Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major shortcoming of present day treatment of leukemia by bone marrow transplantation (BMT) remains leukemia relapse. It has become clear that a graft-versus-host reaction (GVHR) is accompanied by a graft-versus-leukemia reaction (GVLR) which may prevent leukemia relapse. In two non-immunogenic rat leukemia models, the Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce 'minimal residual disease' (MRD). Subsequently, it was attempted to evoke a GVLR by using syngeneic or allogeneic BMT, with or without addition of graded numbers of lymphocytes. In both leukemia models the addition of high numbers of syngeneic lymphocytes to the syngeneic graft had no antileukemic effect. Allogeneic marrow grafts, which contain at the most 8% lymphocytes, only resulted in a GVLR when splenocytes were added. The therapeutic window was found to be narrow, i.e. in fully mismatched BMT the number of allogeneic splenocytes resulting in a significant GVLR (2-3 log leukemic cell kill) without inducing (lethal) acute GVHD was critical. Increasing the number of allogeneic spleen cells added to the allogeneic BM graft induced lethal acute GVHD. To date, our data indicate that the GVLR is an allogeneic effect, inseparable from GVHD.
 ...
PMID:Quantitative studies on graft-versus-leukemia after allogeneic bone marrow transplantation in rat models for acute myelocytic and lymphocytic leukemia. 795 Nov 3

Cure of leukemia by allogeneic BMT is achieved by the combined effect of the myeloablative preparative regimen and an allo-immune response of donor cells to residual leukemia termed the graft-versus-leukemia (GVL) effect. In the first year following BMT for CML, PCR used to detect the leukemia-specific BCR/ABL message frequently reveals subclinical levels of persisting leukemia. In a meta-analysis of reports on qualitative PCR findings after BMT for CML in 12 recently published series, we found that for unmanipulated BMT in chronic phase, PCR detection was not associated with a higher relapse risk and that most patients became PCR negative within 2 years post-BMT. In contrast, PCR detection of BCR/ABL transcripts was a more reliable predictor in recipients of T cell-depleted BMT and in those transplanted in accelerated or blastic phase of their disease. For accurate prediction of relapse, serial quantitative PCR is necessary. It could also be used to monitor efficacy of experimental treatments of relapse with interferon or donor lymphocyte transfusions. Furthermore, studies of the association of GVHD with PCR detection of BCR/ABL message may shed light on the relationship of GVL with minimal residual disease in CML.
 ...
PMID:Minimal residual disease after bone marrow transplantation for chronic myelogenous leukemia and implications for graft-versus-leukemia effect: a review of recent results. 799 33

Immune mechanisms superimposed to the myeloablative conditioning regimens exert an additional powerful effect in eradicating leukemia and in achieving immunological control of minimal residual disease. The impact of GVHD-independent GVL has been evaluated to be absent, or near absent, in ALL, about 30% in AML and about 40% in CML. While until little time ago most of the evidence in favor of an immune antileukemia mechanism exerted by allo BMT in CML was indirect, based on the lack of GVL, there is now solid evidence of a positive type, based on the antileukemia effect of donor lymphocyte infusions in patients having relapsed after transplant. There are three lines of indirect clinical evidence for GVL in CML: they include the classical linkage between GVHD and reduced relapse rate, increased relapse rate after identical twin allografts, and increased relapse risk after effective GVHD prophylaxis, with T lymphocyte depletion in the foreground. The eradicating effects of donor lymphocyte infusions in relapsed patients are the ultimate demonstration that allogeneic immune competent cells are capable of recognizing and destroying the Ph-positive clone. However the frequency of irreversible aplasia indicates that donor lymphocytes act in the same way on residual host hematopoiesis, so that a second graft, without repeat conditioning, should be programmed for such cases.
 ...
PMID:The graft versus leukemia (GVL) effect after allogeneic bone marrow transplantation for chronic myelogenous leukemia (CML). 825

Immunologic reactions occurring after allogeneic bone marrow transplantation, known as graft-versus-leukemia effect, contribute significantly to the control of minimal residual disease and decreased risk of relapse post-transplant. Graft-versus-leukemia reactions occur with or without graft-versus-host disease and are either mediated through T-cells or are independent of T-cells. The contribution made by graft-versus-leukemia reactions to improvement in overall survival depends upon the underlying type of leukemia, the nature of the marrow graft and the morbidity of any associated graft-versus-host disease. This article reviews the evidence demonstrating graft-versus-leukemia effect in clinical bone marrow transplantation, some approaches to dissociate graft-versus-leukemia from graft-versus-host disease, and attempts to induce graft-versus-leukemia reactions in the setting of autologous bone marrow transplantation by immunotherapy.
 ...
PMID:Graft-versus-leukemia reactions in clinical bone marrow transplantation. 840 Nov 79

The use of high-dose chemotherapy with stem-cell rescue (HDC-SCR) in the treatment of breast cancer is reviewed. The rationale for HDC-SCR in breast cancer is based on the principles of dose response and dose intensity. After conventional-dose chemotherapy, hematopoietic progenitor cells are harvested from the bone marrow or peripheral blood. The patient then undergoes HDC-SCR. Peripheral-blood progenitor cells are becoming the preferred cells for hematopoietic rescue. Most clinical trails of HDC-SCR in metastatic breast cancer have resulted in high overall objective response rates (57-100%), with the highest rates occurring in patients with minimal residual disease or chemotherapy-sensitive disease at the time of high-dose treatment. Most protocols now include induction therapy before HDC-SCR; only patients who show sensitive disease proceed to high-dose therapy. In most studies published to date, the median duration of remission was less than one year from the time of high-dose therapy; however, 10-15% of patients achieved complete remissions lasting two or more years. Most patients relapse, however. Some studies have suggested value of HDC-SCR as consolidation therapy in the adjuvant setting for women at high risk of relapse. Short-term toxicities of HDC-SCR are manageable in experienced hands. Notable long-term adverse effects include leukemia, sterility, pulmonary toxicity, and hemolytic uremic syndrome. Unresolved issues include the utility of purging occult cancer cells from stem-cell-bearing specimens, the best preparative regimen, the implications of autologous graft-versus-host disease, the use of sequential cycles of high-dose chemotherapy, cost-effectiveness, and effectiveness compared with standard therapy. HDC-SCR appears to be a valid option for selected patients with metastatic breast cancer, and in the adjuvant setting for patients at high risk of recurrence. The cost-benefit profile remains to be defined in randomized trials.
 ...
PMID:High-dose chemotherapy with stem-cell rescue for the treatment of breast cancer. 869 12

Myeloablative treatment followed by lymphohaematopoietic reconstitution with stem cells from umbilical cord blood (UCB) can cure children with leukaemia. The clinical experience of UCB transplantation with HLA 2- and 3-antigen mismatched siblings is rather limited and there are no reports of such patient being given UCB significantly contaminated with maternal T lymphocytes. In this study, we report our experience in treating a child with chronic myeloid leukaemia in blast crisis who was transplanted using UCB cells from mismatched sibling donor containing a significant number of maternal T cells. The patient received 1.17 x 10(8) nucleated cells/kg after conditioning with Ara-C, busulphan, TBI and cyclophosphamide. GVHD prophylaxis was with cyclosporine and an anti-CD25 monoclonal antibody. Although engraftment was somewhat slow it was complete as documented by cytogenetic analysis and DNA studies. Results of minimal residual disease monitoring by RT-PCR for the hybrid BCR/ABL gene showed no evidence of leukaemic mRNA post-transplant. Acute GVHD, skin only, developed on day +14 but promptly responded to low-dose steroids. The technique used for UCB collection may have cell contamination found. In spite of these potential disadvantages: advanced disease, HLA antigen disparate donor and significant maternal T cell contamination, the transplant was successful and at a follow-up of 14 months the child is well with no evidence of chronic GVHD. Immune naivety of cord blood and lack of immunological reactivity of maternal T cells in this context may have played a significant role in the outcome of this case.
 ...
PMID:Haploidentical cord blood transplant contaminated with maternal T cells in a patient with advanced leukaemia. 873 18

We investigated the persistence of host-type hematopoiesis as defined by mixed chimerism (MC) in 28 male patients with chronic myelogenous leukemia (CML) who underwent opposite sex, non-T cell-depleted bone marrow transplantation (BMT) by amplification of Y-chromosome specific sequences, and correlated these results with the detection of minimal residual disease (MRD) by BCR/ABL mRNA amplification. Patients were studied at two time periods (> 3 months and > 24 months post-BMT). All but two patients were conditioned with total body irradiation (TBI) and cyclophosphamide (CY). One patient received busulfan (Bu), thiothepa (Thio) and CY, another patient CY and Bu. Detection of MRD occurred exclusively among patients with a MC (significance P < 0.04). Six of 18 patients with MC had detectable MRD, four of these consecutively developed cytogenetic and hematological relapse. Of 28 patients studied more than 3 months post-transplant, 18 (64%) had mixed chimerism and 10 (36%) had exclusively donor-derived blood cells. Nineteen patients were followed for their chimeric status between 24 months and 136 months post-BMT. Four patients converted from MC to complete chimerism and 10 patients (53%) remained mixed chimeric. The high incidence of MC in patients who underwent BMT without T cell depletion was measured by using a PCR assay with a sensitivity of 0.001%. As previously described by other investigators patients with complete chimerism developed more acute GVHD grade I-II (seven of 10 patients (70%) than patients with MC (nine of 18 patients (50%), not significant). This study also suggests that chimeric status might depend upon the regimen to prevent GVHD. One of four patients who received weekly methotrexate as GVHD prophylaxis developed MC, whereas in 11 of 18 patients receiving short course methotrexate and cyclosporine MC was detectable. All of six patients, prophylactically treated with a murine monoclonal antibody directed to the human alpha/beta T cell receptor in combination with cyclosporine, were mixed chimeras.
 ...
PMID:Detection of minimal residual disease and persistence of host-type hematopoiesis: a study in 28 patients after sex-mismatched, non-T cell-depleted allogeneic bone marrow transplantation for Philadelphia-chromosome positive chronic myelogenous leukemia. 875 Feb 76

We investigated 23 patients for their chimerism status who underwent allogeneic transplantation using peripheral blood progenitor cells (PBPCT) for chronic myelogenous leukemia (CML) (n = 14), acute myelogenous leukemia (AML) (n = 5), acute lymphoblastic leukemia (n = 1), myelodysplasia (MDS) (n = 1), and Hodgkin's disease (HD) (n = 2). These data were compared with those of patients after allogeneic BMT after matching them for disease and disease stage, sex of donor and recipient, GVHD prophylaxis, conditioning therapy and degree of HLA disparity. Patients were studied monthly up to 16 months post-transplant. In 11 of 23 (48%) patients who were transplanted with PBPCs and in 18 of 23 (78%) patients after BMT a mixed chimerism was detected at 1 month post-transplant. After 3 months, six of 21 (29%) evaluable patients after PBPCT remained mixed chimeric as opposed to 12 of 21 (57%) patients after BMT. We also assessed minimal residual disease using detection of the chimeric BCR/ABL transcripts by PCR of CML patients in this study. In four of 14 (29%) patients who underwent PBPCT, the BCR/ABL chimeric transcript was detected, while after BMT eight of 14 (57%) CML patients remained BCR/ABL positive. In two of these BMT patients, a cytogenetic relapse developed subsequently, and one other patient suffered a hematological relapse, whereas one of the CML patients relapsed after PBPCT. The present data may indicate that after PBPCT the incidence of leukemic relapse is similar or even lower than after BMT.
 ...
PMID:Molecular studies of chimerism and minimal residual disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation. 886 52

Campath-1 is a rat anti-human (CDw52) monoclonal antibody (MoAb) which is currently used for T cell depletion of allogeneic bone marrow and more recently peripheral blood stem cells prior to transplantation to prevent graft-versus-host disease (GVHD). In addition, in vivo Campath-1 is presently administered for the purpose of achieving increased immunosuppression during pre-transplant conditioning to aid in the prevention of graft rejection following T cell-depleted bone marrow transplantation (BMT). Graft-versus-leukemia (GVL) effect is an immunological effect that is of importance in controlling minimal residual disease (MRD) and reinducing remission post-BMT. It is thought that large granular lymphocytes (LGLs) and natural killer (NK) cells play a role in GVL. However, no data are available on the GVL effect post-Campath-mediated T cell-depleted allogeneic peripheral blood stem cell transplantation (alloPBSCT). In the present work, we assessed the effect of Campath-1G on the cytotoxic and proliferative capabilites of peripheral blood derived LGLs and NK cells. Campath-1G significantly inhibited binding of LGLs to tumor cells as well as resting and interleukin-2 (IL-2)-activated LGL and NK cell cytotoxic capabilites, which may be of clinical importance.
 ...
PMID:Campath-1G impairs human natural killer (NK) cell-mediated cytotoxicity. 889 85

The feasibility of inducing graft versus leukemia (GVL) effects with allogeneic T cells in recipients of autologous bone marrow transplantation (BMT) was studied in a murine model (BCL 1) of human B cell leukemia/ lymphoma. Allogeneic cell therapy, induced by infusion with peripheral blood lymphocytes, a mixture of allogeneic spleen and lymph node cells and allogeneic activated cell therapy, induced by in vitro recombinant-interleukin-2(rIL-2)-activated allogeneic bone marrow cells in tumor-bearing mice, prevented disease development in adoptive BALB/c recipients. Concomitant in vivo activation of allogeneic lymphocytes with rIL-2 suppressed even more effectively the development of leukemia in secondary adoptive recipients of spleen cells obtained from treated mice. In contrast, in vivo administration of rIL-2 after syngeneic BMT, with or without equal numbers of syngeneic lymphocytes, led to disease development in secondary recipients. Our data suggest that effective cell therapy can be achieved after SBMT by allogeneic but not syngeneic lymphocytes and that anti-leukemic effects induced by allogeneic lymphocytes can be further enhanced by in vitro or in vivo activation of allogeneic effector cells with rIL-2. Therefore, cell therapy by allogeneic lymphocytes following autologous BMT could become an effective method for inducing GVL-like effects on minimal residual disease provided that graft versus host disease can be prevented or adequately controlled.
 ...
PMID:Induction of graft versus leukemia effects by cell-mediated lymphokine-activated immunotherapy after syngeneic bone marrow transplantation in murine B cell leukemia. 895 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>