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)

After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4(+) and CD8(+) T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non-host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non-host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.
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PMID:Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immune reconstitution in mice with graft-versus-host disease. 1039 5

Cord blood is increasingly used in transplantation as it is a readily available source of progenitor cells and is reputed to generate less severe graft-versus-host disease (GVHD) than adult bone marrow. We have compared apoptosis of cord blood lymphocytes (CB) and adult lymphocytes (PBMC) after stimulation via HLA class I, HLA class II or CD3 in order to reproduce in vitro some of the stimuli occurring after allotransplantation. CB spontaneously apoptose more than PBMC ex vivo, stimulation via HLA class I dramatically increased CB apoptosis without altering viability of PBMC. Expression of Fas was markedly lower on CB than on PBMC and this difference was maintained even after activation. Fas ligand was expressed in CB and in PBMC. CB were activated via either HLA class I or class II molecules although proliferation was not observed. Only phorbol ester pre-activation allowed Fas to subsequently induce a death signal. Proliferation of PBMC via CD3 led to enhanced Fas signals. CB therefore differ from PBMC with regard to both spontaneous and activation induced apoptosis and either allo- or CD3 mediated stimulation. Finally, the apoptosis of CB via HLA-class I could have an important role in the moderation of graft-versus-host disease.
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PMID:An in vitro model of allogeneic stimulation of cord blood: induction of Fas independent apoptosis. 1042 77

The lung is one of the primary targets of acute graft-versus-host disease (GVHD), which is the principal complication that occurs after allogeneic intestinal transplantation. The purpose of this study is to investigate the involvement of Fas/Fas ligand system in pulmonary injury after rat semi-allogeneic intestinal transplantation. The lungs were serially harvested from LEW x BN F1(LBNF1) recipients of either LEW heterotopic intestinal allografts or LBNF1 isografts, on days 1, 3, 5, 9, and 13 posttransplant. In light microscopy, pulmonary injury became apparent on day 13 in the allogeneic combination, showing a thickening of the alveolar septa. The incidence of apoptosis, examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) biotin nick end-labeling, was observed to increase steadily in the alveolar cells accompanied by a progression of GVHD. In an immunohistochemical study, Fas was constitutively expressed in the lung, although Fas ligand was expressed most extensively on day 9. The immunoreactivity of both Fas and Fas ligand were observed in alveolar cells, in addition to leukocytes. An analysis by reverse transcription polymerase chain reaction also revealed that the expression of Fas mRNA was constitutive without any significant change, although that of Fas ligand mRNA increased substantially and peaked on day 9, which was significant compared to the isogeneic combination. In conclusion, transcriptionally up-regulated Fas ligand and increased number of apoptosis suggests that the Fas system may play a role in the pathophysiology of GVHD-induced pulmonary injury.
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PMID:Analysis of Fas system in pulmonary injury of graft-versus-host disease after rat intestinal transplantation. 1053 30

The acute graft-versus-host disease (GVHD) generated in BDF1 mice by the injection of spleen cells from the C57BL/6 parental strain induces a direct cell-mediated attack on host lymphohematopoietic populations, resulting in the reconstitution of the host with donor hematopoietic stem cells. We examined the effect of GVHD on the donor and host hematopoiesis in parental-induced acute GVHD. The bone marrow was hypoplastic and the number of hematopoietic progenitor cells significantly decreased at 4 weeks after GVHD induction. However, extramedullary splenic hematopoiesis was present and the number of hematopoietic progenitor cells in the spleen significantly increased at this time. Fas expression on the host spleen cells and bone marrow cells significantly increased during weeks 2 to 8 of GVHD. Host cell incubation with anti-Fas Ab induced apoptosis, and the number of hematopoietic progenitor cells decreased during these weeks. A significant correlation between the augmented Fas expression on host bone marrow cells and the decreased number of host bone marrow cells by acute GVHD was observed. Furthermore, the injection of Fas ligand (FasL)-deficient B6/gld spleen cells failed to affect host bone marrow cells. Although Fas expression on repopulating donor cells also increased, Fas-induced apoptosis by the repopulating donor cells was not remarkable until 12 weeks, when more than 90% of the cells were donor cells. The number of hematopoietic progenitor cells in the bone marrow and the spleen by the repopulating donor cells, however, decreased over an extended time during acute GVHD. This suggests that Fas-FasL interactions may regulate suppression of host hematopoietic cells but not of donor hematopoietic cells. Hematopoietic dysfunctions caused by the reconstituted donor cells are independent to Fas-FasL interactions and persisted for a long time during parental-induced acute GVHD.
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PMID:Effect of graft-versus-host disease (GVHD) on host hematopoietic progenitor cells is mediated by Fas-Fas ligand interactions but this does not explain the effect of GVHD on donor cells. 1055 93

It is known that an important curative benefit of allogeneic bone marrow transplantation (BAMT) in the treatment of hematolymphoid malignancies is a graft-vs.-tumor (GVT) effect. GVT activity has been attributed to mature immune cells contained within the graft because T-cell depletion of bone marrow results in increased rates of disease relapse post-transplantation. We previously demonstrated successful engraftment of highly purified hematopoietic stem cells (HSCs) transplanted across major histocompatibility complex (MHC) barriers in mice. In the present study, we have developed a preclinical model of allogeneic HSC transplantation into lymphoma-inoculated mice, allowing us to directly test whether purified HSCs have measurable GVT activity. We then performed cotransfer studies of HSCs with purified immune cells to identify which population(s) confers tumor protection and the mechanism by which such cells suppress tumor growth. MHC-mismatched donor-recipient combinations were studied. All of the GVT activity was contained in the CD8+ cell fraction and, at the doses of CD8+ cells tested, tumor protection was separable from acute graft-vs.-host disease (aGVHD). Although there appears to be no functional difference between BM- and splenic-derived CDS8+ cells with regard to GVT activity without aGVHD, this was not the case for purified CD3+ cells. CD3+ cells derived from BM were tumor protective, whereas transplantation of equivalent doses of CD3+ cells purified from spleen resulted in lethal GVHD. The mechanism by which the GVT-conferring cells protect recipient mice from tumors was studied using immune defective mice as donors. We found that an intact pathway of perforin-dependent cytolysis, as well as an intact Fas-ligand pathway, is required in order to exert maximal anti-tumor activity.
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PMID:Graft-vs.-lymphoma effect in an allogeneic hematopoietic stem cell transplantation model. 1059 13

The graft-versus-host disease (GVHD) generated in BDF1 mice by the injection of spleen cells from the C57BL/6 parental strain induces a direct cell-mediated attack on host lymphohaematopoietic populations, resulting in the reconstitution of the host with donor cells. We examined Fas-Fas ligand (FasL) interactions in donor and host haematopoietic cells over a prolonged period of parental-induced GVHD. Fas expression on bone marrow cells of both donor and host origin increased at 2 weeks. Host cell incubation with anti-Fas antibody induced apoptosis, and the number of haematopoietic progenitor cells decreased. Fas-induced apoptosis by the repopulating donor cells, however, did not increase until 12 weeks, when more than 90% of the cells were donor cells. The expression of various cytokines, such as interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and FasL gene expression in the bone marrow increased concomitantly. To examine directly whether FasL has a major role in the development of donor cell engraftment, FasL-deficient (gld) mice were used as donors. Injection of B6/gld spleen cells induced significantly less host lymphohaematopoietic depletion, resulting in a failure of donor cell engraftment. Furthermore, injection of IFN-gamma gene knockout (gko) B6 spleen cells failed to augment Fas and FasL expression in recipient mice, resulting in a failure of donor cell engraftment. This suggests that the induction of apoptosis by Fas-FasL interactions in host cells may contribute to a reconstitution of the host with donor cells and that donor-derived IFN-gamma plays a significant role for Fas-FasL interactions in host cells during parental-induced GVHD.
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PMID:Graft-versus-host-disease-associated donor cell engraftment in an F1 hybrid model is dependent upon the Fas pathway. 1065 46

Bile-duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune-mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas-mediated cell death in this immune-mediated cholangiopathy. In this study, we first showed the constitutive expression of Fas receptor by cholangiocytes in situ from normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody-(Jo2)-induced cholangiocyte apoptosis confirmed by DNA-ladder formation and annexin V staining. Cholangiocytes from Fas-deficient mice (MRL lpr/lpr) did not show Jo2-induced apoptosis. Interferon-gamma augmented Fas expression and Fas-mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver-infiltrating lymphocytes from the recipient showed dose-dependent cytotoxicity against (51)Cr-labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas-Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas-Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results showed the involvement of Fas-mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas-Fc protein may have a therapeutic potential for hepatic GVHD.
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PMID:Fas-mediated cholangiopathy in the murine model of graft versus host disease. 1073 54

Fas ligand triggers cell death after interaction with its receptor Fas. Altered expression of Fas has been associated with lymphoproliferation and autoimmune disorders in both mice and man. Apoptosis of lung and liver tissue is seen in Fas ligand transgenic mice. It is not known whether constitutive expression of Fas ligand can cause a similar human disease. Four patients with aggressive large granular lymphocyte (LGL) leukaemia involving lung and liver were studied. All four patients were severely ill with pulmonary involvement. Two patients presented with hypoxia and were oxygen dependent; the other two patients had severe pulmonary hypertension. Lung biopsies showed interstitial infiltration by leukaemic LGL. The infiltrating lymphocytes expressed both Fas and Fas ligand, whereas normal pneumocytes expressed only Fas. Similar findings were observed in liver biopsies from these patients. Features mimicking the pathological changes of graft-versus-host disease were observed, including pneumocyte apoptosis. All four patients had high levels of circulating Fas ligand. Successful treatment with oral methotrexate or 2-chlorodeoxyadenosine was associated with disappearance or marked reduction of circulating Fas ligand. These results suggest that dysregulated expression of Fas ligand can lead to human disease with pathological features resembling graft-versus-host disease.
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PMID:Clinicopathological features of aggressive large granular lymphocyte leukaemia resemble Fas ligand transgenic mice. 1079 74

It has recently been shown that the Fas-Fas ligand (FasL) system may be one of the pathogeneses for acute graft-versus-host disease (GVHD), and it has been reported that serum soluble Fas ligand (sFasL) increases with the presence of acute GVHD. However, there is no report on a correlation between the Fas-FasL system and chronic GVHD. We present two cases of chronic GVHD with elevated levels of serum sFasL. Its level in each case was high at the onset of chronic GVHD, but it decreased with steroid therapy. Liver dysfunction also improved as the level of serum sFasL decreased. It appears in these cases that the Fas-FasL system was related to the pathogenesis of liver damage.
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PMID:Two cases of chronic graft-versus-host disease with elevated levels of soluble Fas ligand in serum. 1081 95

The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.
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PMID:Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. 1089 51


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