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)

CD4+ and CD8+ TCR alpha beta+ T-cell clones were derived from 4 leukaemia patients early (4-6 weeks) after allogeneic bone marrow transplantation. Leukemia inhibitory factor (LIF) secretion in response to the activation signal accessory cells (AC) + phytohaemagglutinin (PHA) was investigated for each individual clone. Only a minority of CD4+ TCR alpha beta+ T-cell clones secreted LIF in response to AC + PHA, whereas most T-cell clones were capable of LIF secretion when exogenous interleukin 2 was added together with AC + PHA. LIF secretion could also be demonstrated for CD8+ TCR alpha beta+ posttransplant T-cell clones. Thus, posttransplant CD4+ and CD8+ TCR alpha beta+ clonogenic T-cells are capable of LIF secretion, and LIF secretion may be a T-cell effector mechanism in graft versus host disease, graft versus leukaemia effects or posttransplant haematopoietic reconstitution.
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PMID:Secretion of leukaemia inhibitory factor after allogeneic bone marrow transplantation: a study of CD4+ and CD8+ TCR alpha beta+ T-cell clones derived from four leukaemia patients. 769 92

Polyclonal antithymocyte globulin (ATG)/antilymphocyte and antilymphoblast globulins (ALG) antibodies have been used successfully in transplantation, aplastic anemia and graft-versus-host disease. Flow cytometry has been used to analyze peripheral blood lymphocyte populations in transplant patients receiving polyclonal ATG/ALG preparations for immunosuppression. Recent reports have indicated clinical dose adjustment based on levels of patient's cells expressing various CD antigens. In vitro analysis of individual polyclonal ATG/ALG CD antigen specificity could identify appropriate antigens for clinical monitoring as well as provide useful in vitro activity data. Therefore, a flow cytometry based assay to characterize and compare activities to specific CD antigens found on the surface of peripheral blood lymphocytes has been developed. Activities found in four lots each of horse ATG (ATGAM, Upjohn), rabbit and horse ATG (thymoglobulin and lymphoglobulin, Merieux), horse ALG (Minnesota), and rabbit ATG (Fresenius) have been compared for CD2, CD3, CD4, CD5, CD7, CD8, CD11a, CD18, CD28, CD44, CD45, and TCR-alpha/beta antigens. Quantitation is achieved by measuring the concentration of ATG/ALG required to give 50% inhibition of antigen specific fluorescent-labeled monoclonal antibody relative to buffer controls. The three horse products tested have similar activity to most antigens tested. However, Fresenius rabbit ATG has the lowest activity for almost all antigens tested whereas the Merieux rabbit ATG has activities closer to the horse products. This technique allows for rapid in vitro comparison of reactivities to individual lymphocyte antigens as well as in vitro analysis of consistency.
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PMID:Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti-CD antigen analysis by flow cytometry. 773 66

Allogeneic bone marrow transplantation has become the therapy of choice in many cases of hematologic malignancy. In both matched related donor transplants--and, to a greater degree, in unrelated donor transplant situations--a major complication of the procedure is GVHD. This problem is caused by mature T cells in the graft, which also facilitate engraftment, and mediate an antitumor effect to reduce relapse. In order to further characterize the T cells that are present at the GVHD site of injury, we have studied 134 fresh tissue biopsies using immunohistochemical methods from 50 consecutive ABMT recipients clinically suspected of having acute GVHD. Antibodies specific for T cells, T cell receptor subsets, B cells, and NK cells were used to characterize the lymphocytic infiltrate in the biopsy tissue from GVHD patients. The data showed that the majority of lymphocytes that had infiltrated the epithelium or epidermis were CD3+ T cells. Using antibodies that distinguished the alpha/beta (beta F1) from the gamma/delta TCR (TCR delta 1)-expressing T cells, we observed that the lymphocytic infiltrates from involved tissues of the gastrointestinal tract, skin, and liver are almost exclusively derived from the alpha/beta expressing T cell subset, and are of the memory cell subset of T cells (CD45RO). This is in contrast to some examples from other disease states, in which a significant proportion of the lymphocytes that infiltrate the epidermal layers are of the gamma/delta type.
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PMID:Immunohistochemical analysis of T cell phenotypes in patients with graft-versus-host disease following allogeneic bone marrow transplantation. 777 Sep 32

One of the principal target organs during graft-versus-host disease (GvHD) is the intestinal epithelium, although the reasons for the preferential involvement of particular organs in this disease are not known. This study analyzed the subset distribution of donor and host lymphocytes in the small intestinal epithelium and the spleen during GvHD in a parent (C57BL/6J) into F1 (C57BL/6JxDBA2/J F1) model. While the donor cell population in the spleen consisted of B and T cells, the donor cell population in the intestine contained only T cells during the course of GvHD. These infiltrating donor cells resembled the host intraepithelial lymphocytes (IELs), which are predominantly CD8+ T cells. This subset distribution of donor cells in the intestinal epithelium was remarkable since they originated from a donor splenocyte population containing few CD8+ lymphocytes. In addition, although the injected donor splenic T cells were virtually all alpha/beta TCR+, several months after GvHD induction more than 30% of the donor cells in the intestine were gamma/delta TCR+, thereby resembling the host IELs not only in their expression of CD4 and CD8, but also in their TCR expression. In contrast, no gamma/delta TCR+ donor cells were detectable in the spleen of GvHD mice. The subset distribution of donor and host IELs remained constant throughout the disease, while in the spleen a decrease of both donor and host B cells and a temporary increase of both donor and host CD8+ cells was observed. These findings demonstrate that in a given target organ during GvHD the disease process affects both donor and host lymphoid populations. In addition the different tissue microenvironments eventually lead to donor cell repopulation with a subset distribution similar to the host natural lymphoid population of the particular target organ.
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PMID:Phenotypic analysis of donor cells infiltrating the small intestinal epithelium and spleen during graft-versus-host disease. 783 51

Little is known about the etiology of the graft-versus-host disease (GVHD) occuring after transplantation of lymphoid cells incompatible for minor histocompatibility antigens (mHAg). Here, the potential role of host endogenous mouse mammary tumor virus (Mtv)-encoded superantigens (SAg) in the development of lethal GVHD was investigated. In a combination of H-2d compatible mice, the presence of Mtv-7 and, to a lesser extent, of Mtv-1, -6, -13 in the host genome, highly increases the rate and severity of GVHD. Kinetic analyses of TCR V beta gene expression in recipient mice consistently indicate a dramatic but transient infiltration of GVHD target organs by Mtv-SAg-specific T cells. This suggests that SAg encoded by endogenous Mtv, by activating large T cell subpopulations, would help the response to mHAg and thus play a critical role in the initiation or aggravation of GVHD.
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PMID:Critical role of endogenous Mtv in acute lethal graft-versus-host disease. 787 97

Bone marrow transplantation is an accepted therapy for hematologic malignancies, aplastic anemia, metabolic disorders, and solid tumors. However, graft-versus-host disease (GVHD) and failure of engraftment have limited the widespread application of this technology to nonmalignant disease states. The use of purified bone marrow stem cells has been suggested as an approach to promote engraftment yet avoid GVHD. Although bone marrow stem cells, purified by cell sorting, engraft and repopulate lethally irradiated genetically identical recipients, they do not engraft in major histocompatibility complex (MHC)-disparate allogeneic recipients. We report for the first time the characterization of a novel cell population of donor bone marrow origin, separate from the hematopoietic stem cell, that facilitates engraftment of purified allogeneic bone marrow stem cells in an MHC-specific fashion without causing GVHD. Although 1,000 purified stem cells (c-kit+/Sca-1+/lineage-) reliably repopulate syngeneic mouse recipients, 10 times that number do not engraft in MHC-disparate allogeneic recipients. The addition of as few as 30,000 facilitating cells (CD8+/CD45R+/TCR-) is sufficient to permit engraftment of purified stem cells in MHC-disparate recipients. The cell surface phenotype of this purified cellular population differs significantly from other characterized lineages of lymphoid or myeloid origin. Based on multiparameter rare-events cell sorting, the facilitating fraction is CD8+, CD3+, CD45R+, Thy 1+, class IIdim/intermediate but alpha beta-TCR- and gamma delta-TCR-. This cellular population comprises approximately 0.4% of the total bone marrow and is separate from the hematopoietic stem cell. The coadministration of purified facilitating cells plus stem cells to optimize engraftment yet avoid GVHD may expand the potential application of bone marrow transplantation to disease states in which the morbidity and mortality associated with conventional BMT cannot be justified.
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PMID:Phenotypic characterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells. 791 63

To characterize skin-infiltrating T lymphocytes during acute GVHD, skin biopsies were obtained from two patients who received unrelated marrow matched for HLA-A, -B, -DR, and -DQ but mismatched for -DP. A total of 120 T-cell clones were generated. Phenotype analysis of the clones showed that the majority of cells were CD4+ and expressed alpha/beta TCR. HLA-DP oligonucleotide genotyping of the clones revealed the presence of lymphoid chimerism. PLT assay showed the lack of HLA specificity, including mismatched HLA-DP. However, mAb to HLA antigens blocked proliferation of the majority of the clones, indicating that the clones recognized HLA-associated molecules. Interestingly, proliferation of two CD4+ T-cell clones was inhibited by class I mAb. A few of the clones revealed augmented proliferation in the presence of CMV antigens and a few revealed cytolytic activity. The above study suggests that (a) CD4+ helper T cells may be primarily responsible for immunopathogenesis of skin manifestations during acute GVHD, (b) there is a mixed lymphoid chimerism in skin during acute GVHD, (c) HLA-DP may not be a factor contributing to the development of acute GVHD, (d) the peptide of the HLA groove or superantigen associated with HLA molecules may be the stimulatory antigen, and (e) CMV antigens appear to stimulate some of the skin-infiltrating T lymphocytes.
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PMID:Characterization of skin-infiltrating cells during acute graft-versus-host disease following bone marrow transplantation using unrelated marrow donors. 804 93

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody- and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70-95% of NK-enriched cells expressed CD3-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-alpha/beta+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40-50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-alpha cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-gamma was increased in both NK and T cells. After i.v. injection of 1-5 x 10(7) cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK- but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-alpha, and IFN-gamma antibodies demonstrated CD56+ cells in association with TNF-alpha and IFN-gamma secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.
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PMID:Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice. 835 98

This study was performed to characterize the intestinal lesions in chronic graft-versus-host disease (GVHD) in mice and to determine a possible role of intestinal intraepithelial lymphocytes (ilEL) in the development of these lesions. Chronic GVHD was induced by transfer of DBA/2 lymphocytes into non-irradiated (C57BL/10 x DBA/2)F1 (BDF1) recipients. There was mild to moderate mucosal oedema with multifocal mixed inflammatory cell infiltrations in the small intestine. The caecum was more severely affected with severe oedema, progressive loss of crypts and severe distortion of the mucosal architecture. The total number of ilEL did not change during the development of chronic GVHD, but there were alterations in the composition of the ilEL population. An increase of CD3+, Thy-1+ cells was accompanied by an increase of TCR alpha beta + cells and a decrease of TCR gamma delta + cells. There was no evidence of infiltration of donor lymphocytes into the intestinal epithelium as determined by the H2K haplotype of the ilEL. These lesions differ from previously described models of chronic GVHD, induced by DBA/2 donor lymphocytes in BDF1 recipients. We suggest that the haemopoietic organs that are used as the source of donor lymphocytes determine the outcome of the GVHD. Modulation of the composition of the donor lymphocyte population may be useful in the establishment of relevant animal models of human enteropathy.
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PMID:Effect of chronic graft-versus-host disease on the intestine in adult BDF1 mice. 839 10

C57BL/6 (B6) (H-2b) mice were lethally irradiated and then reconstituted with T cell-depleted MRL/Mp-lpr/lpr (MRL/lpr) (H-2k) bone marrow cells. The mice showed a short survival with splenic atrophy and fibrosis, as previously described as lpr-graft-vs-host disease (GVHD). However, when these mice received bone marrow transplantation (BMT) plus bone grafts (to recruit donor-derived stromal cells) from MRL/lpr mice, they survived for almost 1 yr without showing GVH symptoms, but showing autoimmune symptoms such as elevated serum IgG2a concentrations, autoantibody production and glomerulonephritis. When MRL/lpr bone marrow cells plus MRL/+ bones (instead of MRL/lpr bones) were transplanted into B6 mice, such improved survival was also obtained, although the MRL/+ bone grafts were less effective in prolonging survival than MRL/lpr bone grafts. H-2 typing of stromal cells in the bone marrow of the B6 mice revealed that the stromal cells had been replaced by donor(H-2k) derived stromal cells. Analyses of TCR repertoires showed that the percentage of CD4+V beta 8.1,2+ cells significantly decreased in the B6 mice that received bone marrow transplantation plus bone grafts from MRL/lpr mice. These findings suggest that stromal cells present in the bone marrow play a crucial role in the development of lpr-GVHD and autoimmune diseases.
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PMID:Prevention of lpr-graft-versus-host disease and transfer of autoimmune diseases in normal C57BL/6 mice by transplantation of bone marrow cells plus bones (stromal cells) from MRL/lpr mice. 859 97


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