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 (BMT) remains the only potentially curative treatment for patients with thalassemia major. However, most candidates for BMT do not have a suitable family donor. In order to evaluate whether BMT from an HLA-matched unrelated volunteer donor can offer a probability of cure comparable to that obtained when the donor is a compatible sibling, we carried out a study involving 68 thalassemia patients transplanted in six Italian BMT Centers. Thirty-three males and 35 females (age range, 2-37 years; median age, 15) were transplanted from unrelated volunteer donors, all selected using high-resolution molecular typing of both HLA class I and II loci. Fourteen patients were classified in risk class 1; 16 in risk class 2; and 38 in risk class III of the Pesaro classification system. Nine patients (13%) had either primary or secondary graft failure. Fourteen patients (20%) died from transplant-related causes. Grade II-IV acute graft-versus-host disease (GVHD) developed in 24 cases (40%), and chronic GVHD in 10 cases (18%). Overall survival (OS) in the cohort of 68 patients was 79.3% (CI 67-88%), whereas the Kaplan-Meier estimates of disease-free survival (DFS) with transfusion independence was 65.8% (CI 54-77%). In the group of 30 thalassemic patients in risk classes 1 and 2, the probability of OS and DFS were 96.7% (CI 90-100%) and 80.0% (CI 65-94%), respectively, whereas in the 38 patients in class 3 OS was 65.2% (CI 49-80%) and DFS was 54.5% (CI 38-70%). These data show that when donor selection is based on stringent compatibility criteria, the results of unrelated transplantation in thalassemia patients are comparable to those obtained when the donor is a compatible sibling.
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PMID:Unrelated bone marrow transplantation for beta-thalassemia patients: The experience of the Italian Bone Marrow Transplant Group. 1633 65

Polymorphisms in genes that encode antigen-presenting molecules, antigen receptors, and immune mediators are crucial determinants of the risk of complications after allogeneic hematopoietic cell transplantation (allo-HCT). Matching for HLA alleles remains the cornerstone of donor selection, and recent studies are refining our understanding and use of HLA typing in allo-HCT. High-resolution allelic HLA matching generally improves transplant outcome but may limit the donor pool and delay transplantation. Allelic mismatches may be permissible in certain circumstances without compromising outcome. There is growing interest in the role of natural killer (NK) cell-mediated immunity in allo-HCT. NK cells express an array of activating and inhibitory killer cell immunoglobulin-like receptors (KIR), and NK cell activation is negatively regulated by KIR interaction with HLA class I molecules. In haploidentical transplants, NK cell alloreactivity in the graft-versus-host direction can be predicted by the HLA class I and KIR genotypes of donor and recipient and has been associated with potent graft-versus-leukemic effects and low rates of graft-versus-host disease. KIR genotype and expression may influence transplantation outcomes in both HLA-matched and -mismatched transplants. Graft-versus-host disease and major infection remain problematic despite HLA matching, and there is mounting evidence that polymorphisms in non-HLA immune mediators and host defense genes influence the risk of these complications. The importance of non-HLA genomics in nonmyeloablative transplants is poorly understood and is under investigation. These findings suggest that tissue typing for allo-HCT is entering an exciting era in which both HLA and non-HLA genomic data may be used in a more sophisticated fashion to select donors, stratify risk, identify novel therapeutic targets, and ultimately improve outcome for allo-HCT recipients.
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PMID:Genomic polymorphism and allogeneic hematopoietic transplantation outcome. 1639 80

Modern understanding of the genetic basis of graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (HSCT) involves knowledge of human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), cytokine genes, and their interactions. Insights into the immunogenetic basis of GVHD come from long-standing clinical experience in the use of myeloablative conditioning regimens and donor bone marrow as the grafting source. Under these circumstances, donor T-cell recognition of host HLA can cause GVHD. The recent elucidation of HLA class I as ligands for natural killer (NK) cell inhibitory KIR demonstrates that GVHD is the result of a complex interplay between the innate and adaptive immune responses. The extent to which T cells and NK cells contribute to clinical GVHD is a function of the host post-conditioning environment, immunosuppressive treatments, and the content of the graft source. The contribution of donor and host genetic differences in cytokine genes in modulating risks of GVHD has recently been recognized.
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PMID:Genetics of risk factors for graft-versus-host disease. 1641 85

Although donor lymphocyte infusion (DLI) induces complete remissions in 70% of patients with relapsed chronic myeloid leukemia (CML) after allogeneic stem-cell transplantation (SCT), some patients are refractory to DLI by showing disease persistence. In a patient who received DLI for relapsed CML, we observed persisting molecular disease despite a hematological and cytogenetic remission in the absence of graft-versus-host disease (GVHD). To determine the nature of this immune response, we isolated leukemia-reactive donor T-cell clones from the bone marrow (BM) of the patient at the time of clinical response. Four different types of CD8+ HLA class I restricted T-cell clones were obtained that were cytotoxic against Ebstein-Barr virus-transformed B-cell lines (EBV-LCL) of the patient, but not the donor, indicating recognition of minor histocompatibility antigens (mHags). By using survival studies with CFSE labelled BM cells populations, a hematopoietic progenitor cell inhibition assay and direct morphological examination we showed that the T-cell clones recognized mature monocytic and myeloid cells, whereas immature BM progenitor cells were insufficiently lysed. This patient's refractoriness for DLI appears to be caused by inadequate lysis of progenitor cells by these cytotoxic T cells. These findings support the hypothesis that for eradication of CML a cytotoxic T-cell response against leukemic progenitor cells is essential.
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PMID:Molecular persistence of chronic myeloid leukemia caused by donor T cells specific for lineage-restricted maturation antigens not recognizing immature progenitor-cells. 1652 95

The authors evaluated the outcome of ten children given hematopoietic stem cell transplantations from Thai unrelated donors (URD-HSCT) selected using DNA high-resolution typing of both HLA class I and II loci. Six patient/donor pairs (60%) were fully matched; four (40%) were 5/6 matched. Patients had either non-malignant (n=9) or malignant (n=1) diseases. In most cases, graft-versus-host disease (GVHD) prophylaxis composed of cyclosporine and short-term methotrexate. The probability of hematopoietic recovery at day 30 was 90%. The cumulative probability of acute GVHD and of chronic GVHD equaled 44.4 and 0%, respectively. Three patients died of transplant-related complications. The probability of transplant-related mortality (TRM) at 30, 100, and 180 days were 10, 30, and 30%, respectively. The overall and disease-free survival rates were 70 and 70%, respectively. URD-HSCT with donor selection based on high-resolution HLA typing is associated with a low incidence of both severe acute GVHD and graft failure. The observed outcome is comparable to that of children transplanted from HLA-identical siblings.
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PMID:Outcome of pediatric hematopoietic stem cell transplantations from Thai unrelated donors matched with high-resolution HLA typing. 1662 93

Matching for HLA class I alleles, including HLA-C, is an important criterion for outcome of unrelated donor transplantation. However, haplotype-mismatched transplantations for myeloid malignancies, mismatched for killer immunoglobulin-like receptor (KIR) ligands in the graft-versus-host (GVH) direction, is associated with lower rates of graft-versus-host disease (GVHD), relapse, and mortality. This study investigated the effect of KIR ligand mismatching on the outcome of unrelated donor transplantation. The outcomes after 1571 unrelated donor transplantations for myeloid malignancies where donor-recipient pairs were HLA-A, -B, -C, and -DRB1 matched (n = 1004), GVH KIR ligand-mismatched (n = 137), host-versus-graft (HVG) KIR ligand-mismatched (n = 170), and HLA-B and/or -C-mismatched but KIR ligand-matched (n = 260) were compared using Cox regression models. Treatment-related mortality (TRM), treatment failure, and overall mortality were lowest after matched transplantations. Patients who received grafts from donors mismatched at the KIR ligand in the GVH or HVG direction and mismatched at HLA-B and/or C but matched at the KIR ligand had similar rates of TRM, treatment failure, and overall mortality. There were no differences in leukemia recurrence between the 4 groups. These results do not support the choice of an unrelated donor on the basis of KIR ligand mismatch determined from HLA typing.
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PMID:The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: a report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. 1686 58

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.
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PMID:Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. 1693 26

Adoptive immunotherapy using natural killer (NK) cells is currently under investigation, especially in situations where anti-neoplastic effect is needed but infusion of T cells is considered hazardous, such as in recipients of haematopoietic stem-cell transplantation (HSCT) from haploidentical donors. NK-cell therapy is mainly but not exclusively investigated in the setting of allogeneic stem-cell transplantation. NK cells may induce potent anti-leukaemic and possibly anti-rejection activity, and may even mitigate graft-versus-host disease (GvHD). It remains to be determined whether such effects are clinically important and whether or not they are mediated mainly or exclusively by KIR-HLA class I interactions. Recent advances in graft engineering has provided methods for isolating large numbers of purified NK cells. Several groups have shown that clinical-grade NK cells at doses up to 10(7)/kg may be collected and purified for the purpose of infusion to patients. Early results in a limited number of patients show that these cell doses may be administered without adverse events and possibly without inducing GvHD. Further study is required to determine whether such infusions will be useful in preventing graft rejection, exerting graft-versus-leukaemia effects, and/or hastening immune recovery.
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PMID:Natural-killer-cell-based treatment in haematopoietic stem-cell transplantation. 1699 85

Natural killer (NK) cell alloreactions against recipient cells in the setting of bone marrow transplantation have been associated with decreased rates of graft-versus-host disease (GVHD) and improved survival in transplant recipients with myeloid leukemia. These alloreactions are predicted by the absence of recipient HLA class I ligands for donor inhibitory killer Ig-like receptors (KIR). We hypothesized that donor NK cell alloreactions against recipient cells may affect the development of T and B-cell functions and incidence of GVHD in infants with severe combined immunodeficiency (SCID). Of the 156 patients with SCID who had received related bone marrow transplants without pretransplant chemotherapy or posttransplant GVHD prophylaxis, 137 patient-donor pairs were evaluated for the absence of recipient HLA class I ligands for donor inhibitory KIR. Analysis showed that the absence of a KIR ligand had no effect on the incidence or severity of GVHD (RR [corrected] = 0.95, p = 0.84), development of T-cell function (RR [corrected] = 1.05, p = 0.69), production of IgA (p = 0.46) or IgM (p = 0.33), or on 5-year survival (RR [corrected] = 1.21, p = 0.10). Further, in patients possessing native NK cells, the absence of KIR ligands in donors for recipient-inhibitory KIR did not alter transplantation outcomes. This study suggests that inhibitory KIR/HLA interactions do not play a significant role in bone marrow transplantation for SCID.
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PMID:The effect of natural killer cell killer Ig-like receptor alloreactivity on the outcome of bone marrow stem cell transplantation for severe combined immunodeficiency (SCID). 1719 Nov 49

In allogenic hematopoietic stem-cell transplantation, an effect of HLA locus mismatch in allele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combination is little known, and its molecular mechanism to induce acute graft-versus-host disease (aGVHD) remains to be elucidated. A total of 5210 donor-patient pairs who underwent transplantation through Japan Marrow Donor Program were analyzed. All HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 alleles were retrospectively typed in all pairs. The impacts of the HLA allele mismatch combinations and amino acid substitution positions in 6 HLA loci on severe aGVHD were analyzed. A total of 15 significant high-risk HLA allele mismatch combinations and 1 HLA-DRB1-DQB1 linked mismatch combinations (high-risk mismatch) for severe aGVHD were identified, and the number of high-risk mismatches was highly associated with the occurrence of severe aGVHD regardless of the presence of mismatch combinations other than high-risk mismatch. Furthermore, 6 specific amino acid substitution positions in HLA class I were identified as those responsible for severe aGVHD. These findings provide evidence to elucidate the mechanism of aGVHD on the basis of HLA molecule. Furthermore, the identification of high-risk mismatch, that is, nonpermissive mismatch, would be beneficial for the selection of a suitable donor.
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PMID:High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism. 1755 59


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