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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)

Previous studies demonstrated that the frequency of donor-versus-host-reactive cytotoxic T-cell precursors (CTL-p) before allogeneic bone marrow transplantation (BMT) from matched unrelated donors correlates with the incidence of graft-versus-host disease (GvH-D). We investigated whether clinical manifestations of GvH-D after HLA-identical sibling BMT are accompanied by an increased frequency of minor histocompatibility antigen (HA)-specific CTL-p. We further asked whether changes of third-party-reactive CTL-p as a measure of overall immunocompetence are related to infectious complications frequently seen immediately after BMT. Eighteen patients (16 with an HLA-identical bone marrow graft, two with either one HLA-A or one HLA-DR mismatch) were studied. Limiting dilution analysis (LDA) was used to assess donor CTL-p frequencies against recipient pre-BMT, donor, and third-party targets in a follow-up study. Eight cases receiving HLA-identical marrow grafts never developed signs of GvH-D. Undetectable or very low frequencies (1/131,458) of minor HA-specific CTL-p were demonstrated pre-BMT. Two recipients, one of an HLA-A- and one of an HLA-DR-mismatched graft, exhibited low frequencies of recipient-specific CTL-p (1/66,920 and 1/85,577, respectively) before transplantation, which further decreased despite mild GvH-D grade I, or decreased within 3 months after grafting in the other case. Eight patients receiving HLA-identical grafts developed GvH-D. Recipient-specific CTL-p were less than 1/300,000 in five patients during limited GvH-D (four with grade I and one with grade II disease of the skin), but were detectable in three patients presenting with extensive GvH-D grades II to III and ranged from 1/7,993 to 1/210,108. The differences in post-BMT recipient-specific CTL-p frequencies between patients with GvH-D grades 0 to I (median, less than 1/300,000) and those with GvH-D grades II to III (median, 1/111,970) were statistically significant (P less than .05). Posttransplant lymphocytes from all 18 patients contained less than 1/300,000 CTL-p with specificity for donor targets. Comparison of third-party-reactive CTL-p frequencies between donor and post-BMT recipient lymphocytes showed a severe and long-lasting depletion subsequent to BMT, which was not related to infectious complications. Again, these differences reached the level of statistical significance (median CTL-p before BMT, 1/4,417; after BMT, 1/14,289; P less than .005).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on the mechanism of tolerance or graft-versus-host disease in allogeneic bone marrow recipients at the level of cytotoxic T-cell precursor frequencies. 154 51

Highly purified populations of L3T4+ and Lyt-2+ T cell subsets were compared for their capacity to cause lethal GVHD in six different H-2-compatible, multiple minor histocompatibility antigen-different murine strain combinations. In four of these combinations (C3H.SW----B6, DBA/2----B10.D2, B10.BR----CBA, and B10.S----SJL), lethal GVHD appeared to be caused almost entirely by Lyt-2+ cells; the injection of L3T4+ cells resulted in low mortality even when these cells were presensitized to the recipient antigens. In the remaining two combinations (B10.D2----DBA/2 and B10.D2----BALB/c), L3T4+ T cells were able to cause a high incidence of GVHD and were more potent than the Lyt-2+ cells. The implications of these findings are discussed.
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PMID:Variable capacity of L3T4+ T cells to cause lethal graft-versus-host disease across minor histocompatibility barriers in mice. 310 46

Graft-versus-host disease (GVHD) across minor histocompatibility antigens was developed in mice and the bile duct lesions were surveyed for up to 7.5 months after spleen and bone marrow cell transplantation. Lymphoid cell infiltration was evident by day 3, reached maximum at 2 weeks, then reduced gradually and persisted during the observation period. Fibrous expansion of the portal tracts paralleled with the time after transplantation, but none of the cases progressed into liver cirrhosis. The infiltrates abutted the interlobular and septal bile ducts and distorted their appearance with a frequent infiltration of mononuclear lymphoid cells into the duct epithelial layer. The duct epithelium showed a variety of degenerative and hyperplastic changes, including nuclear enlargement with anisonucleosis, nuclear pyknosis, cytoplasmic and nuclear darkness, cytoplasmic vacuolization, focal epithelial dropout, formation of apoptotic bodies, and micropapillary infolding. Disappearance of the bile ducts and formation of granuloma around the bile ducts were not seen. Immunocytochemical study revealed the exclusive preponderance of helper/inducer T cells in the portal infiltrates and marked expression of I-A antigen on the bile duct epithelium in GVHD mice. These results suggest that immunological mechanisms by helper/inducer T cells against minor histocompatibility antigen on bile duct epithelium in association with class II molecules of MHC are important in the pathogenesis of the bile duct lesions. A putative role of such lymphocytes is discussed.
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PMID:Histological changes of bile duct in experimental graft-versus-host disease across minor histocompatibility barriers. I. Light microscopic and immunocytochemical observations. 330 87

We have developed a murine model of acute and chronic forms of graft-versus-host disease (GVHD) as defined by clinical features that develop in response to minor histocompatibility antigen (minor HA) differences. C57BL/6J (B6) and LP/J mice were selected for serologic identity at H-2 and for mutual nonreactivity in mixed lymphocyte culture (MLC). Lethally irradiated B6 recipients were transplanted with anti-Thy-1.2-treated LP bone marrow cells plus various numbers of untreated LP spleen cells. The B6 recipient mice developed acute and chronic forms of GVHD that showed clinical and histological similarities to the acute and chronic forms of GVHD seen in human recipients of bone marrow transplants from HLA-identical and MLC-nonreactive donors. The definition of acute and chronic GVHD by clinical criteria appears to have biological significance in predicting subsequent survival patterns of recipient mice with GVHD. The incidence of acute and chronic GVHD in the mouse model was a function of the number of donor spleen cells transplanted. Using this model, we demonstrate that both acute and chronic forms of GVHD are initiated by donor lymphocytes. Based on these results, acute and chronic forms of GVHD induced to minor HA appear to be two manifestations of the same T-cell-mediated disease process rather than two different diseases.
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PMID:Acute and chronic graft-versus-host disease induced by minor histocompatibility antigens in mice. 634 39

Graft-vs-Host disease (GVHD) remains a devastating problem in human bone marrow transplantation (1, 2). Because removal of Thy-bearing cells from the donor inoculum has prevented GVHD in murine models (3, 4), it has been hoped that a similar cell surface antigen or combination of antigens could be found in humans. Unfortunately, treatment of human donor cells with various T cell antisera has not yet been successful in preventing GVHD (5). Encouraging results have been reported in five patients who received bone marrow depleted of T cells by the sequential use of soybean agglutinin and the differential sedimentation of cells forming rosettes with sheep red blood cells (6). Although donor T cells are thought to be necessary for initiating GVHD, the immunopathogenesis of GVHD is still not understood. Because donors and recipients are routinely major histocompatibility complex matched and chosen to be nonreactive in mixed lymphocyte cultures human GVHD is thought to result from minor histocompatibility antigen disparities. Lopez and coworkers (7, 8) found a strong association between the incidence of human GVHD and the pretransplant levels of natural killer (NK) activity of the recipients; when the recipient NK activity was low, GVHD rarely developed. They speculated that the NK cell lineage is serving as an important stimulator-inducer. We therefore examined the in vivo effects of anti-asialo GM1 on a murine model of GVHD based on minor antigen disparity. This antiserum has several immunologic effects, including a profound NK suppression. We found that the mice treated with this antibody have normal survival rates, even though they do develop histologic GVHD in the skin. This finding suggests the possibility of a new prophylactic approach to human GVHD and raises many questions regarding the function of asialo GM1-bearing cells in immune regulation.
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PMID:Prevention of lethal, minor-determinate graft-host disease in mice by the in vivo administration of anti-asialo GM1. 635 91

With a model in which CBA T cells cause lethal graft-versus-host disease (GVHD) in irradiated B10.BR mice (H-2-compatible mice that express multiple minor histocompatibility antigen [HA] differences), information was sought on whether the induction phase of GVHD to minor HA is H-2 restricted. When unprimed CBA (H-2k) T cells were recirculated from blood to lymph for 1 d through irradiated H-2-compatible B10.BR or B10.K mice, the T cells underwent specific negative selection to the minor HA of the host, i.e, the filtered T cells failed to cause GVHD after transfer to B10.BR mice. With filtration through totally H-2-different B10 (H-2b), B10.D2 (H-2d), or B10.S (H-2s) mice, by contrast, no selection occurred, i.e., the filtered cells were unimpaired in their capacity to kill B10.BR mice. Selection was marked after filtration through H-2-semiallogeneic (B10 X CBA)F1 mice. These data, together with the results of filtering T cells through various H-2 recombinant strains, indicated that selection depended upon the donor and filtration host sharing determinants encoded by both the K- and D-ends of the H-2 complex. Compatibility only in the I region failed to cause demonstrable selection.
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PMID:Negative selection of T cells causing lethal graft-versus-host disease across minor histocompatibility barriers. Role of the H-2 complex. 696 18

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.
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PMID:Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. 767 Jan 18

Minor histocompatibility antigens (mHags) are involved in the induction of graft-versus-host disease (GVHD) after HLA-identical bone marrow transplantation. Previously, we isolated a series of HLA-A*0201-restricted cytotoxic T-cell (CTL) clones specific for the same mHag HA-1 from peripheral blood of three unrelated patients who were suffering from GVHD. We have now analyzed the composition of the T-cell receptor (TCR) V regions of 12 of these mHag HA-1-specific HLA-A*0201-restricted CTL clones by DNA sequencing of the alpha and beta chains. Of these 12 clones, derived from three unrelated individuals, five independent TCR alpha V- and beta V-region sequences were established. The TCR alpha chains were composed of varying TCR alpha V and TCR alpha J genes with no obvious similarities in structure in the N regions. However, the TCR beta chains all used the TCR beta V6S9 gene segment, and showed remarkable similarities within the N-D-N regions; ie, three independent beta-chain sequences (originating from donors Ha and Gy) shared a leucine/valine amino acid pair, whereas the other two (originating from donors Ha and Wi) shared a serine/threonine pair, all at positions 99 and 100 of the TCR beta V region. In conclusion, the TCR analysis of HA-1 mHag-specific CTL clones has shown that the HA-1 mHag/HLA-A*0201 complex selects for highly similar TCR beta V regions.
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PMID:Interindividual conservation of T-cell receptor beta chain variable regions by minor histocompatibility antigen-specific HLA-A*0201-restricted cytotoxic T-cell clones. 772 78

Donor lymphocyte responses to minor histocompatibility antigen (mHA) differences are involved in allo-responses between HLA matched pairs causing GVHD and graft-versus-leukaemia (GVL). Since some mHA are tissue-restricted, GVHD and GVL responses may be separable. We studied donor lymphocyte responses to patients with CML in a series of 10 HLA-matched sibling and 10 unrelated donor-recipient pairs comparing proliferation to recipient PHA blasts and CML cells and attempting to selectively deplete responses to PHA blasts in vitro. Responses in counts per min (c.p.m) to CML cells and PHA blasts were, respectively, 2809 +/- 2205 (SD) and 7376 +/- 1877 in related and 12,107 +/- 7191 and 26,136 +/- 22,479 in unrelated pairs. Autologous responses to PHA blasts were significantly lower (mean 779 +/- 735) (p < 0.001). Results correlated with clinical outcome: higher responses to recipient cells correlated with transplant-related death (p = 0.02 for CML and p = 0.06 for PHA blasts). Higher responses to CML correlated with GVHD grade > or = II (p = 0.025). Donor lymphocytes exposed to recipient PHA blasts for 5 days and treated with a ricin-conjugated anti-CD25 antibody retained over 75% of their response to CML but < 10% to PHA blasts. Similarly, depletion of response to CML but not to PHA blasts occurred when CML was the primary challenge. These results indicate that distinct populations of donor T cells respond to recipient leukaemic and non-leukaemic cells, and provide the basis for a clinically applicable technique to selectively deplete donor GVHD reacting cells while conserving GVL.
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PMID:Distinct T cell populations distinguish chronic myeloid leukaemia cells from lymphocytes in the same individual: a model for separating GVHD from GVL reactions. 785 26

HLA-DP typing is not routinely performed before allogeneic BMT. This highly polymorphic class II locus is implicated in immune response and DP molecules may act as transplantation antigens. HLA-DP incompatibilities contribute to MCL. In BMT performed between siblings, HLA-DP mismatches are rare and the role of such incompatibility in GVHD is probably lower than minor histocompatibility antigen disparity. In unrelated BMT, the rate of HLA-DP mismatches is high and DP incompatibility cannot be used as an exclusion criterion in the selection of unrelated donors. Even if in vitro studies show that the HLA-DP antigen may be the target for GVHD, analysis of large numbers of unrelated BMT shows that DP incompatibility is not a risk factor for acute GVHD.
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PMID:HLA-DP and allogeneic bone marrow transplantation. 792 Feb 90


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