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)

Monitoring of human allografts requires to use histological, immunohistochemical and functional techniques to characterize graft infiltrating cells. Granzyme B and perforin gene expression is of major importance in functional studies. Those proteins are present in the cytoplasmic granules of cytotoxic T lymphocytes and are secreted during granule exocytosis at the effector/target cell interface. Gene expression of both proteins has been studied by in situ hybridization using specific riboprobes on serial sections of biopsies in two pathological models. Our results show that cells infiltrating early skin lesions of patients with acute GVHD after bone marrow graft are exclusively composed of T cells, among which some of them express granzyme B and perforin genes. Similarly the presence of granzyme B and perforine-expressing cells in endomyocardial biopsies of heart transplanted patients has been associated to early and severe crisis of rejection. In contrast, the absence of functional markers in lymphoid infiltrates was coinciding with less aggressive and late episodes of rejection. Taken together, our data indicate that granzyme B and perforin gene expression in skin infiltrating lymphocytes during GVH or within heart infiltrating cells during crisis of rejection are in favor of severe processes. The study has allowed to predict during heart transplantation the apparition of a rejection crisis and to show the necessity for treating the patient with immunsuppresive drugs. This is also the case for patients with GVHD at the time of the first skin rash.
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PMID:Perforin and granzyme B: predictive markers for acute GVHD or cardiac rejection after bone marrow or heart transplantation. 181 99

To study the role of functionally active cytotoxic lymphocytes in human graft-versus-host disease (GVHD), perforin expression in infiltrating mononuclear cells was immunohistochemically investigated in skin biopsy specimens. Perforin is a component of intracytoplasmic granules of cytotoxic lymphocytes and serves as a specific marker of functionally active cytotoxic lymphocytes. The study included two cases of transfusion-associated GVHD, seven cases of acute GVHD and five cases of lichenoid chronic GVHD after allogeneic bone marrow transplantation. All specimens obtained from transfusion-associated GVHD and one case of acute GVHD with extracutaneous involvement contained a significant number of perforin-positive lymphocytes. In contrast, perforin-positive lymphocytes were few or absent in the other six cases of acute GVHD and in all five cases of lichenoid chronic GVHD after bone marrow transplantation. These findings suggest that perforin-mediated cytolysis by cytotoxic lymphocytes may be a major effector mechanism in transfusion-associated GVHD and at least in some cases of acute GVHD after bone marrow transplantation.
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PMID:Immunohistochemical identification of perforin-positive cytotoxic lymphocytes in graft-versus-host disease. 852 17

Graft-versus-host disease (GVHD) is the main complication after allogeneic bone marrow transplantation. Although the tissue damage and subsequent patient mortality are clearly dependent on T lymphocytes present in the grafted inoculum, the lethal effector molecules are unknown. Here, we show that acute lethal GVHD, induced by the transfer of splenocytes from C57BL/6 mice into sensitive BALB/c recipients, is dependent on both perforin and Fas ligand (FasL)-mediated lytic pathways. When spleen cells from mutant mice lacking both effector molecules were transferred to sublethally irradiated allogeneic recipients, mice survived. Delayed mortality was observed with grafted cells deficient in only one lytic mediator. In contrast, protection from lethal acute GVHD in resistant mice was exclusively perforin dependent. Perforin-FasL-deficient T cells failed to lyse most target cells in vitro. However, they still efficiently killed tumor necrosis factor alpha-sensitive fibroblasts, demonstrating that cytotoxic T cells possess a third lytic pathway.
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PMID:Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. 862 78

The role of cell-mediated cytotoxicity in the complex pathophysiology of graft-versus-host disease (GVHD) has remained poorly defined for several decades. We transplanted T cells from Fas-ligand (FasL)-defective and perforin-deficient mutant donor mice into lethally irradiated MHC-matched allogeneic recipient mice to characterize the role of cell-mediated cytotoxicity in GVHD. Although recipients of allogeneic FasL-defective donor T cells underwent severe GVHD-associated cachexia, they exhibited only minimal signs of hepatic and cutaneous GVHD pathology. Recipients of perforin-deficient allogeneic donor T cells developed signs of acute GVHD, but the time of onset was significantly delayed. These findings demonstrate that Fas-mediated anti-recipient cytotoxicity may be critical for the development of hepatic and cutaneous GVHD, but is not required for GVHD-associated cachexia. In addition, perforin-mediated anti-recipient cytotoxicity appears to play an important role in the kinetics of GVHD pathophysiology, but is not required for GVHD-associated tissue damage.
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PMID:The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. 867 85

Blood transfusion can result in a variety of immunologic responses, including alloimmunization, transfusion-associated graft-versus-host disease, and immunosuppression that results in increased postoperative infection rate, and can also result in increased survival of allografts. One of the many factors influencing the resulting immunologic responses from a blood transfusion is the persistence of the donor leukocytes. A recent study has shown that almost all (99.9%) allogeneic leukocytes are removed within 2 days following transfusion but did not characterize the mechanism responsible for the rapid removal of allogeneic donor cells. Using a murine model these studies show that it is recipient CD8+ T cells that are responsible for the rapid elimination of allogeneic lymphocytes in naive recipients. Effective elimination was dependent on the donor/recipient combination and required that the donor cells express at least one MHC class I disparity to be recognized by the recipient CD8+ cells and that the donor cells also be able to induce additional responses that were needed by the CD8+ cells to manifest full activity. The perforin pathway was the predominant pathway used by the recipient CD8+ cells to mediate this elimination.
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PMID:Recipient CD8+ cells are responsible for the rapid elimination of allogeneic donor lymphoid cells. 894 82

Granzymes are neutral serine proteases that are stored in the specialized lytic granules of cytotoxic lymphocytes. A mutation introduced into the granzyme B locus leads to a severe defect in the ability of cytotoxic lymphocytes to induce apoptosis in susceptible target cells, and reduces the severity of class I-dependent acute graft-versus-host disease (GvHD). However, granzyme B-independent cytotoxicity also exists: in CD8+ cells, most of it is perforin-dependent, but in CD4+ cells, the Fas system and an additional pathway are involved. The identification of these pathways and their physiological relevance may lead to new approaches for inhibiting cytotoxic lymphocyte functions.
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PMID:The role of granzyme B cluster proteases in cell-mediated cytotoxicity. 919 23

Graft-versus-host disease (GvHD) is the major limiting toxicity of allogeneic bone marrow transplantation. T cells are important mediators of GvHD, but the molecular mechanisms that they use to induce GvHD are controversial. Three effector pathways have been described for cytotoxic T lymphocytes: one requires perforin and granzymes, the second Fas (APO-1; CD95) and its ligand. Thirdly, secreted molecules (e.g., TNF-alpha, gamma-IFN) can also mediate cytotoxicity. Together, these mechanisms appear to account for virtually all cytotoxicity induced by activated CTL in standard in vitro lytic assays. Using transplants across histocompatibility barriers, we were able to analyze the contributions of these effector molecules to cell-mediated cytotoxicity in vivo in a GvHD model. We found that Fas ligand is an important independent mediator of class II-restricted acute murine GvHD, while perforin/granzyme-dependent mechanisms have only a minor role in that compartment. In contrast, perforin/ granzyme-dependent mechanisms are required for class I-restricted acute murine GvHD, while Fas ligand is not. The perforin/granzyme pathway may therefore represent a novel target for anti-GvHD drug design. In support of this approach, we provide additional data suggesting that specific perforin/granzyme inhibitors should not adversely affect hematopoietic recovery after transplantation.
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PMID:Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. 925 90

Perforin-deficient (-/-) mice were used as T-cell donors for infusion into irradiated major histocompatibility complex (MHC)-disparate recipients to investigate the requirement for perforin-mediated cytolysis during graft-versus-host disease (GVHD) generation. Administration of 5x10(6) C57BL/6 (H2b) perforin -/- splenocytes was significantly less effective in inducing GVHD lethality when given to MHC class I + II disparate B10.BR (H2k) recipients, as compared with wild-type (+/+) controls. Perforin expression by donor T cells was not required for GVHD induction because recipients given fivefold higher numbers of perforin -/- donor splenocytes uniformly succumbed to lethal GVHD. Because both CD4+ and CD8+ donor T cells are required for optimal GVHD lethality in this strain combination, to discern the relative contribution of perforin-mediated cytolysis by CD4+ and CD8+ T cells, additional studies were performed. For these latter studies, we used a sensitive assay involving the infusion of highly purified CD4+ or CD8+ T cells into sublethally irradiated MHC class II or I disparate recipients, respectively. As compared with recipients of perforin +/+ T cells, recipients of either CD4+ or CD8+ perforin -/- T-cell subsets had a significant reduction in GVHD-mediated lethality at T-cell doses that were uniformly lethal. T-cell dose titration studies established that GVHD lethality in recipients of perforin -/- CD4+ or CD8+ T cells was reduced by approximately threefold. These data are the first to indicate that approaches to limit perforin-mediated cytolysis should be similarly effective in situations in which CD4+ or CD8+ T cells dominate the GVHD response.
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PMID:CD4+ and CD8+ T cells each can utilize a perforin-dependent pathway to mediate lethal graft-versus-host disease in major histocompatibility complex-disparate recipients. 929 67

T-cell cytotoxicity is primarily mediated by two cell surface proteins, Fas ligand (FasL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and intracellular perforin and granzyme granules. FasL-deficient and perforin-deficient T lymphocytes maintain cytotoxicity but fail to induce graft-versus-host disease (GVHD) when transplanted into mice. suggesting that GVHD and graft-versus-tumour (GVT) effects can be dissociated, and that TRAIL is not involved in the pathogenesis of GVHD. Because TRAIL could mediate a favourable GVT effect it became important to study the spectrum of its activity and to investigate factors that can dissociate its expression from FasL. TRAIL induced apoptosis in 11/41 (27%) tumour specimens of haematological origin compared to 16/41 (39%) induced by FasL. Although eight specimens were sensitive to both FasL and TRAIL, no synergism was observed between these two ligands. TRAIL induced apoptosis in a dose and time dependent manner with an ED50 of 0.5 microg/ml and EDmax of 1 microg/ml. TRAIL activity was not reduced by the over-expression of the multidrug resistant (MDR) protein, and was not enhanced by 9-cis retinoic acid (RA), which can down-regulate bcl-2 protein. Both ligands were simultaneously up-regulated in normal peripheral blood lymphocytes in response to IL-2, IL-15 and anti-CD3 antibody, whereas IL-10 had no effect. Together, our data show that (1) TRAIL can mediate cell death in a variety of human haematological malignancies, (2) resistance to TRAIL is not mediated by MDR protein, (3) the lack of synergy between TRAIL and FasL suggests that either one is sufficient to mediate T-cell cytotoxicity, and (4) within the panel of cytokines tested, the expression of TRAIL and FasL could not be dissociated.
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PMID:Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies. 940 Oct 75

Natural killer (NK) cells can kill target cells by either necrotic or apoptotic mechanisms. Using the 51Cr-release assay to measure necrotic death of target cells, neonatal NK cells had low NK activity (K562 targets) and high lymphokine-activated killer (LAK) activity (Daudi targets) compared with adult cells, as has been previously reported. Using a 125I-deoxyuridine (125I-UdR) release assay, cord cells were shown to also have higher apoptotic LAK activity against YAC-1 target cells. Interleukin-4 (IL-4) inhibited interleukin-2 (IL-2)-induced necrotic killing of target cells by adult effectors but had no such inhibitory effect on cord cells. In contrast, IL-4 inhibited both adult and cord LAK cytotoxicity of YAC-1 target cells by apoptotic mechanisms with higher suppression observed in cord cell preparations. Using a colorimetric substrate conversion assay, IL-2 induced higher, and IL-4 had a more significant suppressive effect on, cord cell granzyme B enzyme activity compared with adult cells, paralleling apoptosis cytotoxicity data. Co-culture of either adult or cord LAK cells with IL-4 had a similar inhibitory effect on granzyme B protein expression, as detected by Western blotting. In contrast, IL-4 did not inhibit perforin expression, thereby defining IL-4 as a cytokine that can differentially regulate the NK cell-mediated cytotoxicity processes of apoptosis and necrosis. The differential sensitivity of cord cells to cytokine regulation of cytotoxicity may also have implications for cord blood transplantations, as NK cells are known to function as an effector cell in both graft-versus-host disease and in the graft-versus-leukaemia phenomena.
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PMID:Differential cytokine regulation of natural killer cell-mediated necrotic and apoptotic cytotoxicity. 965 23


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