45RA+ T cells do not acquire similar activation status as their adult counterparts. These findings may help in understanding the reduced graft-versus-host disease (GVHD) observed in cord blood stem cell transplantation.
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PMID:Cord blood CD4+ CD45RA+ T cells achieve a lower magnitude of activation when compared with their adult counterparts. 915 47

A patient with acute myeloid leukemia secondary to therapy of choriocarcinoma underwent T cell non-depleted allogeneic bone marrow transplantation from an unrelated donor in first untreated relapse. Persistent/relapsed leukemia 4 months after transplantation did not respond to cessation of cyclosporine. Due to logistic difficulties in obtaining donor leukocytes, she was treated with interleukin-2 and interferon-alpha 2b. Although the interleukin could be administered for a short period only, the interferon was continued for 4 months. Interferon was stopped when limited chronic graft-versus-host disease developed, but was followed by extramedullary and early marrow relapse. Reinstitution of interferon resulted in the development of scleroderma-like extensive chronic GVHD and remission. Interferon was given for 5 months. GVHD improved slowly with treatment, but scleroderma-like changes still persist. The patient is alive with no evidence of disease and a Karnofsky score of 90% 41 months after relapse and 26 months after stopping cyclosporine. We conclude that cytokines alone may occasionally result in a durable response of acute leukemia relapsing after allografting, and should be considered in patients with a low tumor burden if it is difficult to obtain donor cells.
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PMID:Sensitivity of secondary acute myeloid leukemia relapsing after allogeneic bone marrow transplantation to immunotherapy with interferon-alpha 2b. 919 60

The feasibility of transplanting peripheral blood mononuclear cells (PBMC) from granulocyte colony-stimulating factor (G-CSF)-treated normal human donors to myeloablated allogeneic hosts has been demonstrated recently. The current work examined the ability of recombinant G-CSF to alter peripheral blood T-cell function and graft-versus-host disease (GVHD) in a murine model of allogeneic G-CSF-mobilized PBMC transplantation. Administration of recombinant G-CSF to C57BL/Ka mice markedly increased the capacity of PBMC to reconstitute lethally irradiated syngeneic hosts. T- and B-lineage lymphocytes were depleted about 10-fold in the bone marrow of the treated mice, and the T-cell yield in the blood was increased about fourfold. The ability of PBMC or purified CD4+ and CD8+ T cells to induce acute lethal GVHD in irradiated BALB/c mice was reduced after the administration of G-CSF. This was associated with decreased secretion of interferon gamma and interleukin-2 (IL-2) and an increased secretion of IL-4. The donor cell inoculum, which was most successful in the rescue of irradiated allogeneic hosts, was the low-density fraction of PBMC from G-CSF-treated mice. These low-density cells were enriched for CD4-CD8-NK1.1+ T cells and secreted about 10-fold more IL-4 than the unfractionated cells from the G-CSF-treated donors.
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PMID:Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation. 920 83

Thirty-two adults (median age 36 years) with leukemia (15 AML, eight CML, six ALL, three CLL) persisting or relapsing 1-40 months (median 4) after allogeneic BMT (20 matched siblings, eight unrelated, four family mismatch) underwent immunotherapy to elicit GVHD. This comprised one or more of: infusion of donor cells (n = 22), stopping cyclosporine (n = 14), and administration of interferon-alpha2b (n = 15) or interleukin-2 (n = 4). Eight acute leukemia patients received chemotherapy as well. The time from relapse to immunotherapy was 0-1344 days (median 4). Acute and/or chronic GVHD developed in 17 patients. Response was not evaluable in three patients due to early toxic death. There was no response in 10 patients, whereas 19 showed objective response. Nine patients died due to toxicity and 10 due to progressive disease. Thirteen patients are alive 4-58 months (median 14) after immunotherapy; 12 in remission (five AML, four chronic phase CML, one ALL, one accelerated phase CML, one CLL) and one with progressive disease (accelerated phase CML). Eleven of 13 patients who are alive had GVHD compared with six of 19 who died (P = 0.005, Fisher's exact test). We conclude that with the exception of CML in myeloid blast crisis, immunotherapy is active in most types of acute and chronic leukemia relapsing after allogeneic BMT. It is associated with considerable toxicity. Clinically obvious GVHD, especially chronic GVHD, results in a higher probability of survival.
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PMID:Induction of graft-versus-host disease as immunotherapy of leukemia relapsing after allogeneic transplantation: single-center experience of 32 adult patients. 924 16

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.
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PMID:Interferon-alpha and interleukin-2 as treatment for leukemia relapse after allogeneic bone marrow transplantation. 938 68

Allogeneic cord blood is now being widely used as a source of stem cells for hematologic reconstitution after myeloablative therapy, with reported significantly lower levels of graft-versus-host disease (GVHD) compared with the use of allogeneic bone marrow (BM). This study was undertaken to investigate biologic aspects of natural killer (NK) cell activity, as recognized effector cells of the GVHD and graft-versus-leukemia (GVL) response, from cord blood and conventional BM. NK-cell activity levels of freshly isolated cells from cord blood and BM against K562 targets were comparable. Lymphokine activated killer (LAK) cells from both hematopoietic cell sources were compared for their ability to kill target cells by necrotic or apoptotic mechanisms using specific target cell lines. Cord blood cells had significantly higher necrosis-mediated cytotoxic activity against Daudi target cells compared with BM-derived cells. Cord blood LAK cells had relatively high levels of apoptotic-mediated cytotoxicity against YAC-1 target cells, whereas BM-derived LAK cells were unable to induce apoptosis in these cells. Interleukin-2 (IL-2) induced significant granzyme B activity in cord cells in contrast to BM cells, in which very little activity was measured. Western blotting confirmed these findings, with IL-2 inducing granzyme B protein expression in cord cells but not detectable levels in BM cells. BM cells had significantly lower cell surface expression of IL-2R and prolonged culture in IL-2 was only partially able to restore their deficient apoptotic cytotoxic activity. Thus, major differences exist between cord blood-derived and BM-derived mononuclear cells with respect to their NK-cell-associated cytotoxic behavior. This could have important implications for stem cell transplantation phenomena, because it suggests that cord blood may have increased potential for a GVL effect.
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PMID:Differential cytotoxicity of cord blood and bone marrow-derived natural killer cells. 941 86

Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for patients relapsing after allogeneic bone marrow transplantation (BMT), indicating that tumor cells resisting chemoradiotherapy may still respond to immunocompetent allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects in six patients with metastatic breast cancer that would be comparable to the graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in hematologic malignancies. The patients were cytoreduced with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and were treated ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor peripheral blood lymphocytes (PBL) activated in vivo with human recombinant interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT was augmented with infusion of donor PBL, preactivated in vitro with rIL-2. Treatment was well tolerated, with low therapy-related toxicity in all patients. Two patients developed signs and symptoms compatible with GVHD grade I-II, one of whom shows no evidence of disease at more than 34 months out. In the remaining patients, progression-free survival following allo-CT ranged between 7 and 13 months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be utilized for induction of GVT in metastatic breast cancer. A search for techniques to boost chimerism without severe GVHD is indicated.
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PMID:Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study. 955 10

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