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)

It now appears unequivocal that three markers exist in a linkage group in chromosome 6 of man: HLA-A, HLA-B and PGM3 (Fig. 1.) Tentatively, two other HLA loci and one Ir gene have been mapped close to HLA-B. The probable map order is HLA-A - HLA-C - HLA-B - HLA-D - Ir. The biological functions of these loci are unknown. However, HLA-A, B and C are important in allograft rejection. Other closely linked loci (HDR, CML) appear to be important in the first events of the allograft rejection (first set) and in generation of killer cells. HLA-D might be important in cellular recognition and graft-versus-host reactions (matching at HLA-D decreases the incidence and severity of graft-versus-host disease), and the Ir genes in the defense against infections. HLA-B and HLA-D loci are important markers in studies of disease susceptibility. HLA-B locus antigens HLA-B27 and HLA-B8 are frequently associated with arthritic or autoimmune disorders. HLA-D determinants have been found in association with multiple sclerosis and C2 deficiency (HLA-DW2); juvenile diabetes and Addison's disease (HLA-DW3) and adult type of rheumatoid arthritis (HLA-DW4).
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PMID:Immunogenetic aspects of allotransplantation. 13 74

The rates of graft-versus-host disease (GVHD) and rejection are significantly higher among recipients of unrelated donor marrow (BM) than in recipients of marrow from HLA-identical siblings, even when donors and recipients are mixed lymphocyte culture (MLC) compatible and serologically and Dw identical. It has been hypothesized that phenotypically silent HLA class I and DP sequence mismatches might be associated with these differences, but little is known about their incidence. We have sequenced the HLA-A, HLA-B, HLA-C, HLA-DPA1, and HLA-DPB1 genes expressed by 12 unrelated marrow transplant pairs, 11 of whom were molecularly matched at DRB, DQA1, and DQB1 loci. Nine of these pairs were also HLA-A and HLA-B matched by serology. Six of these nine "HLA-identical" pairs were HLA-A (2 of 6), HLA-B (1 of 6), and HLA-C (6 of 6) mismatched at the sequence level. The mismatched class I alleles of all these pairs had strikingly different sequence motifs in the six specificity pockets of their antigen recognition site, and in five pairs they also had sequence differences at positions implicated in T-cell receptor (TCR) binding. Two of the three pairs who were serologically mismatched for one HLA-A or HLA-B antigen were also sequence mismatched at HLA-C. Finally, 10 of 11 pairs tested expressed different DP sequences. These data indicate that HLA class I, especially HLA-C, and DP sequence mismatches are frequent among unrelated subjects defined as HLA identical by current typing methods. We speculate that these sequence differences may explain, at least in part, the higher incidence of acute GVHD and rejection in unrelated BM transplantation as opposed to transplantation between HLA-identical siblings. Because of their high frequency, the role of HLA-A, HLA-B, HLA-C, and HLA-DP mismatches in transplantation outcome is now amenable to direct study.
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PMID:Frequent HLA class I and DP sequence mismatches in serologically (HLA-A, HLA-B, HLA-DR) and molecularly (HLA-DRB1, HLA-DQA1, HLA-DQB1) HLA-identical unrelated bone marrow transplant pairs. 820 3

The clinical outcomes of unrelated and of family related allogeneic bone marrow transplantation (BMT) were correlated with HLA disparity in a study in which molecular phenotyping of HLA-C was performed for unrelated donor-recipient pairs. The study included 30 patients who underwent BMT from unrelated donors and 43 patients who underwent BMT from family related donors. The unrelated group included 14 full match pairs, 12 class-I-C (molecular HLA-C) mismatched pairs, and 4 haploidentical pairs. The family related group included 9 full match pairs, 19 class-I mismatched pairs, and 15 haploidentical pairs. In the unrelated BMT group, the transplant-related complications of mortality, graft-versus-host disease (GVHD), and graft rejection, were significantly higher in molecular HLA-C mismatched than matched patients (67% vs 14%, P < 0.02; 50% vs 7%, P < 0.02; 42% vs 0, P < 0.02). The actuarial survival and the disease free survival (DFS) at 18 months was better for molecular HLA-C matched than for HLA-C mismatched unrelated transplants: 33% vs 18% (P = 0.065, NS), and 29% vs 16%, respectively. For the family related BMT group, the actuarial survival at 18 months was significantly higher for patients who were fully matched compared to those who were class-I mismatched, or those who were haploidentical pairs: 67%, 37%, and 13% respectively (P < 0.02). The actuarial DFS at 18 months of patients who were fully matched and of those who were class-I mismatched was similar, and better than that of haploidentical patients 45%, 37% (NS) and 13% respectively (P < 0.045). A lower incidence of transplant-related mortality occurred in class-I mismatched, family related (37%) than in locus-C mismatched unrelated patients (67%), and no difference was observed in the fully matched family related and unrelated patients. We conclude that a mismatch in locus C may be detrimental to BMT outcome and should therefore be included as a risk factor in the routine pre-BMT HLA phenotyping.
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PMID:Bone marrow transplantation using unrelated and family related donors: the impact of HLA-C disparity. 893 42

The use of unrelated donors for bone marrow transplantation (BMT) is associated with an increased morbidity and mortality when compared with HLA-identical donors, primarily due to an increased rate of graft-versus-host disease, but also to increased susceptibility to infections and graft failure. HLA matching for donors and recipients is the single most important factor influencing the outcome of BMT. However, unrelated donor selection generally relies on matching only for HLA-A, -B and -DR antigens without considering potential incompatibility for other HLA loci, such as HLA-C, -DQ and -DP. In addition, other factors that affect the outcome of BMT need to be taken into consideration in selecting the best unrelated donor. In this review, we will focus on the effects of HLA-associated factors in determining the result of a transplant procedure. We will also mention other relevant factors, drawing on our experience of laboratory studies performed at The Anthony Nolan Research Institute and clinical studies at the Hammersmith Hospital in London.
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PMID:Factors influencing the outcome of bone marrow transplants using unrelated donors. 925 28

Interest in the complexity of the HLA system and its relevance in the selection of unrelated bone marrow donors has had an important impact on our understanding of the immunogenetics of HLA and non-HLA or minor histocompatibility systems. More than 50 genes on the short arm of chromosome 6, which carries the information for HLA, have been identified and there are more to come. HLA-class I and HLA-class II each have more than 200 alleles, and the number is growing. The HLA-C antigens appear to act as targets for natural killer cells. New inroads have been made in the recognition of the minor histocompatibility antigens HA-1 to -5, which can be recognized by cytotoxic T-cell clones and are inherited in a Mendelian fashion. A mismatch for HA-1 might lead to graft-versus-host disease. The introduction of new technologies, especially polymerase chain reaction, has been immensely helpful in mapping the genetic complexity of HLA. Methodology now allows typing for HLA on the level of DNA in a matter of a few hours and is most useful when selecting a suitable bone marrow donor. The new genetic information available makes it clear that many so-called HLA matched unrelated bone marrow transplants performed in the past were actually mismatched. Nevertheless, many of them had a good clinical outcome. It is clear that one of the most important challenges is to determine which mismatched transplants will fare well and which should be avoided. Recent findings in organ transplantation might be helpful here.
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PMID:Immunogenetics. 937 18

The dysregulation of cytokines is thought to play a role in the inflammatory and allospecific components of graft-versus-host disease (GVHD) and graft rejection (GR) post allogeneic bone marrow transplantation (BMT). Both complications occur post unrelated BMT at significantly higher frequencies than post BMT from identical sibling donors. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta, IL-6, IL-10 and IL-12 following unrelated BMT were measured to examine cytokine dysregulation involvement in GVHD and GR. Of the 26 patients included in this study, 15 developed GVHD (14 acute; 1 acute and chronic), 5 had GR and 6 had uneventful BMT. TNF-alpha was markedly elevated in 13/15 of the patients with GVHD and in 3/5 patients with GR. IL-6 was elevated in patients with acute GVHD and with GR. IL-12 levels were similar in pre- and post-BMT sera. No correlation was found between HLA-C match and cytokine levels. In conclusion, a positive correlation was found between elevated levels of TNF-alpha, IL-6 and IL-10, and GVHD (p < 0.05, p < 0.005 and p < 0.002 respectively) and GR (p < 0.01).
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PMID:Dysregulation of inflammatory cytokines in unrelated bone marrow transplantation. 982 41

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.
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PMID:Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection. 984 54

Because of the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes, a person's natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. This study investigated the role of NK cell alloreactivity in human HLA haplotype-mismatched hematopoietic stem cell transplantation and, specifically, the role of the three major NK specificities, ie, those for HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR epitope incompatibility and functional analyses of donor NK cell clones predicted donor NK cells could cause graft-versus-host (GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor origin were obtained from transplanted recipients and tested for lysis of recipient's cryopreserved pretransplant lymphocytes. Despite the absence of GVH disease, we detected high frequencies of NK clones which killed recipient's target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which was missing in the recipient. The alloreactive NK clones also killed the allogeneic leukemia. Transplants from these KIR epitope incompatible donors had higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.
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PMID:Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 1038 30

The impact of donor-recipient DPA1 and DPB1 matching was examined in 122 unrelated bone marrow transplant pairs. All pairs were serologically matched at the time of transplantation for HLA class I and II and a majority also DRB1 allele matched. Retrospective A, B, C, DRB1, DQA1, DQB1 in addition to DPA1 and DPB1 allele matching was performed by molecular techniques. The percentage of pairs that were allele matched was as follows; HLA-A = 91% (n = 80), HLA-B = 94% (n = 80), HLA-C = 78% (n = 80), HLA-DRB1 = 96% (n = 122), HLA-DQA1 = 99% (n = 80), HLA-DQB1 = 92% (n = 122). 92 recipient/donor pairs with informative clinical data were available for analysis. DPA1 identity (no incompatibility in either direction) was observed in 57% and DPA1 compatibility in 76% of pairs with no apparent beneficial effect of matching on patient survival or Graft Versus Host Disease (GVHD). DPB1 identity was observed in 11% and compatibility in 27% of pairs. A significant improvement in patient survival was observed in DPB1 matched compared to one DPB1 mismatch (p < 0.01) and combined one and two DPB1 mismatched transplants (p = 0.03). This beneficial effect remained when allele mismatches at HLA-A, B, C, DRB1, DQA1, DQB1 were excluded (p = 0.05, p = 0.03, respectively). There was a significant association of increased frequency of severe GVHD (grades III-IV) compared to mild GVHD (grades I-II) with DPB1 mismatched transplants compared to DPB1 matched transplants (p = 0.04). In DPB1 mismatched transplants an association between patient survival and matching for individual DPB1 polymorphic regions was not observed; however in the HLA-A, B, DRB1, DQA1, DQB1 allele matched transplants a non significant increase in the frequency of Grade IV GVHD was observed in recipients who were negative compared to those who were positive for DPB1 alleles coding for glutamic acid at position 69.
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PMID:Matching for HLA DPA1 and DPB1 alleles in unrelated bone marrow transplantation. 1040 3

Disparity for HLA in unrelated donor bone marrow transplantation (BMT) increases the risk of graft rejection and graft-versus-host disease (GVHD) and may compromise transplant outcome. We have compared the outcome of matched and mismatched transplants from unrelated donors in 137 children with acute lymphoblastic leukemia (ALL). Their disease status was complete remission (CR)-1, 24 patients; CR-2, 88 patients; CR-3, 18 patients; CR-4, 2 patients; and relapse, 5 patients. CAMPATH monoclonal antibodies were used for T-cell depletion and cyclosporin A was given to 134 children together with short-course methotrexate in 43, mainly when there was HLA disparity. Fifty-two donor/recipient pairs were HLA-mismatched, 41 at HLA-A and -B and 11 at HLA-DR and -DQ loci. Overall graft failure was increased in recipients of marrow mismatched at either HLA-A, -B, -DR, or -DQ (15.7% v 4.8%; P =.057) mainly because there was a higher proportion of children with primary graft failure (11. 8% v 1.2%; P =.012). The presence of an HLA-C locus mismatch did not independently increase the likelihood of graft failure. There was no significant difference in the incidence of acute GVHD >/= grade 2 between the matched and mismatched groups (P =.849). For patients in CR-2, the risk of relapse post-BMT was significantly lower if leukemic relapse occurred off-treatment (P =.005). The Kaplan-Meier overall and leukemia-free survival (LFS) estimates for recipients of matched and mismatched BMT, respectively, at 36 months were 49% versus 42% (P =.380) and 45% versus 40% (P =.654). Although HLA mismatching results in an increased occurrence of primary graft failure with T-cell-depleted allografts, it allows more donors to be identified rapidly for children with ALL without compromising overall transplant outcome.
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PMID:Children with acute lymphoblastic leukemia who receive T-cell-depleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome. 1049 94


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