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)

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 International Marrow Unrelated Search and Transplant (IMUST) Study has prospectively assessed outcome of unrelated donor BMT (UD-BMT) in comparison with a matched cohort of patients treated by HLA-identical sibling BMT (ID-BMT). We report an interim analysis of the first 165 UD-BMT and 368 ID-BMT. Eighty-two percent of UD-BMT pairs were matched by serology for HLA-A, B and DR, 10% were less well matched and HLA matching data was incomplete in 8%. The Kaplan-Meier estimated probability of survival until day 400 was 0.42 (95% confidence limits 0.33-0.51) after UD-BMT and 0.62 (0.56-0.68) after ID-BMT (p = < 0.001). Probability of engraftment by day 100 was 0.90 (0.85-0.95) and 0.95-0.99) after UD-BMT and ID-BMT, respectively (p = < 0.001). Cumulative probability of acute GVHD by day 100 was 0.52 (0.45-0.60) and 0.42 (0.37-0.47) after UD-BMT and ID-BMT, respectively (p = 0.009). After UD-BMT, 52% of patients with early disease survived until day 400 (40-64%) and 27% (14-40%) with advanced disease (p = < 0.001). Multifactorial analysis of survival showed success was related to the centre's experience of UD-BMT and this effect was modified by conditioning protocol. Increased probability of survival after UD-BMT in centres with most experience of the procedure is novel finding. We conclude UD-BMT is a more difficult procedure than ID-BMT but results are acceptable in patients with early disease and when UD-BMT is carried out in experienced centres.
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PMID:Prospective evaluation of unrelated donor bone marrow transplantation. The International Marrow Unrelated Search and Transplant (IMUST) Study. 827 37

One hundred twelve patients less than 36 years old received marrow grafts from unrelated donors as treatment for hematologic malignancy. Seventy donor/recipient pairs were phenotypically identical for HLA-A, -B, and -D, while 42 had a "minor" disparity at one HLA locus. There was an increase in the risk of acute graft-versus-host disease (GVHD) in patients receiving HLA-partially matched grafts compared with those receiving HLA-matched grafts (51% v 36% probability of grades III-IV acute GVHD). However, in this cohort of patients, there was no significant difference in survival (at 1.5 years, 46% v 51% for good-risk patients, 44% v 30% for poor-risk patients). This finding suggests that some degree of HLA disparity can be tolerated in young patients transplanted from unrelated donors for malignant disease, thus making transplantation an option available to larger numbers of patients.
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PMID:Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus. 841 95

Between January 1985 and March 1992, 48 patients with chronic phase CML underwent BMT from volunteer unrelated donors (MUD) serologically identical at HLA-A, B and DR loci. 19 patients received donor marrow ex vivo T-cell depleted (EX-TCD) with Campath monoclonal antibodies. 29 patients received unmanipulated donor marrow with CsA/MTX GVHD prophylaxis; 28 received additional intravenous antilymphocyte therapy from day +1 to +5 (IN-TCD). Overall 26 patients survive at median follow up of 362 days; actuarial survival at 3 years is 50%. 3 patients have sustained haematological relapse; actuarial leukaemia-free survival is 38%. There is no difference in overall survival between the EX-TCD and IN-TCD groups, but primary graft failure (n = 4) occurred only in the EX-TCD group, while GVHD (grade II or greater) occurred more frequently in the IN-TCD group (61% vs. 29%, p = 0.084). The optimum method for GVHD prophylaxis in MUD BMT remains uncertain.
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PMID:Matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia in chronic phase: comparison of ex vivo and in vivo T-cell depletion. 844 31

Precise HLA typing is crucial in the selection of marrow donors for the treatment of patients with hematologic malignancy. This study was undertaken to characterize an unusual variant of HLA-A30, designated HLA-A30JS, identified in a patient with leukemia who was a candidate for unrelated donor marrow transplantation. IEF and cDNA-sequencing analyses revealed that A30JS is a novel variant differing from the IEF-defined subtype A30.1 (encoded by the A*3002 allele) by a single amino acid substitution. An unrelated marrow donor was identified who was matched with the patient for HLA-A3, B7, B18, DR2, and DR3, but mismatched within the A30 antigen family for the two distinct alleles A*3002 versus A30JS. These two alleles encode a single amino acid substitution, Arg versus Gly, at position 56 in the alpha 1 domain. Position 56 is located outside the antigen-binding cleft of the class I molecule, suggesting that this substitution may not be functionally significant. Transplantation from this donor was performed and the patient is surviving free of leukemia for more than 700 days after transplant. The maximum acute GVHD observed was scored as grade II, but immunosuppressive therapy is still required for control of chronic GVHD. This study demonstrates how the molecular characterization of a novel HLA-A allele in a patient could facilitate the selection of an unrelated donor. Lacking this information, it would not have been possible to select a donor for this patient, and thus apparently successful marrow transplant could not have occurred.
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PMID:Selection of an unrelated donor for marrow transplantation facilitated by the molecular characterization of a novel HLA-A allele. 845 35

The role of HLA-DPB1 disparity in the development of acute graft-versus-host disease (GVHD) following unrelated donor (URD) marrow transplantation is unknown. We studied 129 patients who underwent marrow transplantation from HLA-A, -B, -DRB, and -DQB matched URDs to determine whether matching for HLA-DPB1 alleles significantly decreased the risk of developing acute GVHD. HLA-DPB1 alleles were determined by sequence-specific oligonucleotide hybridization and by the number of patient DPB1 alleles not shared by the donor scored. The Kaplan-Meier probability of developing grades II to IV acute GVHD was determined for patients incompatible for zero (group A), one (group B), or two (group C) DPB1 alleles. Of the 129 pairs, there was no recipient DPB1 incompatibility in 28 (22%), one DPB1 mismatch in 72 (56%), and two DPB1 mismatches in 29 (22%). The probability of grades II to IV acute GVHD was 0.69 (0.50, 0.86) for group A, 0.83 (0.73, 0.91) for group B, and 0.72 (0.56, 0.87) for group C (P = .63). These results indicate that matching patients and unrelated donors for HLA-A, -B, -DRB, and -DQB does not predict for matching at DPB1. However, recipient incompatibility for DPB1 alleles does not detectably influence the risk of acute GVHD. Therefore, HLA-DP disparity should not be used as an exclusion criterion for donor selection in unrelated marrow transplantation.
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PMID:The role of HLA-DPB1 disparity in the development of acute graft-versus-host disease following unrelated donor marrow transplantation. 846 76

As compared with related HLA-identical sibling donors, bone marrow transplantation (BMT) with phenotypically HLA ABDR-compatible unrelated donors is associated with increased mortality. This may be due to hidden HLA incompatibilities not detected by conventional typing. We have analyzed 44 unrelated patient-donor pairs who were matched for HLA-A, -B, and -DR by routine tissue typing. Our comprehensive HLA typing approach consisted of serology, cytotoxic T-cell precursor (CTLp) tests, T-cell cloning, oligotyping, and DNA sequencing. Using these techniques, we identified numerous HLA allele mismatches not detected by the previously applied routine typing. Twenty-four patient-donor pairs were highly matched and had a low CTLp frequency, whereas the remaining 20 pairs were allele-mismatched for HLA-A, -B, -C, -DR, -DQ antigens and/or had a positive result of the CTLp test. Patient and donor age, diagnosis, and treatment did not differ significantly between the matched and mismatched transplants. The probability for severe acute graft-versus-host disease grades III-IV was 21% in the matched and 47% in the mismatched patients (P = .0464). Transplant-related mortality was 21% and 57% (P = .0072) and actuarial patient survival rates at 3 years were 61% and 13% (P = .0005). We conclude that both HLA class I and class II allele mismatches between unrelated phenotypically ABDR-compatible patient-donor pairs are frequent and associated with increased incidence of posttransplant complications.
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PMID:High resolution HLA matching associated with decreased mortality after unrelated bone marrow transplantation. 863 8

Analysis of a large number of unrelated bone marrow transplantations (BMT) has shown that HLA-DP incompatibility did not detectably influence the risk for acute graft-versus-host disease (aGVHD). Accordingly, it was proposed that HLA-DP determinants did not function as transplantation antigens in the same way as HLA-A, -B, or -DR. We have previously shown that HLA-DP (as well as HLA-A, -B, -DQ, or -DR)-specific T cells could be isolated from skin biopsies of patients who developed an aGVHD after semiallogeneic BMT. Nevertheless, whether a single HLA-DP mismatched allele could induce a detectable allo-specific reaction in vivo after BMT remained to be established. To directly address this issue we studied one patient who presented aGVHD after receiving purified CD34+ bone marrow (BM) cells from an unrelated donor with a single HLA-DP mismatch in the GVHD direction. To characterize the immunological events associated with GVHD, we analyzed the peripheral T cell repertoire, the T cell receptor Vbeta diversity, and the specificity of T cells invading a skin biopsy at the onset of GVHD. Our results demonstrated that a large fraction of skin-infiltrating lymphocytes, which expressed diverse T cell receptors, were reactive against this single HLA-DPB1 *0501 mismatch and consequently that a single HLA-DP mismatch between BM donor and recipient can activate a strong T cell response in vivo.
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PMID:Acute graft versus host disease due to T lymphocytes recognizing a single HLA-DPB1*0501 mismatch. 869 Jul 80

Twenty-eight out of 31 children that underwent bone marrow transplantation (BMT) from unrelated donors between 1984 and 1995 received HLA-A, HLA-B and HLA-DR matched unrelated donor (MUD) marrows as defined by serologic HLA class I and genomic HLA class II typing. Compared with 28 case-matched controls transplanted with HLA identical sibling donors, MUD patients received a more intensive conditioning. Twenty-six patients (93%) engrafted while two died of septicaemia during the aplastic phase. Two patients rejected their grafts and four developed Evans syndrome. All controls engrafted without incidents of rejection or Evans syndrome. The probability of acute graft-versus-host disease (GVHD) of grade II or above was 27% after MUD-BMT and 7% in the controls. The 5-year probability of survival was 60% in MUD patients and 89% after sibling BMT (p = 0.03). Leukaemia-free survival was 60% with one relapse in the MUD patients, and 59% with five relapses in the sibling group. Three children who received a mismatched donor marrow died, two of severe GVHD and one after graft rejection. In conclusion, today, a matched unrelated donor BMT is an acceptable alternative for many children who need a BMT but lack a suitable related donor.
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PMID:Bone marrow transplantation in children using unrelated donors at Huddinge Hospital. 869 91

Six patients with high risk haematological malignancies received peripheral blood progenitor cells (PBPC) from unrelated donors. Four patients received PBPC as primary treatment and 2 following graft failure. Five donors were HLA-A, -B and -DR identical and one had a one antigen mismatch. PBPC were mobilised by treatment with G-CSF for 4-6 days. The patients received a range of 3.4 to 11.4 x 10(8) mononuclear cells/kg and 1.0 to 15.0 x 10(6) CD34 positive cells/kg. Four patients were given Campath 1G and 2 ATG prior to transplantation. The patient with one antigen mismatch received in vitro T-cell depleted PBPC using Campath 1M. All received cyclosporin and 5 in addition methotrexate. All recipients were given G-CSF and all engrafted. The patients developed no or mild acute GVHD. Two patients had limited chronic GVHD of the skin. The recipient of the mismatched graft died from extensive chronic GVHD. Three patients have had a relapse and two are alive and free of leukaemia.
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PMID:Transplantation of peripheral blood progenitor cells from unrelated donors. 872 40


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