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)

Certain marrow transplant protocols can now result in a 50-70% long disease-free survival and low relapse rates in acute leukemia (AL) in CR1, CR2, or CML following cytoreduction and HLA-identical marrow infusion. Two-thirds of deaths are due to acute and chronic graft-versus-host disease (GVHD) or viral infection. The other deaths are due to toxicities of the cytoreductive treatment. Prevention of GVHD has been tried by treatment after the transplant or treating the marrow (lymphocyte depletion). Cyclosporine (CsA) or CsA plus methotrexate has reduced acute GVHD but not chronic GVHD. Marrow has been treated with monoclonal antibodies and lectins or elutriated to decrease numbers of T lymphocytes. Some studies have been effective, but the majority have shown an increased number of rejections or leukemic relapses. Apart from teratogenic effects, thalidomide has minimal toxicity. It effectively prevents and treats acute and chronic GVHD in rodent models. Clinical trials will soon begin. Mismatched related or matched unrelated donors have been employed in the clinic with limited success. Alternatively, autologous transplantation in acute leukemia has shown promising results. Possible solutions to remaining problems and strategies will be discussed.
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PMID:Problems and strategies for bone marrow transplantation in acute leukemia and chronic myelogenous leukemia. 305 40

The probability of long term survival for allogeneic graft patients was 63% for ALL, 60% for ANL and 47% for CML in the 1st remission or 1st chronic phase of each leukemia. The major causes of death were interstitial pneumonia, relapse of leukemia and infections. On relationship of GVHD and the long term survival, the probability of 5 years survival was 38%, 47% and 25% in grade 0, I and II-IV of acute GVHD respectively. The difference might be due to that of relapse rate of leukemia. And the relationship between the relapse rate and GVHD, the patients with both of acute and chronic GVHD showed the lowest relapse rate 15.9%, the patients without GVHD showed the highest relapse rate 37.8% and the patients with either of GVHD showed the rate of between those of two groups. This may suggest that GVHD both acute and chronic might have an ability that can suppress the relapse of leukemia, i.e. GVL reaction. Interstitial pneumonia occurred in 32% of allograft patients and was often lethal complication (53%). Among many of prophylaxis tested, the followings were effective, a lower dose rate of total body irradiation, the selection of CMV-seronegative platelets donor, and the prophylactic administration of anti-CMV high titer globulin. Colony stimulating factor of human urine was also effective for shortening the granulopenic period after transplantation to prevent severe infections.
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PMID:[Allogeneic bone marrow transplantation]. 305 76

100 Ph+ CML patients submitted to BMT were studied cytogenetically before grafting and serially after transplantation. The 12 European institutions participating in the study, including transplant units and laboratories of cytogenetics, collected a total of 520 studies. The Ph chromosome was observed after BMT in 22 patients who did not enter relapse during the observation time (10-1400 days--median 420 d) following initial detection of the chromosome. This abnormality was observed in 1 to 30% of the cells analyzed. In 10 patients, abnormal cells were detected only within the first 90 d after BMT, in 5 patients both before and after 90 d and in 7 patients only after 90 d. 44% of these 22 patients had a moderate-to-severe cGVHD. Future studies are needed in order to better evaluate the real incidence of persistent disease and the correlations with the GVHD.
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PMID:Cytogenetic follow-up of 100 patients submitted to bone marrow transplantation for Philadelphia chromosome-positive chronic myeloid leukemia. Cooperative Study Group on Chromosomes in Transplanted Patients. 327 55

In Essen 121 bone marrow transplantations were carried out. The indications were severe aplastic anemia (n = 18), acute leukemia in relapse (n = 20), acute leukemia in remission (n = 46) or chronic myeloid leukemia (n = 37). The conditioning regimen consisted of cyclophosphamide or the combination of cyclophosphamide and total body irradiation. All patients were treated under strict gnotobiotic care. To mitigate the risk of CMV infections intravenous CMV-hyperimmunoglobulin and CMV-negative blood products have been applied routinely since two years. MTX was used as prophylaxis against GVH-disease. In case of severe aplastic anemia 13 patients (72%) are still alive with a median observation time of 24 months. In the prognostically unfavourable group of acute leukemia in relapse only one patient showed long term survival. In this patient leukemic relapse occurred six years after transplantation. The survival rate of AML patients grafted during the first remission is 55% (15/27) with a median observation time of 40 months. For patients grafted in first or consecutive remission of ALL the survival rate is 42% (5/12) with a maximal observation time of 29 months. Out of 37 patients grafted because of CML, eight were in an advanced stage of the disease. 13 patients are still alive, the maximal observation time is 37 months. The overall incidence of GVHD in patients at risk was 28% in aplastic anemia, 26% in AML, 9% in ALL and 63% in CML. In aplastic anemia no patient developed an interstitial pneumonia. In leukemia the risk of fatal interstitial pneumonia was 34%.
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PMID:Bone marrow transplantation in severe aplastic anemia and acute or chronic leukemia. 351 96

We studied the effect of eliminating T cells from donor grafts of mice in a system in which bone marrow was transplanted across major histocompatibility barriers. BALB/c bone marrow (added as a source of hematopoietic stem cells) combined with equal volumes of spleen cells (added as a source of GVHD-promoting cells) was pretreated in vitro with monoclonal anti-Lyt-1.2 or Lyt-2.2 plus absorbed rabbit complement before injection into C57BL/6 total-body-irradiated recipients. Functional activity of anti-Lyt monoclonal antibodies was determined in CML assay. Treatment with anti Lyt-1.2 plus C did not have any anti-stem cell activity, as measured by CFU-S assay, and protected recipients from the onset of lethal GVHD. Treatment with Lyt-2.2 plus C also did not reduce CFU-S; however, mice receiving treated marrow did develop GVHD and were all dead by 2 mo, as were untreated control mice. Surviving "anti-Lyt-1.2 + C chimeras" demonstrated a high percentage of donor mononuclear cells in their peripheral blood. Similar results were obtained when C3H/HeN donor BMS was treated with monoclonal anti-Lyt-1.1 plus C and injected into C57BL/6 recipients. These findings show that monoclonal antibodies directed against determinants unrelated to Thy-1 can eliminate T cells in the presence of C and successfully protect transplanted mice from lethal GVHD. They also suggest that these anti-Lyt antibodies may be useful tools in determining subpopulations of T cells that contribute to the development of GVHD.
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PMID:Bone marrow transplantation across major histocompatability barriers in mice. III. Treatment of donor grafts with monoclonal antibodies directed against Lyt determinants. 617 13

Impairment in T cell proliferation in response to E. coli and in CML to unrelated alloantigens was usually observed in patients early after marrow grafting and persisted in long-term patients with chronic GVHD but not in those without chronic GVHD. We analyzed various cellular functions in the pathway of T cell activation and found that in patients with immunodeficiency, (1) their M phi usually could process and present antigens to normal T cells, (2) their T cells did not proliferate even in the presence of normal antigen-pulsed M phi, (3) IL-2 production by T cells was deficient, and (4) exogenous IL-2 restored CML activity in cells of most patients early after grafting but not in cells of most patients with chronic GVHD. Therefore, failure to induce proliferation and cytotoxicity in T cells of marrow recipients is not likely due to M phi defects but because of ineffective communication among T cell subsets, probably related to impaired IL-2 production and/or unresponsiveness to IL-2.
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PMID:Ineffective cellular interaction and interleukin 2 deficiency causing T cell defects in human allogeneic marrow recipients early after grafting and in those with chronic graft-versus-host disease. 639 Aug 48

Treatment of murine spleen cells with normal guinea pig serum selectively abrogated responsiveness of these cells to the T cell mitogens PHA or Con A, but failed to affect responses to LPS, i.e., a B cell-specific mitogen. Although pretreatment with GPS inhibited the in vitro immune response of mouse splenocytes to SRBC, responses were normal after restoration with T cells only, indicating that B cells had been spared by GPS. Consistent with these results, incubation with GPS resulted in the loss of reactivity of mouse lymphoid cells in MLC as well as CML systems, both of which test for T cell activities. Furthermore, parental spleen cells treated with GPS were no longer capable of inducing a GVH reaction in F1 hybrids. When compared, the effects of GPS and anti-Thy-1.2 antibodies plus C were found to be comparable. These results indicate that GPS can selectively remove a number of T cell functions from heterogeneous murine lymphoid cell suspensions. Since spleen macrophages were insensitive to GPS cytotoxicity, lack of T cell function is not likely to be due to depletion of these accessory cells.
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PMID:Selective removal of T cell function from mouse lymphocyte suspensions by treatment with normal guinea pig serum. 698 3

Marrow transplant is potentially curative therapy for CML. Allogeneic sibling-donor marrow transplant may be the therapy of choice for younger patients early in the course of disease. Early transplant is an important influence on disease-free survival and relapse after related-donor transplant therapy, although additional patient characteristics influencing outcome can be identified and may have cumulative adverse effects. The 5-year disease-free survival of patients transplanted within one year of diagnosis and without signs of advanced disease is greater than 65%. Significant problems remain, however, including early mortality (primarily from infection, pneumonia, and pneumonitis) and relapse of CML following transplant, including late relapse occurring more than 5 years posttransplant. For patients without a matched, related donor, unrelated-donor marrow transplant may be a treatment option and can result in successful outcome for patients with CML. Relapse following unrelated-donor marrow transplant is rare. However, the use of an unrelated donor is associated with significant toxicity, including early mortality, engraftment failure, and ongoing morbidity and mortality associated with acute and chronic graft-versus-host disease. For patients who lack an available matched-related or -unrelated donor, autologous marrow transplant has been developed as an alternative approach to therapy. Long-term survival following autologous marrow transplant is possible and may even approach the survival for allogeneic related-donor recipients, although cure of disease is not achieved.
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PMID:Bone marrow transplantation for chronic myelogenous leukemia: clinical outcomes. 754 49

Eighty-eight children 0.5 to 17 years of age (median, 9 years of age) received an unrelated donor marrow transplant for treatment of chronic myeloid leukemia (CML; n = 16), acute lymphoblastic leukemia (ALL) in first or second remission (n = 15) or more advanced stage (n = 28), acute myeloid leukemia (AML; n = 13), or other hematologic diseases (n = 16) between June 1985 and April 1993. All patients were conditioned with cyclophosphamide and total body irradiation and received a combination of methotrexate and cyclosporine as graft-versus-host disease (GVHD) prophylaxis. Fourty-six patients received transplants from HLA-identical donors and 42 patients received transplants from donors who were minor-mismatched at one HLA-A or B or D/DRB1 locus. The Kaplan-Meier estimates of disease-free survival and relapse were 75% and 0% for patients with CML, 47% and 20% for ALL in first or second remission, 10% and 60% for ALL in relapse or third remission, 46% and 46% for AML in first remission (n = 1) or more advanced disease (n = 12), and 29% and 69% for other diseases. HLA disparity was not significantly associated with lower disease-free survival, but the results suggest more relapses in HLA-matched recipients and there was significantly more transplant-related mortality in mismatched recipients (51% v 24%, P = .04). Most deaths were due to infections associated with acute or chronic GVHD and occurred within the first 2 years after transplantation. Granulocyte engraftment occurred in all evaluable patients. Sixty-three percent of HLA-matched and 57% of HLA-mismatched recipients were discharged home disease-free at a median of 98 and 103 days, respectively, after transplantation (P = not significant [NS]). The incidence of grades II-IV acute GVHD was 83% in HLA-matched and 98% in HLA-mismatched recipients (P = .009). The incidence of chronic GVHD was 60% in HLA-matched and 69% in HLA-mismatched recipients (P = NS). One or multiple late adverse events such as cataracts, osteonecrosis of the hip or knee, restrictive or obstructive pulmonary disease, and hypothyroidism have occurred in 11 of 33 (33%) surviving patients. Immunosuppression was discontinued in 58% of surviving patients, including all 12 patients surviving more than 3.2 years, all of whom have a Lansky or Karnofsky score of 100%. These data show that marrow transplantation from fully or partially HLA-matched unrelated donors can be effective therapy for children with hematologic disorders and that pretransplantation disease status and posttransplantation GVHD remain important factors affecting patient outcome.
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PMID:Unrelated donor marrow transplantation in children. 757 22

It has been suggested that cord blood T cells may be less able to mediate GVHD than marrow-derived T cells due to their naive status. A decreased potential for GVHD may be advantageous for allogeneic transplant, but this benefit might be counteracted by loss of the GVHD associated graft-versus-leukemia (GVL) effect. The GVL potential of cord blood could be doubly compromised since cord blood NK cell activity is also decreased. To assess these issues we have performed extensive comparative functional and immunophenotypic evaluations of cord and adult mononuclear cells. We found a somewhat reduced alloproliferative, allostimulatory and allocytolytic capacity of cord blood mononuclear cells in bulk assays but not by limiting dilution assays. Immunophenotyping revealed no significant differences in the proportion of major lymphocyte subsets with the exception of the previously recognized predominance of CD45RA+ cells in both CD4 and CD8 cord blood T cells. Cord blood T cells expressed normal percentages of the cellular adhesion molecules, CD11a, CD18 and LFA-3; however, the antigen density of each of these molecules was less than that found on adult T cells. Fewer resting cord blood T cells expressed CD54, the ligand for LFA-1. Cord blood B cells and monocytes expressed normal levels of HLA-class I and HLA class II DR, DP and DQ antigens, suggesting that the decreased expression of cellular adhesion molecules or their receptors rather than a decrease in expression of HLA might have contributed to the lower alloreactivity of cord blood. Although the percentages of NK cells and NK cell subsets in adult and cord blood were similar our data confirmed that cord blood has very low NK lytic activity. In contrast, LAK activity was much more readily induced in cord blood compared with adult PBMC, a finding which could be explained in part by a higher frequency of LAK precursors and a more rapid expansion of NK cells in response to culture with medium containing of NK cells in response to culture with medium containing IL-2. Cord blood LAK cells were readily able to lyse fresh leukemia targets from patients with ALL, AML and CML. The data indicate that although the alloreactive potential of cord blood cells may be somewhat decreased, it is not absent and must be considered a factor in cord blood transplants. LAKp with the potential to lyse leukemia are present in increased numbers in cord blood and might contribute to the GVL effect of a cord blood transplant.
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PMID:Characterization of the alloreactivity and anti-leukemia reactivity of cord blood mononuclear cells. 759 66


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