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)

Intrauterine bone marrow transplantation (BMT) may represent a new approach for correction of a large variety of genetic disorders in utero. The procedure may become feasible for more genetic disorders in the future, since a large majority of potentially correctible diseases can be diagnosed at an early stage of gestation in utero using molecular probes that permit analysis of small biologic samples and even few cells that may be obtained by chorionic villi biopsy and/or amniocentesis. Haploidentical paternal marrow (2 cases) and sibling bone marrow cells from a disease-free family members, were infused into the fetus. GVHD was avoided following in vitro T-lymphocyte depletion using monoclonal antilymphocyte (CDW52) antibodies (Campath-1) without affecting stem cell viability, similarly to the procedures in routine use in clinical BMT programs in man. Three women underwent intrauterine BMT at 34, 23 and 25 weeks of gestation for metachromatic leucodystrophy (Arylsulfatase A deficiency, 2 cases) and beta thalassemia major (1 case), respectively. A total of 33 x 10(8), 30 x 10(8) and 30 x 10(8) bone marrow cells were infused intraperitoneally (1 case), intraportally plus intraperitoneally (2 cases) with no fetal distress. Although the procedure was uneventful and no clinical evidence of GVHD was observed following delivery, correction of the basic disorders was not accomplished because of anticipated rejection of marrow allografts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical application of intrauterine bone marrow transplantation for treatment of genetic diseases--feasibility studies. 150 65

Recent data from the CAMPATH users group are reported. Different protocols have been tested using the CD52 antibodies Campath-1M and Campath-1G for prevention of GVHD and graft rejection in allogeneic transplants from both sibling and volunteer unrelated donors. Leukaemia relapse remains a significant problem for patients with CML, but in other diseases the recent results using T cell depletion appear to be as good as, or better than, published data with conventional GVHD prophylaxis. In addition, the morbidity and mortality associated with chronic GVHD are substantially reduced. Future collaborative studies to consolidate these findings include a randomised trial of the humanised antibody Campath-1H organised under the auspices of the EBMT. There are also plans to carry out experimental studies using Campath-1 antibodies to deplete T cells from peripheral blood stem cell harvests.
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PMID:Recent results using CAMPATH-1 antibodies to control GVHD and graft rejection. 870 78

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT, 19 patients had relapsed on and 31 off therapy. Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II-IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure. These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.
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PMID:Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission. 879 Jan 60

Campath-1G is a CD52 (rat IgG2b) moAb used in bone marrow transplantation (BMT) to prevent graft-versus-host disease (GVHD) by the elimination of T cells via antibody-dependent cell cytotoxicity (ADCC) in vivo. We have previously reported that Campath-1G induces T cell proliferation, activation, and production of cytokines which in turn causes an enhancement of megakaryocytopoiesis in vitro. In view of the fact that recent studies have indicated that natural killer (NK) cells may also be involved in the regulation of megakaryocytopoiesis, we undertook the study of the in vitro effect of Campath-1G-treated NK cells on the regulation of megakaryocytopoiesis. Early burst-forming BFU-MK and late colony-forming CFU-MK were grown from 2 x 10(5) peripheral blood non-adherent mononuclear cells (NAMC) in plasma clots in the presence of aplastic canine plasma (PICS-J) which was used as megakaryocyte colony-stimulating factor (MK-CSF). The first step in elucidating this series of events was to investigate the direct influence of NK cells on megakaryocytopoiesis. Co-culturing NK cells (>85% CD16+) with autologous NAMC at a ratio of 1:1 resulted in a significant increase in the proliferation of CFU-MK and BFU-MK over NAMC cultured alone. This effect was further enhanced upon exposure of NK to Campath-1G (0.1-3 microg/ml). To investigate the possible influence of soluble factors released from NK cells treated with Campath-1G on MK maturation, conditioned medium (CM) derived from Campath-1G-treated-enriched populations of NK cells was found to enhance MK progenitor growth. Our data demonstrate that resting and Campath-1G-treated NK may be involved in the immunomodulation of megakaryocytopoiesis.
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PMID:Enhancement of megakaryocytopoiesis by Campath-1G-treated natural killer cells. 933 53

T-cell depletion of bone marrow for allogeneic transplantation is known to increase the risks of Epstein-Barr virus-driven lymphoproliferative disorders that may result in fatal lymphoma, especially with transplants from unrelated or mismatched donors. Over the past 15 years, we have monitored the outcome of 2,582 transplants using CAMPATH-1 (CD52) antibodies to deplete lymphocytes from donor and/or recipient to prevent graft-versus-host disease or rejection. Unlike many other methods of T-cell depletion, CAMPATH-1 antibodies also deplete B lymphocytes. The actuarial risk of lymphoproliferative disease using CAMPATH-1 for depletion of donor lymphocytes was up to 1.3%, hardly different from reported figures for conventional nondepleted transplants. In contrast, the risk in a small group of patients transplanted from unrelated donors using E-rosette depletion was as high as 29%, comparable to other reports of specific T-cell depletion. We conclude that the additional depletion of B cells is beneficial, possibly because it reduces either the virus load or the virus target until the time when T cells begin to regenerate.
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PMID:Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants. CAMPATH Users. 953 22

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P <.001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P <.001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P =.04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v 52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.
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PMID:Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. 984 24

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.
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PMID:Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity. 1079 80

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 microg/ml and 120 microg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection.
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PMID:CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells. 1091 7

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52.6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14.5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV-negative patients survival at 5 years was 60% vs. 42% in CMV-positive patients (P = 0.006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV-seronegative recipients of MUD allografts, but in CMV-seropositive patients this approach is associated with an increased non-relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.
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PMID:Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis. 1116 9

Graft-versus-host disease (GVHD), a major complication after allogeneic transplantation, can be abrogated by the Campath (anti-CD52) monoclonal antibody. The induction of acute GVHD requires host antigens to be presented to donor T cells by antigen-presenting cells (APCs). Recent evidence has suggested that only host APCs can interact with donor T cells in the induction of GVHD. Because CD52 has been reported to be expressed on DCs, we reasoned that pretransplant Campath-1G might have a direct effect on circulating DCs in addition to any effects on donor T cells. Using direct immunostaining, we demonstrated expression of CD52 on DCs and that Campath-1G killed purified DCs in vitro. In vivo Campath also depleted DCs. Twenty-four hours after the first dose of Campath-1G, circulating DCs were reduced by a mean of 79% (range, 44%-96%). By day 0 after 5 doses of Campath-1G and chemoradiotherapy conditioning, DCs became undetectable in 7 of 9 cases, whereas in 6 of 7 patients receiving conditioning therapy without Campath-1G, host DCs were still detectable. The reconstitution of circulating DCs after transplantation was not affected by Campath-1G and in both groups DC1 (CD11c(+)) recovered more rapidly than DC2 (CD11c(-)). Analysis of chimerism confirmed that the DCs recovering after transplantation in patients receiving Campath-1G were of donor origin. We conclude that in vivo Campath-1G causes a rapid depletion of host circulating DCs and that this may, in part, explain the low incidence of acute GVHD. The reconstitution of donor DCs was not delayed, which may be important in preserving immune reconstitution.
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PMID:Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution. 1189 97

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