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)

Disparity for the minor histocompatibility antigen HA-1 between patient and donor has been associated with an increased risk of acute graft-versus-host disease (GvHD) after allogeneic human leucocyte antigen (HLA)-identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA-A2-positive patients who received an HLA-identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA-1 antigen mismatch. Disease-free survival and overall survival were also analysed. We detected 34 patient-donor pairs mismatched for HA-1 antigen (15.8%). Grades II-IV acute GvHD occurred in 51.6% of the HA-1-mismatched pairs compared with 37.1% of the non-mismatched. The multivariate logistic regression model showed statistical significance (P: 0.035, OR: 2.96, 95% CI: 1.07-8.14). No differences were observed between the two groups for grades III-IV acute GvHD, chronic GvHD, disease-free survival or overall survival. These results confirmed the association between HA-1 mismatch and risk of mild acute GvHD, but HA-1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival.
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PMID:Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation. 1156 88

Disparities at minor histocompatibility antigens (mHA) are thought to be responsible for acute graft-versus-host disease (aGVHD) in patients receiving bone marrow transplantation (BMT) from a human leucocyte antigen (HLA)-matched donor. Although some mHA have been identified in humans, their role in aGVHD has not. Patients (n = 150) receiving a BMT from an HLA-matched donor were investigated for a correlation between aGVHD and donor/recipient incompatibility for seven polymorphisms previously proposed for mHA (HA-1, H-Y, CD31-codon 125, CD31-codon 563, HPA-1, HPA-3 and HPA-5). Only mismatch at CD31-codon 563 predicted grade II-IV aGVHD. The risk derived from CD31-codon 563 mismatch was the same as that derived from the use of bone marrow from an unrelated donor. We suggest that donor/recipient compatibility at CD31-codon 563 should be added to HLA-typing for donor selection and/or adjustment of aGVHD prophylaxis.
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PMID:Donor-recipient incompatibility at CD31-codon 563 is a major risk factor for acute graft-versus-host disease after allogeneic bone marrow transplantation from a human leucocyte antigen-matched donor. 1156 91

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymidine kinase (HSV-tk) gene transduction of donor T cells followed by treatment with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by distinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine antibody infusion or genetically deficient mice. This study takes a different approach that allows simultaneous investigation into both the mechanisms underlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 promoters (IL-2-tk and IL-4-tk, respectively) was used, thus allowing investigation into the roles of T1 and T2 cells in ongoing GVHD reactions. To assess treatment rather than prevention of GVHD, GCV was started at peak disease. Remarkably, treatment at this late time point rescued mice from the clinical effects of GVHD caused by T cells expressing either transgene. Thus, both T1 and T2 cells play an important role in clinical GVHD in a minor histocompatibility antigen-mismatched setting. In addition, because clinical disease was reversible even at its maximum, these observations provide controlled evidence that this strategy of treating ongoing GVHD could be effective clinically.
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PMID:Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. 1171 76

Relapse of leukemia remains a common event after allogeneic bone marrow transplantation, despite potential donor antihost alloreactivity present in most transplants. This work examined posttransplant relapse of the DBA/2 P815 mastocytoma in a murine model of MHC-matched, minor histocompatibility antigen (mHAg)-mismatched bone marrow transplantation (BALB/c donors into DBA/2 recipients). Antihost alloreactivity was associated with reduction of posttransplant tumor burden and prolongation of survival, but posttransplant relapse commonly occurred. No evidence of acquired resistance to immune control was found in 12 relapse reisolates. Relapse tumors remained sensitive to donor antihost CTLs in vitro, suggesting continued expression of mHAgs. Reisolates also continued to express Fas. However, loss of posttransplant alloreactivity was observed at 3 weeks. This was temporally associated with the time of relapse. Antihost alloreactivity could be reactivated in stable graft-versus-host disease-free recipients by immunization with host cells. The results of this study suggest that one mechanism for relapse after bone marrow transplant is acquired tolerance of allogeneic minor histocompatibility antigens and that posttransplant immunotherapy directed against mHAgs may induce antitumor activity.
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PMID:Down-regulation of antihost alloreactivity after bone marrow transplant permits relapse of hematological malignancy. 1178 79

T-cell receptors (TCRs) of a series of minor histocompatibility antigen (mHag) HA-1-specific cytotoxic T-cell (CTL) clones isolated from 3 unrelated patients have been shown to use the same BV6S4A2 segment with conserved amino acids in the CDR3Vbeta region. This suggests that different HA-1-specific TCRs interact similarly to the HA-1 antigen presented by the HLA-A2 molecule. The mHag HA-1 forms an immunogenic complex with HLA-A2 and induces strong alloimmune responses after stem cell transplantation (SCT). It was questioned, therefore, whether clonal and polyclonal HA-1-specific CTL responses can be antagonized by a single TCR antagonistic peptide. Functional analysis and molecular modeling of single and double amino acid substitutions of TCR contact residues, adjacent residues, and HLA-A2 binding residues resulted in 4 peptides with high affinity for HLA-A2 and with the capacity to inhibit the lysis of endogenously HA-1-expressing EBV-BLCL by 3 different HA-1-specific CTL clones. These peptides also efficiently antagonized HA-1-specific polyclonal CTL lines derived from 3 patients and significantly reduced the number of interferon-gamma-producing HA-1-specific CTL of a patient with graft-versus-host disease after HA-1-mismatched SCT. These data show that general TCR antagonists can be developed that inhibit HLA-A2-restricted HA-1-specific CTL responses on the clonal and the polyclonal level and that TCR antagonists may modulate the immunodominant mHag HA-1 responses.
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PMID:General T-cell receptor antagonists to immunomodulate HLA-A2-restricted minor histocompatibility antigen HA-1-specific T-cell responses. 1180 3

Powerful immunologically-mediated antitumor efforts can be observed in allogeneic hematopoietic stem cell transplantation. In the absence of specific immune interventions, this graft versus tumor effect is closely associated with graft versus host disease. In the work summarized here, the influence of cellular tumor vaccines on graft versus tumor activity and graft versus host disease is examined in a murine model of MHC-matched, minor histocompatibility antigen-mismatched bone marrow transplantation. The experiments have generated the following conclusions. First, complex cellular vaccines, which include recipient minor histocompatibility antigens, when administered to allogeneic donors generate powerful graft versus tumor effects but also induce unacceptable exacerbations of graft versus host disease. Second, cellular tumor vaccines, which contain recipient minor histocompatibility antigens, can be administered to transplant recipients after transplant without significant exacerbation of GVHD and with retention of clinically significant graft versus tumor effects. Third, immunization of donors with molecularly defined tumor-associated antigens, which are not recipient minor histocompatibility antigens, can be coupled with post-transplant immunization of recipients with cellular vaccines without exacerbation of GVHD.
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PMID:Influence of tumor vaccines on graft versus tumor activity and graft versus host disease in allogeneic bone marrow transplantation. 1200 52

To understand the relationship between host antigen-presenting cells (APCs) and donor T cells in initiating graft-versus-host disease (GVHD), we followed the fate of host dendritic cells (DCs) in irradiated C57BL/6 (B6) recipient mice and the interaction of these cells with minor histocompatibility antigen- (miHA-) mismatched CD8+ T cells from C3H.SW donors. Host CD11c+ DCs were rapidly activated and aggregated in the T cell areas of the spleen within 6 hours of lethal irradiation. By 5 days after irradiation, <1% of host DCs were detectable, but the activated donor CD8+ T cells had already undergone as many as seven divisions. Thus, proliferation of donor CD8+ T cells preceded the disappearance of host DCs. When C3H.SW donor CD8+ T cells were primed in vivo in irradiated B6 mice or ex vivo by host CD11c+ DCs for 24-36 hours, they were able to proliferate and differentiate into IFN-gamma-producing cells in beta(2)-microglobulin-deficient (beta(2)m(-/-)) B6 recipients and to mediate acute GVHD in beta(2)m(-/-) --> B6 chimeric mice. These results indicate that, although host DCs disappear rapidly after allogeneic bone marrow transplantation, they prime donor T cells before their disappearance and play a critical role in triggering donor CD8+ T cell-mediated GVHD.
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PMID:Preterminal host dendritic cells in irradiated mice prime CD8+ T cell-mediated acute graft-versus-host disease. 1202 Dec 49

Donor lymphocyte infusions (DLI) can induce a graft-versus-leukaemia (GvL) reaction in patients with relapsed disease. However, the mechanisms involved in remission induction are not completely known. A patient with chemotherapy-refractory relapse 1 year after human leucocyte antigen (HLA)-identical, unrelated stem cell transplantation (SCT) for bcr/abl-positive common acute lymphoblastic leukaemia (ALL) received a DLI from the original donor, and achieved complete cytogenetic and molecular remission concomitantly with extensive graft-versus-host disease (GvHD). Seven CD8+, donor-derived, alloreactive T-cell clones were generated by stimulating post-DLI remission cells with the patient's pretransplant mature dendritic cells. The minor histocompatibility antigen (mHag) recognized by these T-cell clones was identified as HA-1, a mHag associated with acute GvHD after SCT. Our finding provides evidence of HA-1-associated GvL effects after DLI that paralleled the eradication of full-blown, chemotherapy-refractory ALL relapse after allogeneic SCT.
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PMID:Induction of HA-1-specific cytotoxic T-cell clones parallels the therapeutic effect of donor lymphocyte infusion. 1206 Jan 33

Allogeneic bone marrow transplantation (BMT) is a treatment modality with the potential of curing otherwise lethal diseases. The predominant indications for BMT are haematological malignancies. In BMT alloreactivity plays a pivotal role for the outcome. Graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) are correlated manifestations of alloreactivity. Severe GvHD is one of the main causes of morbidity and mortality post-BMT. In the absence of GvL the risk of relapse is high. The main effector cells are T lymphocytes. Donor leukocyte infusion (DLI) for treatment of leukaemic relapse after BMT can induce durable remissions. DLI causes GvHD in the majority of the responding patients. However, a GvL effect may be present without evidence of GvHD and vise versa. The importance of alloreactivity for the treatment outcome prompted the interest for a predictive test of alloreactivity. Interleukin 2 (IL-2) producing helper T lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis (LDA) in the graft-versus-host direction were explored. The HTLp assay was optimized and the sources of error minimized to ensure sensitive and reproducible results. The IL-2 dependent cell line, CTLL-2 was optimized to detect 0.6 pg IL-2. UV-B irradiation of the cells was demonstrated to effectively terminate proliferation of the responder cells and thus allow IL-2 to be detected in the whole culture volume. The design of the assay was explored by Monte Carlo simulations resulting in a design yielding frequencies with a coefficient of variation of 20% in the range of 1:20,000-1:1,000,000. The influence of autoreactivity of the donor and recipient cells was minimized as well as the risk of the stimulator cells producing IL-2. The HTLp frequencies correlated with the degree of human leukocyte antigen (HLA) disparity and the assays were able to detect minor histocompatibility antigen mismatches. The HTLp frequencies of 28 HLA-identical sibling BMT pairs and 20 HLA-matched unrelated and partially HLA-matched related BMT pairs were determined. HTLp frequencies from the HLA-identical sibling BMT pairs had a median of 1:557,362 (range 1:9.511 to < 1:2,500,000). The HTLp frequencies from the HLA-matched unrelated and partially HLA-matched related BMT pairs had a median of 1:88,110 (range 1:4.139-1:736,123). Analysis of the HLA-identical sibling BMT pairs in a high and a low HTLp frequency group above and below 1:500,000 showed a trend towards a higher risk of acute GvHD > or = grade II and a significantly higher risk of chronic GvHD in the high HTLp frequency group. This group had a significantly lower risk of relapse as well as a significantly better overall survival and leukaemia free survival. The HLA-matched unrelated and partially HLA-matched related BMT pairs were split evenly in a high and a low HTLp frequency group above and below 1:90,000. There was a significantly higher risk of acute GvHD > or = grade II and a trend towards a higher treatment related mortality (TRM) in the high HTLp frequency group. There were no differences in chronic GvHD, risk of relapse, overall survival and leukaemia free survival. Analyzing all 48 patients the risk of acute GvHD > or = grade II and TRM was significantly higher with HTLp frequencies > 1:100,000 and there was a trend towards a higher risk of relapse with low HTLp frequencies < 1:400,000. Patients in the intermediate HTLp frequency group 1:100,000-1:400,000 had a trend towards improved survival. The HTLp frequency seems to detect clinically significant differences in alloreactivity, that can be useful in donor selection, graft-engineering, T cell add-back and the pharmacological immunosuppression used after BMT.
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PMID:Alloreactivity and the predictive value of anti-recipient specific interleukin 2 producing helper T lymphocyte precursor frequencies for alloreactivity after bone marrow transplantation. 1206 93

A murine model of minor histocompatibility antigen-mismatched bone marrow transplantation (BMT) was used to study the role of timing of donor lymphocyte infusion (DLI) in eliciting graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity. We gave DLI at weeks 3 and 12 after BMT and related its ability to induce a GVL effect with (1) evolution of T cell chimeric status and (2) the extent to which DLI could elicit lymphohematopoietic GVH (LHGVH) reactivity. All mice remained free of GVH disease, but only week 3 DLI chimeras exhibited a significant GVL response when challenged with host-type leukemia cells. In these week 3 DLI chimeras, host-reactive T cells were found to proliferate in vivo (5- [and-6]-carboxyfluorescein diacetate, succinimidyl esther [CFSE]-labeled DLI inocula, TCR-Vbeta6(+) T-cell frequency) and T-cell chimerism rapidly converted from mixed into complete donor type, indicating the occurrence of LHGVH reactivity. In week 12 chimeras, DLI elicited none of the activities noted at week 3. Yet, in both instances, splenocytes, recovered following DLI, generated an equally strong antihost proliferative response in a mixed lymphocyte reaction, thereby arguing against a decisive role of regulatory cells. The lack of in vivo LHGVH reactivity after week 12 DLI was associated with a substantially increased level of pre-existing host-type T-cell chimerism. We conclude that elicitation of a GVL effect may require LHGVH reactivity and that the reason why timing of DLI was critical for obtaining LHGVH reactivity and the desired GVL effect may lie in the evolution of chimeric status. A possible direct involvement of residual host-type antigen-presenting cells in eliciting LHGVH reactivity after DLI should be studied using models that allow chimerism analysis in non-T-cell lineages.
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PMID:Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants. 1217 14


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