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 main advantage of allogeneic stem cell transplantation over autologous stem cell transplantation for hematologic malignancies is the ability to perform cellular immunotherapy using donor-derived immune effector cells after transplantation. In HLA-matched allogeneic stem cell transplantation, the beneficial graft-versus-leukemia effect of donor lymphocytes appears to be caused mainly by alloreactive T cells that are capable of recognizing minor histocompatibility antigens on the malignant cell population from the patient. The tissue distribution of minor histocompatibility antigens probably determines the clinical result of T-cell responses against these antigens. Whereas T cells recognizing broadly expressed antigens cause not only graft-versus-leukemia but also graft-versus-host disease, T cells recognizing minor histocompatibility antigens specifically expressed on hematopoietic cells may mainly eliminate hematopoietic cells from the recipient, including the malignant cells, without affecting donor hematopoiesis or normal nonhematopoietic tissues. Graft-versus-host disease may still occur because of the induction of inflammatory responses against hematopoietic cells in the tissues. Vaccination of patients after transplantation or vaccination of stem cell donors before transplantation using minor histocompatibility antigen-specific peptides, production of minor histocompatibility antigen-specific T cells, and redirection of T-cell specificity by gene transfer of T-cell receptors may be strategies to eradicate specifically the malignant cells after allogeneic stem cell transplantation.
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PMID:Minor histocompatibility antigens as targets of graft-versus-leukemia reactions. 1239 71

A murine model of minor histocompatibility antigen (miHCag)-mismatched bone marrow transplantation (BMT) was used to study the development of immunoregulatory cells in the posttransplantation period and their possible involvement in the dissociated graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity of posttransplantation donor lymphocyte infusions (DLIs). DLI, applied immediately after BMT, induced GVH disease (GVHD), but when DLI was delayed for 3 weeks, GVHD was avoided while a distinct GVL response was allowed to develop. A population of Mac1+Ly6-G+Ly6-C+ immature myeloid cells, found in small numbers in normal mice, strongly expanded in spleens of chimeras, reaching a maximum level at week 3 and returning to base level by week 12. Upon isolation, these cells exhibited interferon-gamma (IFN-gamma)-dependent, nitric oxide (NO)-mediated suppressor activity toward in vitro alloresponses, suggesting that, after in vivo DLI, they are activated by IFN-gamma to produce NO and suppress GVH reactivity. Because not only alloactivated T-cell proliferation but also leukemia cell growth was found susceptible to inhibition by exogenous NO, in vivo activation of these cells after DLI may explain the occurrence of a GVL effect despite suppression of GVHD. This suggested sequence of events was supported by the finding that the ex vivo antihost proliferative response of spleen cells, recovered shortly after in vivo DLI, was characterized by strong mRNA production of the monokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-alpha) and of inducible nitric oxide synthase (iNOS). Our data suggest that transiently expanding Mac1+Ly6-G+Ly6-C+ immature myeloid cells (probably as a result of extramedullary myelopoiesis) may play a role in controlling GVH while promoting GVL reactivity of DLI after allogeneic BMT.
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PMID:Transient expansion of Mac1+Ly6-G+Ly6-C+ early myeloid cells with suppressor activity in spleens of murine radiation marrow chimeras: possible implications for the graft-versus-host and graft-versus-leukemia reactivity of donor lymphocyte infusions. 1267 88

After allogeneic hematopoietic cell transplantation (HCT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse requires that calculated measures be taken to reduce GVHD pathology while retaining the graft-versus-leukemia (GVL) effect. We sought to determine whether donor CD4(+)CD25(+) regulatory T cells could control ongoing GVHD, thereby providing an initial window of time in which the alloreactive anti-host response is permitted to begin, with the intent of most effectively eliminating residual leukemia cells. Prevention of lethal GVHD by infusion of donor CD4(+)CD25(+) cells early after HCT (day 2) was achieved across a major histocompatibility complex barrier in the haploidentical C3H-->(B6xC3H)F(1) model. However, in vitro expansion of donor CD4(+)CD25(+) T cells, stimulated by recipient cells in the presence of high-dose interleukin-2, was required for successful regulation. In contrast, in the major histocompatibility complex-matched, minor histocompatibility antigen-disparate, CD8-mediated B10.BR-->CBA GVHD model, lethal disease could be completely prevented by a single infusion of freshly isolated donor CD4(+)CD25(+) cells administered as late as 10 days after HCT. Of importance, this late regulatory effect required only a 3:1 ratio of effector CD8:CD4(+)CD25(+) T cells, indicating a strong potential for the delayed infusion of CD4(+)CD25(+) cells to control GVHD across minor histocompatibility antigen barriers. Furthermore, this regulation did not interfere with complete and lasting donor engraftment of the hematopoietic compartment. Of most significance, the day 10 infusion of donor CD4(+)CD25(+) cells into CBA HCT recipients that had been challenged with the MMCBA6 myeloid leukemia cell line did not block an effective GVL response, despite reducing lethal GVHD. These results suggest that donor CD4(+)CD25(+) T cells infused soon after transplantation can ameliorate the development of GVHD without sacrificing a sufficient GVL effect.
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PMID:Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. 1272 Feb 17

Incompatibility of minor histocompatibility antigen (mHa) is a major cause of acute graft-versus-host disease (GVHD) following bone marrow transplantation in human leukocyte antigen (HLA)-matched donor-recipient pairs. To avoid acute GVHD, as many mHa genes as possible need to be identified. In this study, we introduce a comparison of two proportions as an association test for detecting mHa genes in HLA-matched pairs with and without GVHD. Assuming multiple mHa loci, each with two alleles, we evaluated the effects of (1). minor allele frequency of the mHa locus of interest (denoted by p), and (2). probability of GVHD developing in a donor-recipient pair being incompatible at an mHa locus (denoted by r) on the powers of association tests for unrelated pairs and for sib pairs. Our results showed that based on a candidate gene approach, an mHa gene with high p and r values can be detected by the association test with a small sample size. Application of the present method to the Japanese population revealed that the association test for unrelated pairs is more suitable for detecting an mHa gene with a high r value than that for sib pairs. The present method will be helpful to researchers who evaluate the power of association study in advance.
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PMID:Power of association test for detecting minor histocompatibility gene causing graft-versus-host disease following bone marrow transplantation [correction]. 1368 Feb 98

The identity of cells within squamous epithelia that represent primary targets in acute graft-versus-host disease (GVHD) has been an enigma. Murine effector T cells implicated in the alloresponse by Vbeta complementarity-determining region-3 spectratype analysis were detected with a Vbeta-specific monoclonal antibody within discrete microdomains of tongue (lingual) squamous epithelium. These microdomains, termed rete-like prominences (RLPs), are similar to the rete ridges of human skin. Cells forming the basal layer of RLPs and of human skin rete ridges were shown to express a distinctive pattern of keratin expression defined by antibodies to cytokeratin 15 (K15). In experimental murine GVHD elicited across minor histocompatibility antigen barriers (miHA), early lesions involved selective apoptosis and loss of K15(+) staining within lingual RLPs. An in vitro organ culture model designed to investigate target cell injury by short-term exposure to tumor necrosis factor-alpha and interleukin-1beta, mediators relevant to GVHD, showed a similar pattern of apoptosis and loss of K15(+) reactivity within RLPs. In aggregate, these findings establish a novel cytoskeletal marker for target epithelial subpopulations that should facilitate evaluation of mechanisms of host cell injury in GVHD. These data may also enable the development of therapeutic approaches to abrogate disease at the level of target cell blockade.
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PMID:An epithelial target site in experimental graft-versus-host disease and cytokine-mediated cytotoxicity is defined by cytokeratin 15 expression. 1450 58

The regulation of graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T) effect is the most important issue in allogeneic stem cell transplantation. Although it is very difficult to separate GVHD and GVL/T, however, we should try to find the way to suppress GVHD and induce GVL/T at the same time. From that point of view, the induction of CTL against minor histocompatibility antigens such as HA-1 and tumor specific antigens such as BCR-ABL chimeric protein may be useful. Also, the new concept of alloreactive NK cells which have inhibitory NK cell receptor seem to be interesting to regulate GVHD and GVL/T. Further study is needed to establish new allogeneic cell therapy to obtain the clinical improvement.
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PMID:[Target antigens for graft-versus-host disease (GVHD) and graft-versus-leukemia/tumor (GVL/T)]. 1451 17

We recently identified a new minor histocompatibility antigen, termed HA-8, which is presented by human leucocyte antigen (HLA)-A*0201 or HLA-A*0202 and expressed ubiquitously among tissues. A retrospective analysis of 577 Caucasian patients with HLA-A*0201 or A*0202 who had received a haematopoietic stem cell transplant from a human leucocyte antigen (HLA)-identical sibling was conducted to determine whether HA-8 disparity correlated with clinical outcome. HA-8 disparity was detected in 72 recipients, and grades II-IV graft-versus-host disease (GVHD) occurred in 46 (64%), compared with 251 (50%) of the 503 patients without HA-8 disparity. After adjusting for known risk factors for acute GVHD, this difference was statistically significant (odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = 0.04). However, the hazards of clinical extensive chronic GVHD, overall mortality and recurrent malignancy were not statistically significantly different between the two groups. These data suggest that the increased risk of acute GVHD associated with recipient HA-8 disparity was not sufficient to change other clinical outcomes.
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PMID:Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling. 1461 71

Minor histocompatibility antigens with expression restricted to the recipient hematopoietic compartment represent prospective immunological targets for graft-versus-leukemia therapy. It remains unclear, however, whether donor T cell recognition of these hematopoietically derived minor histocompatibility antigens will induce significant graft-versus-host disease (GVHD). Using established bone marrow irradiation chimeras across the multiple minor histocompatibility antigen-disparate, C57BL/6-->BALB.B combination, we studied the occurrence of lethal GVHD mediated by CD4+ T cells in recipient mice expressing only hematopoietically derived alloantigens. Even substantial dosages of donor C57BL/6 CD4+ T cells were unable to elicit lethal GVHD when transplanted into [BALB.B-->C57BL/6] chimeras. Instead, chimeric mice displayed transient cachexia with reduced target-tissue injury over time, reflecting an early, limited, graft-versus-host response. On the other hand, the importance of minor histocompatibility antigens derived from nonhematopoietic tissues was demonstrated by the finding that [C57BL/6-->BALB.B] chimeric mice succumbed to C57BL/6 CD4+ T cell-mediated GVHD. These data suggest that severe acute CD4+ T cell-mediated GVHD across this minor histocompatibility antigen barrier depends on the expression of nonhematopoietically rather than hematopoietically derived alloantigens for maximal target-tissue infiltration and injury.
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PMID:Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell-mediated graft-versus-host disease model. 1467 83

CXB-2/By (CXB-2) recombinant inbred mice express a subset of the minor histocompatibility antigen (miHA) repertoire expressed by C.B10-H2(b)/LiMcdJ (BALB.B) mice. On lethal irradiation and the transplantation of H2(b)-matched C57BL/6 (B6) T cell-depleted bone marrow cells, along with naive unfractionated T cells, both strains succumb to acute graft-versus-host disease (GVHD). Although alloreactive B6 CD4(+) T cells are a necessary source of T-cell help for the B6 CD8(+) component of the GVHD response in both recipient strains, they are capable of mediating severe GVHD by themselves only in BALB.B mice. Previous CD4(+) T-cell receptor repertoire analysis demonstrated overlapping oligoclonal Vbeta use between the CD4(+) B6 anti-BALB.B and B6 anti-CXB-2 responses, with indications of additional BALB.B unique T-cell responses (Vbeta2 and Vbeta11). We report here that the more severe B6 anti-BALB.B response is not due to a quantitative difference in the responding cells, because the frequency of alloreactive donor CD4(+) T cells over time was equivalent in the spleens of BALB.B versus CXB-2 recipients. The responses were also similar in the number of infiltrating B6 CD4(+) T cells in the lingual epithelium of the 2 recipients. In contrast, a significantly greater degree of infiltration and injury of BALB.B intestinal epithelium correlated with the increased level of clinical GVHD severity. Of most significance, despite the involvement of at least 11 Vbeta-associated CD4(+) T-cell families in the overall B6 anti-BALB.B response, the development of severe GVHD correlated with the presence of Vbeta2- and Vbeta11-positive donor T cells. Transplantation of donor CD4(+) T cells from Vbeta-associated families that were shared between the B6 anti-BALB.B and anti-CXB-2 responses resulted in minimal GVHD potential. These data suggest that severe GVHD across miHA barriers depends on the involvement of a restricted number of potent T-cell specificities and implies that there are only a limited number of corresponding responsible miHAs.
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PMID:Specific donor Vbeta-associated CD4 T-cell responses correlate with severe acute graft-versus-host disease directed to multiple minor histocompatibility antigens. 1475 75

Immunocompetent alloreactive donor lymphocytes directed against minor histocompatibility antigens are supposed to be responsible for graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity after allogeneic stem cell transplantation. The authors describe the detection of HA-1-specific T cells by peptide-loaded dimers and flow cytometry in the peripheral blood of a patient in complete remission but without GvHD after donor lymphocyte infusion for chemotherapy-resistant Philadelphia chromosome-positive acute lymphoblastic leukemia. The HA-1-specific T cells were sorted and an alloreactive, polyclonal T-cell line with specific lytic activity against HA-1-positive target cells, including leukemic cells, was established. Although P190 bcr/abl peptide-specific CD8positive T cells were detected in the peripheral blood at the same time, these T cells could not be expanded. Furthermore, no P190 bcr/abl peptide-specific T-cell response could be induced in vitro, even when peptide-loaded dendritic cells were used as stimulator cells. The authors conclude that in the absence of GvHD, HA-1-specific rather than P190 bcr/abl-specific T cells are responsible for ongoing GvL activity.
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PMID:Hematopoietic lineage-restricted minor histocompatibility antigen HA-1 in graft-versus-leukemia activity after donor lymphocyte infusion. 1477 87


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