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)

Bone marrow transplantation has been undertaken with encouraging results as therapy for a wide variety of lysosomal storage diseases. We report a case of Niemann-Pick disease Type IA in which, despite the presence of only mild hypotonia with depressed reflexes, the clinical course of the disease appeared to be only slightly modified by this procedure, which was performed at the earliest practical opportunity. The patient was diagnosed early when asymptomatic, because of a family history of an affected sibling who died at 14 months. He received a bone marrow transplant from an HLA-identical, MLC non-reactive sibling donor, whose leukocyte sphingomyelinase activity was in the homozygote normal range. There was adequate engraftment as evidenced by persistently normal leukocyte sphingomyelinase activities, and there was no evidence of graft-versus-host disease. Visceral storage and neurological impairment were less rapidly progressive than in his untreated sibling but he eventually died at 30 months. Autopsy confirmed that this was essentially due to the effects of the underlying Niemann-Pick disease. We conclude that despite some success in other neurovisceral lysosomal storage disorders, bone marrow transplantation is not likely to be an adequate treatment for Niemann-Pick disease Type IA.
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PMID:Bone marrow transplantation for Niemann-Pick type IA disease. 129 89

KM2210, a conjugate of estradiol and chlorambucil (CBL), which was originally developed as an anti-breast cancer agent, inhibits proliferative response of human mononuclear cells to alloantigens in mixed lymphocyte culture in a dose-dependent manner, but has no effect on their response to phytohemagglutinin. Neither estradiol benzoate nor CBL alone showed these unique actions. The suppressive effect of KM2210 on MLC was abrogated by adding of anti-transforming growth factor-beta (TGF-beta) antibody to the culture, but was not affected by the addition of interleukin-2, suggesting that KM2210, unlike CBL, displays its actions via TGF-beta. In experimental allogeneic bone marrow transplantation using mice, daily oral administration of KM2210 (2 mg/kg/day) for 30 days posttransplant significantly inhibited the alloantigen-specific immune reactions. Furthermore, the survival rate of the KM2210-treated mice was significantly higher than that of the cyclosporine-treated (2 mg/kg/day, p.o.) mice, and no adverse effect of KM2210 on hematopoietic recovery was found. These results strongly suggest possible clinical benefits of KM2210 as a new immunosuppressive agent for the prevention and treatment of graft-versus-host disease and other allospecific immune reactions.
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PMID:The alloantigen-specific immunosuppressive activity of estradiol-chlorambucil conjugate (KM2210) and its beneficial effect on allogeneic bone marrow transplantation in mice. 138 90

Bone marrow transplantation from unrelated donors is being used increasingly for the treatment of patients with leukemia and several other hematologic disorders. Selection of unrelated bone marrow donors currently relies on serological HLA identity and negative mixed lymphocyte reactions between donor/recipient pairs. As serological HLA-DP typing is not feasible, we used the HLA-DPB1 oligonucleotide typing method to investigate whether the current selection procedure can guarantee complete MHC class II identity. In 40 consecutive patients, one third (62/193) serologically HLA-A, -B, -C, -DR and -DQ identical donors were found to be MLC negative with a relative response below 5%. HLA-DPB1 oligonucleotide typing of these MLC negative donors revealed that again only one third (20/62) was also identical for DP with their presumptive recipients. In the majority of pairs a disparity in graft-versus-host direction or in host-versus-graft direction of at least one allele was seen. These data indicate that in spite of the strict MLC criteria used, the current procedure did not warrant complete MHC class II identity. This implies that oligotyping for DPB1 can improve matching and should be introduced for typing of volunteers. We speculate that DP differences may contribute to the higher incidence of graft-versus-host disease or graft rejection in unrelated transplants.
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PMID:Selection of unrelated bone marrow donors: does the current procedure warrant complete MHC class II identity? 149 53

In a prospective randomized study, five European transplant centers compared recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; mammalian glycosylated) with placebo. rhGM-CSF was administered in a dose of 8 micrograms glycoprotein (5.5 micrograms protein)/kg/d, as a continuous intravenous (IV) infusion for 14 days, starting 3 hours after bone marrow infusion. Fifty-seven patients entered and completed the study. Median age of the recipients was 34 years (range, 17 to 51 y). All donors were HLA-identical, MLC-nonreactive siblings. Marrow grafts were depleted of T lymphocytes either by counterflow centrifugation (n = 42) or by immunological methods (n = 15). Twenty-nine patients received rhGM-CSF and 28 patients placebo. The leukocyte count and the absolute neutrophil count were significantly higher in the rhGM-CSF-treated group from day +9 to day +14 after bone marrow transplantation (BMT). This was also true for the monocyte count from day +12 to day +21. Early neutrophil (greater than 0.1 and greater than 0.3 x 10(9)/L) and early leukocyte (greater than 0.3 and greater than 0.5 x 10(9)/L) recovery was significantly faster for the patients given GM-CSF. The incidences of graft-versus-host disease (GVHD) and transplant-related mortality were not different in both groups. However, the number of bronchopneumonias was significantly lower in the rhGM-CSF-treated group (P = .03). Long-term follow-up showed a trend to better overall disease-free survival at 2 years and a trend to a lower relapse risk in patients treated with rhGM-CSF. This study shows that rhGM-CSF significantly increases neutrophil and monocyte counts during periods of 6 to 10 days in the second and third week after BMT. This shortened period until myeloid cell recovery after transplantation resulted in a decreased number of pneumonias, without an increase in incidence of GVHD or relapse.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor accelerates neutrophil and monocyte recovery after allogeneic T-cell-depleted bone marrow transplantation. 153 59

Six children with clinical and hematologic features of juvenile chronic myelogenous leukemia (JCML) underwent bone marrow transplantation (BMT) using T cell-depleted marrow from non-HLA-matched related or closely HLA-matched unrelated donors. Patient ages ranged from 1.2 to 5 years. Four patients received cytoreductive chemotherapy prior to BMT conditioning, and four had undergone pretransplant splenectomies. The donor-recipient matching included: four transplants disparate at one HLA locus (three from unrelated donors and one from a related donor), one transplant disparate at two HLA loci, and one transplant from a one haplotype-mismatched donor. All patients were MLC reactive with their donors. Graft-versus-host disease (GVHD) prophylaxis consisted of in vitro T cell depletion with a monoclonal antibody directed against CD3, and complement in conjunction with cyclosporin A begun on day -1. Conditioning included busulfan, cytosine arabinoside, cyclophosphamide, methyl-prednisolone, and hyperfractionated total body irradiation. All patients engrafted, with median time to neutrophils greater than 500 x 10(6)/l and platelets greater than 25 x 10(9)/l of 20 and 21 days, respectively. Acute GVHD was less than or equal to grade II in all patients. Two patients died of infection (Candida, CMV) at days 74, 157. One patient relapsed at day 177, and subsequently died on day 939. Three patients are alive and disease free at 180 +, 1610 + and 2400 + days from BMT. Although intensive chemotherapy may play a role in providing transient disease control in patients with JCML, allogeneic BMT is the only curative therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Allogeneic marrow transplantation using T cell depletion for patients with juvenile chronic myelogenous leukemia without HLA-identical siblings. 157 10

We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC-compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval [CI], 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.
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PMID:T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission. 159 77

Fourteen children with high risk leukaemia received allogeneic bone marrow transplants from HLA-identical MLC-compatible sibling donors. All bone marrows were T cell depleted and a T cell addback was prepared from the donor's peripheral blood so that the mean total number of CD3+ cells given was 2.6 (1.0-4.1) x 10(5)/kg recipient body weight. This was administered as a short infusion prior to the bone marrow. The children were conditioned with 1440 cGy fractionated total body irradiation and cyclophosphamide 120 mg/kg and were not given cyclosporin A or methotrexate. All patients engrafted and none showed late graft rejection. Acute graft-versus-host disease (GVHD) developed in nine of 14 children and required treatment with steroids. Two children with grade IV GVHD and one with grade I acute GVHD who subsequently developed severe chronic GVHD died. There have been two relapses (both fatal) and one death from cytomegalovirus pneumonitis. Survival is currently 57% (8/14) with a mean follow-up of 548 days (range 384-810). A high incidence of GVHD which was fatal in three patients can occur despite infusion of low T cell numbers in the absence of post-graft immunosuppression.
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PMID:Graft-versus-host disease in children receiving HLA-identical allogeneic bone marrow transplants with a low adjusted T lymphocyte dose. 176 70

Ultraviolet irradiation inhibits alloreactive and mitogen-induced responses and might reduce both graft-versus-host and host-versus-graft reactions after bone marrow transplantation (BMT). We have studied proliferative responses to mitogens and reactivity in mixed lymphocyte culture after irradiation with ultraviolet (UV)-B light using splenocytes from Balb/c (H-2d) and CBA (H-2k) mice. Response to mitogens and in MLC was strongly inhibited by 20 J/m2 and abolished at 50 J/m2. Clonogenic cell recovery (CFU-GM; CFU-S) after UV-B irradiation was also reduced. When bone marrow and spleen cells were transplanted from parent (Balb/c) animals into F1 hybrid (Balb/c X CBA) recipients, all animals died with features indicative of graft-versus-host disease (GVHD) in 34 days. If the grafts were first irradiated with 100 J/m2 of UV-B at a mean wavelength of 310 nm, then 76% survived to day 80 when they were killed and shown to have normal marrow cellularity. The remainder died in marrow aplasia or of GVHD. H-2 typing in a group of surviving recipients showed either donor hematopoiesis only (8 of 15), mixed allogeneic chimerism (5 of 15), or recipient type hematopoiesis (2 of 15). Higher doses (200 to 300 J/m2) were detrimental to survival with 88% of recipients dying in marrow aplasia. Syngeneic BMT in Balb/c mice showed slower hematopoietic reconstitution when the grafts were first irradiated with 100 J/m2. After BMT from Balb/c to CBA mice all recipients of unirradiated grafts died within 54 days. By contrast, after graft irradiation with 100 J/m2 survival of recipient animals to day 80 was 59%. If these grafts were treated with 50 J/m2 survival was only 26% with an increase in deaths due to GVHD. Hematopoiesis at day 80 in a group of survivors studied by Ig heavy chain allotyping indicated donor type hematopoiesis in 6 of 10 (50 J/m2) and 2 of 9 (100 J/m2). These data indicate that UV-B irradiation inhibits lymphocyte reactivity and can prevent GVHD. However, there is clear in vitro and in vivo evidence of stem cell damage, such that autologous marrow recovery was demonstrated in a proportion of recipients. In parent----F1 UV-irradiated transplants, sustained hematopoietic recovery was effected in the majority by donor stem cells.
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PMID:Studies of allogeneic bone marrow and spleen cell transplantation in a murine model using ultraviolet-B light. 182 55

A combination of density flotation centrifugation and counterflow centrifugation (elutriation) allows the elimination of 98% of the T-lymphocytes, present in a marrow aspirate. This reduces substantially the occurrence of graft versus host disease (GvHD) after transplantation without loss of the repopulation capacity. A limitation of the traditional Beckman elutriator rotor is the relatively small size of the elutriation chamber, which makes five to six runs, of one hour each, necessary to process the whole bone marrow graft. We developed a new elutriator rotor, containing four disposable elutriator chamber (Dijkstra BV, Amsterdam, The Netherlands), which allows to complete the lymphocyte elimination from the bone marrow graft within 2 hours. Ninety-nine consecutive patients were transplanted with elutriated MLC-negative bone marrow grafts from histocompatible siblings. Indications for transplantation were: AML (n = 32), ALL (n = 34) and CML (n = 33). The grafts contained after counterflow centrifugation a mean of 12.1 (+/- 2.4)% of the nucleated cells, 1.9 (+/- 1.4)% of the T-lymphocytes, and 93.5 (+/- 59.4)% of the CFU-GM, originally present in the collected bone marrow. Immunoprophylaxis post grafting was given to 97 BMT recipients. Primary graft failure occurred in 5 of 95 evaluable patients (5%). The probability of acute GvHD greater than grade 1 at day 100 after BMT was 16%. The projected 3-year estimate of extensive chronic GvHD was 13%. The low incidence of GvHD was associated with a relatively low transplant related mortality in patients above the age of 40 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prevention of graft-versus-host disease by lymphocyte depletion of the bone marrow graft with use of counterflow centrifugation. 186 51

In a study carried out for patients receiving intrafamilial HLA-A,B,DR identical, MLC negative bone marrow transplants, RFLP profiles of HLA-class II for 27 donor recipient pairs were analyzed. Twenty-four pairs were found HLA-class II identical while three pairs were HLA-DP incompatible. The patients of these three pairs did not reveal any acute GVHD greater than or equal to grade II. The seven cases of acute GVHD greater than or equal to grade II found in our panel were HLA-DR, DQ, and DP compatible. Thus, in practical terms pretransplantation HLA-DP typing does not seem necessary for intrafamilial HLA-identical, MLC negative BMT. On the other hand, this work confirmed that it is possible to type for HLA-DP using molecular biological techniques, and this in itself may have some important implications for unrelated BMT.
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PMID:HLA-DP genotyping in HLA-A,B, and DR identical intrafamilial bone marrow transplantation. 196 10


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