Gene/Protein Disease Symptom Drug Enzyme Compound
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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 cultured bone marrow cells from patients receiving bone marrow transplantation (BMT) to assay bone marrow fibroblast colony-forming cells (CFU-F) and hematopoietic progenitors (CFU-mix, CFU-C, BFU-E and CFU-E), and compared the mean values obtained from patients with and without graft-versus-host disease (GVHD). The value of CFU-F colonies from 15 patients was always less in patients with acute GVHD Grade II,III than in those with Grade 0,I over the period 30 to 110 days after BMT. The CFU-F colonies from patients with Grade 0,I consisted of approximately the same number of small and large colonies, whereas virtually all CFU-F colonies from patients with Grade II,III were small. Fibroblasts collected from bone marrow cells cultured for 2-3 weeks were incubated with IL-1 (50 U/ml) for 24 h. The concentrations of G-CSF in the culture supernatants from patients with Grade II,III were higher than in those with Grade 0,I. The results of assays of hematopoietic progenitors from 48 patients showed that the number of hematopoietic progenitors decreased as the severity of acute GVHD increased. These results suggest that the myelosuppression seen in GVHD may be associated with reduced numbers of CFU-F in bone marrow.
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PMID:Stromal fibroblastic and hematopoietic progenitors in patients with graft-versus-host disease (GVHD). 172 15

Relapse continues to be a problem after bone marrow transplantation (BMT) for hematologic malignancies, particularly in recipients of autologous or T-cell-depleted allogeneic grafts and in patients with advanced disease. Interferon (IFN) has shown antiproliferative activity in several malignant hematologic diseases and potentially may be of benefit when administered early after BMT when the number of residual cells is minimal. We tested in a phase I study the maximum tolerated daily dose of recombinant IFN alpha-2b in patients who had received a transplant for a disease at high risk for relapse (acute myeloid leukemia or non-Hodgkin's lymphoma beyond first remission, advanced myelodysplastic syndrome, acute lymphoblastic leukemia at any stage, chronic myeloid leukemia in accelerated or blast phase. Recombinant IFN alpha-2b was started at a dose of 0.5 x 10(6) IU/m2 and escalated by 0.5 x 10(6) IU/m2 in groups of three or four patients. The intention was to administer IFN as soon as stable engraftment after BMT was achieved (defined as an absolute neutrophil count of greater than 2.0 x 10(9)/L and platelet count greater than 100 x 10(9)/L for 5 consecutive days) and continued for 2 months. A total of 14 patients were enrolled after autologous (n = 3) or allogeneic (n = 11) BMT. Dose-limiting toxicity was myelosuppression. Significant (grade 2 to 4) neutropenia and thrombocytopenia led to discontinuation or dose reduction in five of eight patients receiving 1.5 x 10(6) or 2 x 10(6) IU/m2 IFN. Mild to moderate (grade 1 or 2) anorexia, weight loss, and fatigue occurred in the majority of patients independent of the IFN dose. De novo acute GVHD responsive to steroid treatment developed in 3 of 11 allograft recipients. Natural killer (NK) cell function was low before IFN treatment and was not improved with the cytokine. Conversely, interleukin-2-activated NK cells showed normal function even before starting IFN and no change was seen during IFN treatment. Clonogenic hematopoietic progenitor studies showed depression of all progenitor lines (colony-forming unit [CFU]-granulocyte, erythroid, monocyte, megakaryocyte, CFU granulocyte-macrophage, burst-forming unit-erythroid) by IFN at all dose levels except at 0.5 x 10(6) IU/m2. Considering this result and the incidence and severity of marrow depression seen at doses greater than 1.0 x 10(6) IU/m2, we would consider this the maximum dose safely tolerated if IFN alpha-2b is administered in this setting for a prolonged course on a daily basis.
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PMID:Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. 174 91

A monoclonal antibody recognizing Ly1, the murine homologue of CD5, was labeled with 90Y. In vivo biodistribution studies showed that 90Y-anti-Ly1 selectively localized in lymphoid tissue. Groups of B10,BR mice (H-2k) were lethally irradiated and given major histocompatibility complex-disparate C57BL/6 (H-2b) bone marrow and spleen cells to induce graft-versus-host disease (GVHD). Eight days later, mice with active GVHD were administered a single i.p. injection of 50 microCi90Y-anti-Ly1. Fifty % of these mice were alive 2 months after treatment. Long term (greater than 4-month) survival was significantly higher than in phosphate-buffered saline-treated mice. Survival was slightly improved in groups of mice receiving control irrelevant antibody labeled with 90Y or mice receiving free 90Y. However, survival in these groups was not significantly different from the phosphate-buffered saline-treated control group. The improved survival was supported by data showing improved mean animal weight. An anti-GVHD effect was confirmed by histopathological analysis. Unlabeled anti-Ly1 monoclonal antibody at comparable doses to 90Y-anti-Ly1 was not effective. Animals that died following 50-microCi treatment did not die of radiation toxicity, since all mice receiving 50 microCi 90Y-anti-Ly1 plus syngeneic bone marrow survived. The window of therapy was narrow in our studies, since 100 microCi 90Y-anti-Ly1 did not confer any survival advantage. Animals that did survive long term were studied for evidence of alloengraftment and found to have high levels of circulating donor mononuclear cells. 90Y-Anti-Ly1 localized in the spleen, thymus, liver, kidney and bone marrow but not in the bowel, lung, muscle, or skin. Animals given similar doses of free 90Y, 90Y-anti-Ly1, or labeled irrelevant antibody eliminated free 90Y fastest, followed by 90Y-anti-Ly1 and then labeled irrelevant antibody. Hematological analysis of peripheral blood from 90Y-anti-Ly1-treated mice showed reduction in total WBC counts, absolute lymphocyte numbers, and absolute neutrophil numbers on day 24 after treatment. Myelosuppression recovered by day 38. These findings indicate that Ly1-positive cells are involved in the effector phase of GVHD and that radiolabeled antibodies may be useful as cell-specific probes for studying the GVHD network. 90Y-Anti-Ly1 protected recipients long term from lethal GVHD, and the fact that it had a rather remarkable inhibitory and selective effect on the lymphoid system of mice suggests that these agents may have broader application in the field of transplantation.
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PMID:Radiotherapy in mice with yttrium-90-labeled anti-Ly1 monoclonal antibody: therapy of established graft-versus-host disease induced across the major histocompatibility barrier. 200 72

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m2-140 mg/m2) divided over 2 consecutive days followed by a rest period of 4 days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.
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PMID:High-dose melphalan and total body irradiation with bone marrow transplantation for refractory malignancies. 352 15

The concept of using total lymphoid irradiation (TLI) for immunosuppression is based on the prolonged and profound immunosuppressive effects observed after TLI in the treatment of patients with Hodgkin's disease. Pre-operative TLI of allograft recipients has been shown to be immunosuppressive when used alone or together with chemical immunosuppression. Fractionated TLI and allogeneic bone marrow injections produce stable chimaerism without graft-versus-host disease in inbred mice, rats and mongrel dogs and transplantation tolerance of skin and cardiac grafts in rats. In the primate, TLI and bone marrow injection result in significant tolerance of liver and kidney allografts. In 1959 sublethal whole-body irradiation was used as an immunosuppressive agent for the first successful related-human renal allografts between non-identical twins. Despite the dangers of myelosuppression, recent clinical experience has shown TLI to be a useful immunosuppressant for organ transplantation, allowing decreased dosage of concomitant immunosuppressive drugs.
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PMID:Application of irradiation as an immunosuppressive agent. 356 93

The immune reactivity of allogeneic lymphocytes plays a major role in the control of leukemia after bone marrow transplantation. In patients with recurrent leukemia after marrow transplantation, chimerism and tolerance provide ideal conditions for adoptive immunotherapy with donor lymphocytes. We studied the effect of donor lymphocyte transfusions on acute and chronic leukemia in relapse after bone marrow transplantation. One hundred thirty-five patients with chronic myeloid leukemia (CML) (N = 84), acute myeloid leukemia (AML) (N = 23), acute lymphoblastic leukemia (ALL) (N = 22), myelodysplastic syndrome (MDS) (N = 5), and polycythemia vera with osteomyelofibrosis (PCV) (N = 1) were treated with transfusions of donor lymphocytes. Patients were monitored for response of leukemia, including in CML, the use of the polymerase chain reaction for bcr/abl mRNA transcripts and for the occurrence of graft-versus-host disease (GVHD) and myelosuppression. Complete remissions were induced by donor lymphocyte transfusions in 54 patients with CML (73%) and in the patient with PCV; complete remissions were also induced in five patients (29%) with AML and a patient with MDS. In contrast, ALL did not respond to adoptive immunotherapy with donor lymphocyte transfusions. Remissions were durable in patients treated for CML in chronic phase (probability of remission: 87% at 3 years). Lymphocyte transfusions were also given to 18 patients with ALL, AML, MDS, and transformed phase CML who were in remission after chemotherapy. These remissions were not durable. Fifty-two patients (41%) developed GVHD of grade 2 or more, and 41 patients (34%) showed signs of myelosuppression. Seventeen patients died without leukemia, 14 patients with GVHD and/or myelosuppression. Donor lymphocyte transfusions exert strong effects against myeloid forms of leukemia and induce durable remissions in CML.
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PMID:Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. 861 35

Infection with HCMV in healthy individuals generally results in mild or subclinical illness. Pathogenic infections occur predominantly in immunodeficient patients, such as transplant recipients, neonates and patients with AIDS. Primary infection is frequently latent or chronic and PBLs represent sites for virus latency and persistence. HCMV can be recovered from PMNL, monocytes and T-lymphocytes. Although virus-related cases of haematopoietic dysfunction are seen infrequently in infected normal persons, the importance of HCMV as a pathogenic agent in haematopoiesis is dramatically illustrated in the case of patients receiving BMT. Primary or reactivated HCMV infections are a common feature in BMT recipients, enhancing failure of marrow engraftment, GVHD, and many opportunistic infections. HCMV can infect both haematopoietic progenitor cells and stromal elements, identifying the entire haematopoietic system as a target for HCMV dissemination and latency. As a result, lympho- and myelosuppression can be due to both direct inhibition of progenitor cell growth as well as the failure of stem cell self-renewal due to stromal cell dysfunction. HCMV can also exert suppressive effects on immune cell function by direct and indirect mechanisms. These effects can have dire consequences, particularly when a state of immunosuppression already exists, as in the HIV infection. The diverse effects of CMV on the lymphohaematopoietic system are summarized in Figure 1.
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PMID:The role of human cytomegalovirus in haematological diseases. 766 45

Allogeneic bone marrow transplantation remains the only therapeutic approach with documented curative potential for patients with multiple myeloma. A survey of recently published trials reveals a 40% long-term survival rate with no evidence of residual disease in a majority of patients. While morbidity and mortality from myelosuppression and graft-versus-host disease are relatively high, allogeneic bone marrow transplantation should be considered early in the course of treatment for patients with high-risk myeloma.
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PMID:Allogeneic bone marrow transplantation for multiple myeloma. 821 Dec 18

Carboplatin is a second-generation platinum complex developed to be less ototoxic and nephrotoxic than cisplatin. The major toxicity was found to be myelosuppression; thus, it was tried in acute leukemia. When given by daily bolus injection for 5 days, carboplatin exhibited some activity but was associated with additional nonhematologic toxicity as well. When administered by continuous infusion, responses were higher and toxicity less. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II study of carboplatin 315 mg/m2 daily given by continuous infusion for 5 days to adults with refractory and relapsed acute leukemia. A second course was given if the bone marrow on day 14 revealed persistent leukemia. Those achieving a complete remission (CR) were given an additional course as consolidation. The median age was 49 years among acute myelogenous leukemia (AML) patients and 46 years in acute lymphoblastic leukemia (ALL) patients. Of 46 eligible patients enrolled in the study (36 AML and 10 ALL), 8 (17%) achieved a CR (6 AML and 2 ALL). Remissions were observed in 2 of 10 primary refractory patients (1 AML and 1 ALL). When treated in first relapse, 5 of 14 patients (36%) achieved a CR. In 38 instances marrow specimens were examined after treatment; 10 (26%) showed no change, 16 (42%) were hypoplastic, and 12 (32%) were hypoplastic with residual leukemic cells. Of the 18 deaths that occurred on study, 14 were due to infection, 2 due to infection and bleeding, 1 due to uncontrolled gastrointestinal bleeding and 1 due to graft-versus-host disease in a patient who had relapsed after bone marrow transplantation. Marrow suppression was usually prolonged. Nonhematologic toxicity was mild. Gastrointestinal toxicity consisted of easily controlled nausea and vomiting. Three patients had grade 3 diarrhea. Grade 3 or more renal toxicity was observed in 8 patients, all of whom had received nephrotoxic antibiotics for treatment of bacterial or fungal infections. One patient died of renal failure that developed near the end of a second induction course. Ototoxicity was observed in 11 patients (24%) and was grade 2 or less in all but 3. These results indicate that carboplatin is an active agent in leukemia. Further studies are under way in combination with other agents such as etoposide, mitoxantrone, 5-azacytidine, and daunorubicin in treatment of acute leukemia and in combination with ifosfamide and etoposide in refractory lymphomas.
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PMID:High-dose carboplatin in the treatment of hematologic malignancies. 823 1

Unexpected neutropenia following allogeneic or autologous bone marrow transplantation may be caused by graft rejection, intrinsic stem cell failure, infection, graft-versus-host disease, relapse of the underlying neoplasm, or drug-induced myelosuppression. Over the past decade an increasing number of reports have documented that the differential diagnosis also includes antibody-mediated neutropenia, a syndrome distinct from conventional graft rejection. In contrast to many of the other common causes of unexpected post-transplant neutropenia, antibody-mediated neutropenia usually responds well to treatment with corticosteroids, plasma exchange, intravenous immunoglobulin, splenectomy, or other similar measures.
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PMID:Antibody-mediated neutropenia following bone marrow transplantation. 847 91


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