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)

Cell-mediated immunity against minor histocompatibility (mH) antigens is assumed to contribute to the development of graft-vs.-host disease in recipients of HLA-identical bone marrow grafts. To investigate the role of antihost-specific cytotoxic effector cells, we analyzed patients' T cell cultures after transplantation, in a chromium release assay using T lymphoblasts from patients and donors as target cells. Sixteen patients were studied between 1 and 25 months after grafting. Specific antihost cytotoxic T cell activity was detected in 4 of 5 patients with acute GVHD and in 5 of 5 patients with chronic GVHD, but also in 5 of 6 patients without any clinical signs of GVHD. Generally, the antihost Tc cell activity appeared within the first 3 months, increased to a maximum between 3 and 6 months, and gradually disappeared thereafter. This time effect was significant (P = 0.002). There was a suggestive trend in patients with chronic GVHD toward developing higher and more persistent levels of antihost Tc cell activity than in those without GVHD. Yet, these results can no longer support our earlier finding that the generation of antihost Tc cells is associated with the development of GVHD, since antihost Tc cells could be generally detected whether or not GVHD occurred. Our findings do not a priori exclude an effector cell role for Tc cells in GVHD but strongly indicate that other risk factors must be involved as well.
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PMID:Effector mechanisms in graft-versus-host disease in response to minor histocompatibility antigens. I. Absence of correlation with cytotoxic effector cells. 236 52

Lethally irradiated mice were transplanted with bone marrow plus spleen cells from H-2 identical donor mice. Five of the six recipient strains developed lethal GVHD, but the sixth strain did not develop any signs of GVHD. Spleen cells from all six transplanted strains were cytotoxic to recipient strain target cells in a short-term chromium release assay. The cytotoxic spleen cells were antigen-specific for recipient strain target cells, Thy-1+ and Lyt-2+--and some were also Lyt-1+. These data demonstrate for the first time that the presence of antirecipient cytotoxic T lymphocytes (CTL) does not correlate with lethal GVHD. Although CTL may contribute to the pathogenesis of GVHD in response to minor histocompatibility antigens, they do not appear to be the primary effector mechanism.
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PMID:Absence of correlation between cytolytic T lymphocytes and lethal murine graft-versus-host disease in response to minor histocompatibility antigens. 638 62

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare but lethal disorder caused when viable donor lymphocytes engraft and proliferate in a susceptible transfusion recipient. Patients with immune deficiency disorders, hematologic malignancies and bone marrow transplants are at risk to TA-GVHD, as are premature newborns and transfusion recipients who are HLA heterozygous for an HLA-haplotype that is shared with an HLA homozygous donor. Irradiation of blood components with 2500 cGy will inactivate donor lymphocytes and prevent TA-GVHD. Platelets and granulocytes are not functionally impaired by this radiation dose, but red cells sustain detectable damage. Red cell units irradiated and stored for 42 days have significantly higher supernatant recovery of chromium-51 labeled cells is sub-optimal. Based on these data, the maximum permissible storage time for irradiated red cells has been reduced to 28 days.
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PMID:Transfusion-associated graft-versus-host disease and the irradiation of blood components. 771 2

Since cyclosporine A(CsA) was introduced into transplantation medicine to prevent graft-versus-host disease (GvHD) as well as graft rejection, side-effects became obvious. When CsA is given and withdrawn GvHD-like symptoms can occur even in an autologous setting. To understand this mechanism we tested the allo- and self-reactivity of murine spleen lymphocytes in an in vitro assay. Mice of four different strains with two distinct MHC class I backgrounds (H-2d and H-2k) were treated with 60 mg/kg/day CsA intraperiteonally for ten days. In an attempt to examine the possibility that the CsA-induced autoimmunity requires the presence of the thymus, half of these four- to six-week-old mice were also thymectomized prior to the CsA treatment. Within one day after CsA was stopped, all mice that received CsA during treatment showed reactivity against self-MHC-bearing spleen cells. This was demonstrated in a primary in vitro stimulation assay followed by a chromium-release assay (H-2d-anti-H-2d and H-2k-anti-H-2k). However, alloreactivity (H-2d-anti-H-2k and H-2k-anti-H-2d) was suppressed. At this point in time, no natural killer (NK) activity was detectable in any of the CsA-treated mice. Ten days after stopping CsA, the autoreactivity was no longer detectable in any mouse strain, whether thymectomized or not, whereas the alloreactivity and the NK activity finally recovered. The in vitro phenomena of self-reactivity, which occurred between day one and day 10 after CsA withdrawal, could be adoptively transferred from syngeneic in vitro reactive T cell populations into H-2 identical mice. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro determination of self-reactivity in the early postcyclosporine period. 808 79

Peripheral blood mononuclear cells (PBMC) from 17 patients receiving HLA-identical sibling bone marrow grafts were stimulated with host pretransplant PBMC. Cytotoxic T-cell lines (TCL) with specificity for host pretransplant PBMC were obtained from 9 of these patients, all presenting with severe graft-versus-host disease (GVHD), but from none of the remaining cases lacking evidence of disease. Cytotoxic TCL were specific for host targets and failed to lyse donor cells. Monoclonal antibodies (MoAbs) blocking experiments and donor population screening analyses demonstrated that minor histocompatibility antigen (MiHA)-specific lysis of host targets was restricted by class I major histocompatibility complex (MHC) determinants. Whereas hematopoietic cells such as phytohemagglutinin (PHA) blasts or lymphoblastoid cell lines were susceptible to lysis by MiHA-specific TCL, keratinocytes (K) representing the natural targets of GVHD were quite resistant. Quantitative radioimmunometric measurements indicated very low constitutive expression of class I MHC antigens on K targets, which was readily increased by treatment with interferon-gamma (IFN-gamma). IFN-gamma treatment at the same time rendered these cells susceptible to lysis by MiHA-specific TCL. Host leukemic cells of 3 patients were recognized by MiHA-specific TCL in a chromium release assay and in one experiment host leukemic cells were effectively killed and their growth specifically inhibited in a leukemia colony assay by a clone. These data demonstrate that (1) host-specific cytotoxic TCL are detected exclusively in the PB of patients with acute GVHD grades II through IV after allogeneic matched bone marrow transplantation, and (2) their target antigens are simultaneously expressed on several host cell lines, including lymphoblastoid cell lines, PHA blasts, leukemic cells, and K. We also extend previous findings by showing that, besides the expression of the nominal MiHA, the density of the restricting class I MHC elements also crucially determines the extent of TCL lysis. Because of its capacity to enhance class I MHC antigen expression, IFN-gamma represents a key cytokine for determining the susceptibility of MiHA targets for lysis by TCL and clones, and in one patient an MiHA-specific clone recognized host leukemic cells and also inhibited host leukemic cell growth in a colony inhibition assay.
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PMID:Correlation of minor histocompatibility antigen-specific cytotoxic T lymphocytes with graft-versus-host disease status and analyses of tissue distribution of their target antigens. 847 80

Graft-versus-leukemia (GvL) has been shown to be an important immune-mediated antitumor effect in hematologic malignancies. It is still unknown whether such an immunemediated antitumor effect has clinical implications in patients with solid tumors. A 32-year-old woman with inflammatory breast cancer received a bone marrow transplant (BMT) from her HLA-identical sibling. During graft-versus-host disease (GvHD) cytotoxic T lymphocytes were grown and tested in a chromium-release assay against B and T lymphocytes of the patient and donor and against a panel of breast cancer cell lines. Resolution of liver metastases was observed simultaneously with clinical GvHD in the first weeks after transplant. In addition, minor histocompatibility antigen (MiHA)-specific and major histocompatibility complex (MHC) class I antigen-restricted cytotoxic T lymphocytes recognizing breast carcinoma target cells were isolated from the blood of the patient. Pretreatment of such target cells with tumor necrosis factor (TNF)-alpha but not with interferon (IFN)-alpha or IFN-gamma increased susceptibility of these cells to lysis by cytotoxic T lymphocytes. Clinical course and in vitro results suggest that a graft-versus-tumor (GvT) effect might exist after allogeneic BMT for breast cancer. However, clinical experience on a larger scale would be required to determine the clinical efficacy of GvT effects in patients with solid tumors.
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PMID:Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. 869 72

Thymoglobulin is an antithymocyte globulin preparation used in hematopoietic stem cell transplantation (HSCT) to prevent rejection and graft-versus-host disease. Because natural killer (NK)-cell alloreactivity improves HSCT outcome, but only in patients receiving thymoglobulin, we investigated the in vitro effects of thymoglobulin on purified NK cells. Thymoglobulin binding to NK cells and NK-cell activation were assessed by flow cytometry. NK surface targets for thymoglobulin were determined by competition inhibition assays using monoclonal antibodies. Chromium 51 (Cr) release assay, Annexin V combined with 7-amino-actinomycin D staining, and carboxyfluorescein diacetate succinimidyl ester staining were used to study cytotoxic activity, apoptosis/cell death, and NK-cell proliferation, respectively. Interferon (IFN)-gamma production was determined by ELISA. Thymoglobulin, thymoglobulin derived-F(ab')2 fragments as well as rabbit IgG bound NK cells, and competed strongly with anti-CD16. Thymoglobulin enhanced the expression of activation (CD69 and NKG2D) and degranulation (CD107a) markers on NK cells. It competed with CD18 binding and decreased NK activity, but not interleukin-15-induced killer activity. Effects on apoptosis/cell death and proliferation were minimal. F(ab')2 fragments and rabbit IgG strongly induced IFN-gamma production by NK cells. Thymoglobulin binds to NK cells by CD16 by its variable and constant regions. The decrease in NK-cell cytotoxic activity is restored by interleukin-15, and contrasts sharply with the induction of activation, degranulation, and IFN-gamma production. These data support the hypothesis that thymoglobulin treatment is required to observe the improvement in HSCT outcome by NK-cell alloreactivity.
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PMID:Binding of thymoglobulin to natural killer cells leads to cell activation and interferon-gamma production. 1930 82