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)

Patients with multiple myeloma must be distinguished from those with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Therapy should be reserved for patients with active or symptomatic multiple myeloma. The pertinent literature on the diagnosis of multiple myeloma, prognostic factors, chemotherapy, and allogeneic bone marrow transplantation, as well as autologous peripheral blood or bone marrow stem cells for rescue, was reviewed. The two most powerful prognostic factors for multiple myeloma are the bone marrow plasma cell labeling index and the beta 2-microglobulin level. Chemotherapy is the preferred initial treatment for overt, symptomatic multiple myeloma. Combinations of alkylating agents produce a higher response rate, but the survival is the same as treatment with melphalan and prednisone. The combination of alpha 2-interferon with multiple alkylating agents produces a good response. alpha 2-Interferon prolongs the duration of the plateau state after a response to chemotherapy, but it apparently does not prolong survival. Allogeneic bone marrow transplantation is possible for only 5-10% of patients with multiple myeloma. Its advantage is that the graft contains no tumor cells that can subsequently produce a relapse. However, there is a significant early mortality, the risk of graft versus host disease is troublesome, and relapse of multiple myeloma is common. Autologous bone marrow transplantation is applicable for more patients because the age limit is higher and a matched donor is unnecessary. However, two major problems exist: (1) eradication of multiple myeloma from the patient may not occur even with large doses of chemotherapy and irradiation, and (2) infused autologous bone marrow or peripheral blood stem cells contaminated by myeloma cells or their precursors may be responsible for relapse.
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PMID:Newer approaches to the management of multiple myeloma. 824 81

A significant proportion of patients relapse after allogeneic BMT for CML. These relapses have been treated by induction of a graft-versus-leukemia effect by transfusing donor leukocytes. We have treated a 27-year-old woman with interferon and donor leukocyte transfusion and a complete haematological and cytogenetic remission was obtained coincident with the onset of GVHD. Her course was complicated by prolonged and profound pancytopenia which was fully reversed by the administration of rGM-CSF. She remains in CR with mild dermatomyositis due to chronic GVHD 17 months after the procedure.
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PMID:Reinduction of remission of chronic myeloid leukemia by donor leukocyte transfusion following relapse after bone marrow transplantation: recovery complicated by initial pancytopenia and late dermatomyositis. 827 41

Major histocompatibility complex (MHC) antigens, termed HLA in man, provide the major barrier to transplantation. Clinical manifestations of the host-versus-graft reaction are generally referred to as rejection and those of the graft-versus-host (GVH) reaction as graft-versus-host disease (GVHD). GVHD can occur after transplantation of marrow or solid organs or transfusion of blood products. GVHD involves antigen-presenting cells, which are recognized by T lymphocytes via the T-cell receptor. CD4 and CD8 serve as accessory molecules. This interaction results in T-cell activation, expression of interleukin-2 receptors (IL-2R) and the production of IL-2 followed, generally, by clonal proliferation and differentiation associated with lymphokine secretion and dysregulation that may involve interferon-gamma; tumor necrosis factor-alpha; IL-2, -3, -4, -5, -6, and -9; granulocyte macrophage colony-stimulating factor (GM-CSF); and other factors. Effector cells such as cytotoxic T cells, natural killer (NK) cells, and macrophages become activated, mostly by bone marrow-derived lymphohemopoietic cells, and contribute to cell and tissue death. Many of the cytokines also alter vascular endothelium; conceivably these changes also affect homing of cells and allogeneic interactions. Another factor is the administration of in vivo GVHD prophylaxis, which may modify both undesirable (GVHD-inducing) and desirable (tolerance-inducing) mechanisms. Exogenous hematopoietic growth factors and cytokines recently introduced into clinical trials may interfere with endogenous feedback loops in a positive or negative fashion. Adverse reactions have been observed with IL-2 and with interferon. Potentially beneficial effects have been reported with the use of soluble IL-1R or IL-1R-antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Graft-versus-host disease: host and donor views. 830 4

Marrow transplant from an HLA-matched sibling donor can cure CML. Best results are observed when patients are transplanted early in chronic phase. T-lymphocyte depletion of donor marrow can effectively prevent chronic graft versus host disease, but is associated with a high incidence of relapse. Hematologic relapse after marrow transplantation can be treated successfully with alpha-interferon, donor buffy coat cells or second transplant. HLA phenotypically matched and, in some cases, 1 HLA antigen mismatched unrelated donors can also be used successfully for marrow transplantation therapy of CML. Complications include an increased incidence of graft failure and graft vs. host disease. Chronic phase patients transplanted early in the disease course have the best outcome. The development of the National Marrow Donor Program in the United States and a network of donor registries throughout the world as well as the establishment of new techniques for histocompatibility testing will increase the availability of unrelated donors and expedite the donor search process. Autologous marrow transplantation can induce complete hematologic and cytogenetic remissions and may prolong survival when compared with results expected from conventional therapy for CML. Strategies are being developed to obtain benign primitive progenitors suitable for autologous marrow transplantation by positive selection techniques and to develop further post-transplant anti-leukemia cell therapy to use as an adjunct to autologous marrow transplantation for CML.
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PMID:Unrelated donor and autologous marrow transplant therapy of chronic myelogenous leukemia (CML). 832 Oct 29

Eight patients who had hematologic relapse of chronic myelogenous leukemia (CML) after undergoing allogeneic bone marrow transplantation (BMT) were treated with leukocyte infusions from the original bone marrow donors. All patients had previously received marrow grafts from HLA-identical siblings. Six patients were in the accelerated phase of their disease and two were in blast crisis. Each patient received a predetermined T-cell dose within a narrow range of 2.5 to 5.0 x 10(8) T cells/kg. Three patients also received short courses of therapy with alpha interferon to control elevated white blood cell counts within the first several weeks after leukocyte transfusions. Seven of eight evaluable patients developed graft-versus-host disease (GVHD) at a median of 32 days after the initial infusion. One patient had fatal GVHD. A second patient had grade 3 acute GVHD, which has responded to immunosuppressive therapy. The remaining patients all had mild grade I GVHD. Six patients continue to require modest doses of prednisone more than 6 months after infusion. Four patients developed marrow aplasia, which in three patients required marrow boosts from the original donors. Two of these three patients have normal hematopoietic function, whereas the third patient remains growth factor and transfusion dependent. Both patients treated in blast crisis have died, one from GVHD and one from disease progression. All six patients in the accelerated phase are alive and in cytogenetic remission at a median of 42 weeks after infusion. Five of these six patients are in molecular remission. This study demonstrates that leukocyte infusions that administered a defined T-cell dose can exert a profound graft-versus-leukemia effect and are an effective form of salvage immunotherapy in allogeneic marrow transplant recipients. This therapeutic approach appears to be a viable alternative to existing chemotherapeutic and immunomodulatory strategies for the treatment of relapsed CML.
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PMID:Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose. 840 Feb 84

To evaluate the remission quality of Philadelphia chromosome (Ph)-positive, BCR/ABL-positive CML patients after allogeneic bone marrow transplantation (BMT) we used the polymerase chain reaction (PCR) to detect BCR-ABL specific RNA in addition to Southern blotting, cytogenetic, and hematological investigation. Fifty-five bone marrow samples of 27 patients in clinical remission were studied by PCR, 0.5 to 99 months (median 8 months) after BMT. The median clinical follow-up of this cohort of patients is 24 months (1-109) after BMT. BCR-ABL transcripts could be detected in 16 out of 27 patients (59%). Risk factors for minimal residual leukemia (MRD) as defined by PCR were the kind of graft-versus-host disease (GvHD) prophylaxis (patients with T-cell-depleted grafts had a higher rate of MRD in comparison to patients treated with methotrexate/cyclosporin A) and the presence or absence of GvHD after BMT (patients without GvHD had a higher incidence of MRD than patients with GvHD). Moreover, the detection of minimal residual leukemia had prognostic significance. Out of 16 patients with minimal residual leukemia as detected by PCR, four patients relapsed clinically and two further cases relapsed cytogenetically. In contrast none of the patients lacking evidence of minimal residual leukemia relapsed. Serial PCR analysis may prove helpful in deciding about further therapeutic interventions (e.g. interferon therapy or adoptive immunotherapy) before leukaemic relapse becomes manifest after BMT.
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PMID:Influence of graft-versus-host disease on the eradication of minimal residual leukemia detected by polymerase chain reaction in chronic myeloid leukemia patients after bone marrow transplantation. 848 29

Serum levels of soluble interleukin-2 receptors (sIL-2R), tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-6 were studied in patients who developed veno-occlusive disease of the liver (VOD) after allogenic bone marrow transplantation (BMT). sIL-2R increased by a mean of 366% in 10 VOD patients. This was significantly higher than in control patients (n = 12) undergoing BMT without major complications (103%, P = 0.002) or in patients (n = 10) with grade II or III acute graft-versus-host disease (aGVHD) (139%, P = 0.003). Peak sIL-2R levels occurred on day 17 +/- 4 (mean +/- SD) after BMT in VOD patients versus on day 29 +/- 11 in patients with grades II-III aGVHD (P = 0.006). Mean maximum sIL-2R values in VOD patients were 4548 +/- 1420 (+/- SD, U/ml), which was significantly higher than the value of 2123 +/- 1023 U/ml in control patients undergoing BMT without major complications (P < 0.001). In patients with grade II or III aGVHD, mean maximum sIL-2R levels were 3076 +/- 2264 U/ml. Serum levels of TNF-alpha, IFN-gamma, and IL-6 were also increased during VOD and aGVHD, with peak levels occurring at the same time as peak sIL-2R levels in most patients. We found no difference in peak levels between VOD and acute GVHD patients. To conclude, an early dramatic increase in sIL-2R was seen in patients with VOD. Inflammatory cytokines like IL-6, TNF-alpha, and IFN-gamma also increased during VOD and aGVHD.
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PMID:Increased levels of soluble interleukin-2 receptor in veno-occlusive disease of the liver after allogenic bone marrow transplantation. 852 24

The option of bone marrow transplantation (BMT) significantly improved prognosis of adult patients with hematologic malignancies aged less than 50 years. Allogeneic BMT using the marrow of an HLA-identical family member still provides the most effective method of BMT. Conventional indications for this form of BMT are chronic myeloid leukemia (CML), acute leukemias presenting with adverse risk factors, myelodysplastic syndromes and severe aplastic anemia. If performed early in the disease course (e.g. during the chronic phase of CML or first remission of acute leukemia and MDS) allogeneic BMT cures 50 to 60% of patients. About 20% die of therapy related complications, e.g. graft versus host disease (GvHD), fatal infections or venoocclusive disease of the liver (VOD) and about 20% of patients succumb to relapse of their hematologic disorder. 80% presenting with severe aplastic anemia can be cured, if allogeneic BMT is performed soon after diagnosis without previous immunosuppressive therapy and blood transfusions. BMT with the marrow of a matched unrelated donor or autologous BMT are increasingly used as alternative procedures. A rate of lethal complications as high as 50% hinders rapid extension of BMT with unrelated donors. Therefore, this form of BMT should be restricted to young patients with leukemias, who cannot achieve long-term remission with conventional chemotherapy (in case of acute leukemias) or alpha-interferon (in case of CML). Reconstitution of hematopoiesis is more rapid after peripheral blood stem cell transplantation (PBSCT) compared with autologous BMT. Therefore, PBSCT will replace autologous BMT in most cases. Most favourable results of PBSCT have been reported in patients with malignant lymphomas after relapse or inferior response to primary induction therapy. Due to the higher relapse rate autologous BMT is inferior to allogeneic BMT in leukemia patients. Trials are required to clarify the potential role of myeloablative therapy with stem cell support in the treatment of patients with solid tumors. Many of the preliminary results already published are unsatisfactory and data of larger trials are still lacking. Therefore, BMT or PBSCT cannot be recommended generally for the therapy of patients with solid tumors.
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PMID:[Indications, technique and risks in bone marrow transplantation in adulthood]. 864 1

Graft-versus-leukemia (GvL) has been shown to be an important immune-mediated antitumor effect in hematologic malignancies. It is still unknown whether such an immunemediated antitumor effect has clinical implications in patients with solid tumors. A 32-year-old woman with inflammatory breast cancer received a bone marrow transplant (BMT) from her HLA-identical sibling. During graft-versus-host disease (GvHD) cytotoxic T lymphocytes were grown and tested in a chromium-release assay against B and T lymphocytes of the patient and donor and against a panel of breast cancer cell lines. Resolution of liver metastases was observed simultaneously with clinical GvHD in the first weeks after transplant. In addition, minor histocompatibility antigen (MiHA)-specific and major histocompatibility complex (MHC) class I antigen-restricted cytotoxic T lymphocytes recognizing breast carcinoma target cells were isolated from the blood of the patient. Pretreatment of such target cells with tumor necrosis factor (TNF)-alpha but not with interferon (IFN)-alpha or IFN-gamma increased susceptibility of these cells to lysis by cytotoxic T lymphocytes. Clinical course and in vitro results suggest that a graft-versus-tumor (GvT) effect might exist after allogeneic BMT for breast cancer. However, clinical experience on a larger scale would be required to determine the clinical efficacy of GvT effects in patients with solid tumors.
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PMID:Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. 869 72

Interleukin-12 (IL-12) is a critical cytokine regulating natural killer (NK) and T-cell function. We hypothesized that the impaired ability of cord blood (CB) to produce normal adult levels of IL-12 in response to stimulation may contribute to the immaturity of CB immunity. Furthermore, exogenous IL-12 may compensate for the immaturity in CB cellular immunity and have the potential for immunotherapy post cord blood transplantation. We compared the expression and production of IL-12 from activated cord versus adult mononuclear cells (MNC), regulatory mechanisms associated with IL-12 expression in CB MNC, and the effects of IL-12 on induction of CB interferon (IFN)-gamma production, NK, and lymphokine-activated killer (LAK) cytotoxicity. Northern analysis and enzyme-linked immunosorbent assay were performed in lipopolysaccharide (LPS)-stimulated CB and adult peripheral blood (APB) MNC. IL-12 mRNA expression was induced within 6 hours with LPS (10 micrograms/ml) and reached peak levels at 12 hours in both CB and APB MNC. However, IL-12 mRNA expression and protein accumulation in CB MNC were 35.8% +/- 4.84% (12 hours, n = 11, P < .05), and 17.6% +/- 1.7% (24, 72, 96 hours, n = 9, P < .05) respectively, when compared with APB MNC. Nuclear run-on assays showed no differences between CB and APB MNC in both the basal levels of transcription and the degree of transcriptional activation. However, the half-life of IL-12 p40 mRNA was approximately threefold lower in activated CB MNC than in activated APB MNC (CB: 114 +/- 3.0 minutes v APB: 353 +/- 7.8 minutes, n = 3, P < .05). Exogenous IL-12 (10 U/mL) induced a significant increase of IFN-gamma from both CB and APB MNC (24 hours, 72 hours, P < .05, n = 3). The stimulated CB IFN-gamma level reached comparable levels produced by unstimulated APB. IL-12 treatment also significantly enhanced CB NK cytotoxicity against K562 and NB-100 cell lines to the comparable levels of APB (P < .05, n = 4). CB MNC was more responsive to IL-12 stimulation with respect to IFN-gamma production, NK, and LAK cytotoxicity when compared with APB. The present study suggests that IL-12 mRNA and protein expression is decreased in activated CB. This discrepancy in IL-12 production is secondary, at least in part, to the altered posttranscriptional regulation. The impaired, ability of CB MNC to produce IL-12 in response to stimulation may contribute to the decrease in IFN-gamma production and NK cytotoxicity. However, IL-12 enhanced IFN-gamma and NK activity in CB MNC up to the comparable levels of APB MNC. These findings suggest that reduced expression and production of IL-12 from activated CB may contribute to the immaturity in CB cellular immunity and contribute, in part, to decreased graft-versus-host disease following CB stem cell transplantation.
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PMID:Decreased interleukin-12 (IL-12) from activated cord versus adult peripheral blood mononuclear cells and upregulation of interferon-gamma, natural killer, and lymphokine-activated killer activity by IL-12 in cord blood mononuclear cells. 870 53


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