UMLS:C0018133 - FACTA Search

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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)

IL-10 plays an important role in the control of immune reactions during systemic infection. Here, IL-10 serum levels were investigated in patients after BMT. The IL-10 levels correlated with the clinical course of the patients and with serum levels of C-reactive protein (CRP) and neopterin (NP). A total of 26 patients with AML (7), ALL (12), CML (2), NHL (3) and multifocal Ewing's sarcoma (2) had received autologous (10) or allogeneic (16) BMT from related (9) or unrelated donors (7). Routine serum samples were obtained prior to BMT and at days 46 and 100 after BMT. However, in patients with severe complications additional samples were drawn at individual points in time. Prior to BMT, IL-10 serum levels were not detectable in 24/24 patients. Post-BMT, 11 patients developed elevated IL-10 levels, of these eight died of complications (DOC), whereas only one of 15 patients with undetectable IL-10 died of complications, indicating that high IL-10 levels were significantly correlated with severe life-threatening complications (chi2, P < 0.01). To determine the pathomechanism and role of the increased IL-10 levels, they were correlated to the respective NP and CRP serum concentrations. CRP and NP concentrations were found significantly elevated in patients with detectable IL-10, indicating a severe acute phase reaction associated with macrophage activation. In conclusion, high IL-10 serum levels in patients after BMT were significantly associated with fatal outcome. Since IL-10 is a strong suppressor of T cell immunity, high IL-10 production in patients with severe complications such as septic shock or GVHD > grade II after BMT might lead to functional immunodeficiency contributing to the poor prognosis of these patients.
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PMID:High interleukin-10 serum levels are associated with fatal outcome in patients after bone marrow transplantation. 933 50

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

Differences in T-cell selection and severity of graft-versus-host (GVH) disease were observed in immunodeficient C.B-17 SCID (SCID) mice after injection of allogeneic T lymphocytes from CBA/J or C57B1/6 (B6) mice. Infiltrating donor cells were analysed in bone marrow (BM), liver and spleen of newborn recipients and 5 days post-engraftment the number of B6 cells significantly exceeded that of CBA/J cells in these organs. At that time, cells in BM of B6 and CBA/J injected recipients were augmented in intracellular IL-4, IL-10, and TNF-alpha, whereas only cells in B6 treated BM were increased in IFN-gamma, and both treated groups of mice had up-regulated endogenous MHC class I and class II expression in the three organs. Already on day 5, and more pronounced day 10, B6 treated SCIDs had a relative decrease of four different TCR-Vbeta specificities among donor cells, whereas CBA/J injected mice had an abnormal expansion of Vbeta14+ donor T cells 10 days post injection. At the same time, the total cell contents of BM and spleen of B6 injected mice were substantially decreased, and this was paralleled by signs of severe GVHD; whereas SCIDs treated with CBA/J exhibited much milder symptoms. Moreover, adult SCID mice injected with Vbeta2, 4, 8 and 14 depleted B6 T cells showed an increased percentage of infiltrating donor cells and an enhanced decrease in BM cell content compared to SCIDs treated with total B6 T cell repertoire. In vitro, the Vbeta2, 4, 8 and 14 depleted population was more responsive to SCID spleen stimulators. Thus, a disturbed immunoregulation among donor T cells, caused by multiple changes in the TCR repertoire, may be responsible for inducing the severe GVHD.
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PMID:Severe graft-versus-host disease in SCID mice is associated with a decrease of selective donor cell TCR Vbeta specificities and increased expression of IFN-gamma and IL-4. 958 95

Irradiated (800 rads) AKR mice received intravenous (i.v.) reconstitution with a mixture of B10.BR T-depleted bone marrow cells and spleen cells. Only in groups of mice treated additionally with i.v. cyclophosphamide (Cy; 150 mg/kg), 24 hr before transplantation, was long-term (> 60% at 50 days) survival seen. In mice receiving only irradiation all animals died by 30 days post-transplantation. Histological changes consistent with graft-versus-host disease (GVHD) were seen in the liver of reconstituted mice at 30 days, along with an organ-specific increase in V beta 3 T-cell receptor-positive (TCR+) cells. No such increase in V beta 3 TCR+ cells was seen in the spleen from the same mice. These data are consistent with a tissue antigen-driven expansion of V beta 3 TCR+ cells associated with GVHD in the liver in this model. When we analysed cytokine production in vitro from CD3+ cells restimulated with 'host' (AKR) antigen-presenting cells (APC), we found a transition in cytokine production from preferential synthesis of type-1 cytokines [interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)] at early times (day 15) post-reconstitution to increased production of type-2 cytokines [IL-4, transforming growth factor-beta (TGF-beta) and IL-10] at later times (day 30) post-reconstitution in Cy-treated recipients. Animals not receiving Cy did not show this 'switch' in cytokine production at later time points. We have observed a similar polarization in cytokine production, along with increased graft survival, in recipients of vascularized and non-vascularized allografts after portal venous (p.v.), but not i.v., pretransplant donor-specific immunization. We next studied AKR mice receiving 800 rads and subsequently reconstituted with B10.BR stem cells via the p.v. route. Again these mice showed prolonged survival (> 50% at 50 days), with polarization to IL-4, IL-10 and TGF-beta on restimulation of CD3+ cells in vitro at 30 days post-transplant and increased V beta 3 TCR+ cells in the liver. Infusion of anti-IL-12 monoclonal antibodies into irradiated mice receiving i.v. cell reconstitution produced a similar pattern of changes to those seen after p.v. reconstitution, while a combination of anti-IL-10 and anti-TGF-beta monoclonal antibodies reversed the changes seen after p.v. reconstitution. These data are consistent with an important role for differential cytokine production in the regulation of GVHD following allogeneic bone marrow transplantation.
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PMID:Analysis of cytokine production and V beta T-cell receptor subsets in irradiated recipients receiving portal or peripheral venous reconstitution with allogeneic bone marrow cells, with or without additional anti-cytokine monoclonal antibodies. 961 72

Donor T cells mediate both beneficial and detrimental immune reactions in the setting of allogeneic BMT (alloBMT). T cells mediate the GVL effect and prevent marrow rejection, but also induce GVHD. In an attempt to favorably influence the balance of these allogeneic responses, we have evaluated the effect of donor CD4+, Th1/Th2 and CD8+, Tc1/Tc2 functional T cell subsets in murine marrow transplantation models. Our studies have identified the CD8+ Tc2 population (which is a cytolytic effector secreting the type II cytokines IL-4, IL-5, and IL-10) as a subset capable of mediating the GVL effect and preventing marrow rejection with reduced GVHD. We have also shown that the Tc2 subset can be generated in humans. These studies indicate that administration of donor CD8+ T cells of Tc2 phenotype represents a strategy for improving allo BMT outcome.
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PMID:CD8+ T cells of Tc2 phenotype mediate a GVL effect and prevent marrow rejection. 970 64

Mosmann first proposed the existence of subsets of CD4+ T cells that produce distinct types of cytokines. Native T lymphocytes (Thp cells) differentiates into either CD4+ Th1 cells that produce IL-2, IFN gamma, and lymphotoxin which promote cell-mediated immunity, or into Th2 cells that produce IL-4, IL-5, IL-6, IL-10 and IL-13, which promote antibody production and humoral immunity. These T cell subsets reciprocally regulate one another since one of the Th1 products, IFN gamma, inhibits the proliferation and functions of Th2 cells, whereas the Th2 products, IL-4 and IL-10, suppress cytokine production by Th1 cells. A distinct Th1/Th2 divergence determine resistance versus susceptibility to diseases such as leishmaniasis and toxoplasmosis in mice. In allergic diseases such as atopic dermatitis and allergic asthma, allergen-specific T cells acquired the Th2 phenotype. These Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. These cytokines induce eosinophilia and an Ig class switch to IgG4 and IgE. These Th2 cells are responsible for the enhanced production of IgE antibodies. These findings indicate that Th2 cytokines play an important role in the development of allergic diseases. The importance of cell-mediated immunity, particularly donor-anti-host CTL, in mediating acute GVHD suggests that Th1 cytokines may be important in the induction of acute GVHD. To further characterize the roles of Th1 and Th2 cytokines in the development of acute GVHD, analysis of IL-2, IFN gamma, IL-4 and IL-10 cytokine genes was performed by RT-PCR on biopsied skin specimen. An increase in mRNA expression for IL-2 and IFN gamma was observed, whereas there was no significant increase in IL-4 and IL-10 mRNA. These data suggest that Th1 cytokines may be essential for the development of acute GVHD. It is apparent that Th1 cytokines are generally harmful to the maintenance of pregnancy. We have shown that Th2 cytokines are produced by maternal T lymphocytes at the maternal-fetal surface (retroplacental blood lymphocytes). This finding strengthens the hypothesis of a significant contribution of Th2 cytokines to a successful pregnancy.
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PMID:[A role for T-helper type 1 and type 2 cytokines in the pathogenesis of various human diseases]. 980 Apr 77

The dysregulation of cytokines is thought to play a role in the inflammatory and allospecific components of graft-versus-host disease (GVHD) and graft rejection (GR) post allogeneic bone marrow transplantation (BMT). Both complications occur post unrelated BMT at significantly higher frequencies than post BMT from identical sibling donors. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-1beta, IL-6, IL-10 and IL-12 following unrelated BMT were measured to examine cytokine dysregulation involvement in GVHD and GR. Of the 26 patients included in this study, 15 developed GVHD (14 acute; 1 acute and chronic), 5 had GR and 6 had uneventful BMT. TNF-alpha was markedly elevated in 13/15 of the patients with GVHD and in 3/5 patients with GR. IL-6 was elevated in patients with acute GVHD and with GR. IL-12 levels were similar in pre- and post-BMT sera. No correlation was found between HLA-C match and cytokine levels. In conclusion, a positive correlation was found between elevated levels of TNF-alpha, IL-6 and IL-10, and GVHD (p < 0.05, p < 0.005 and p < 0.002 respectively) and GR (p < 0.01).
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PMID:Dysregulation of inflammatory cytokines in unrelated bone marrow transplantation. 982 41

Intercellular adhesion molecule-1 (ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti-ICAM-1 and anti-LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r =.58, P <.05) between day 3 and 28. Treatment with anti-ICAM-1 (but not anti-LFA-1) decreased both the mean grades of portal inflammation (P =.003) and NSDC (P =.002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti-ICAM-1 and anti-LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti-ICAM-1, alone (P =.02). Anti-ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P <.01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti-ICAM-1 nor anti-LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC.
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PMID:Role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model. 1005 78

Growth factor-mobilized peripheral blood stem cells (PBSCs) engraft rapidly in myeloablated recipients compared to conventional BM, but this procedure also mobilizes mature lymphocytes and monocytes which can impact immune reconstitution and GVHD. Hence, we serially evaluated immune reconstitution and cytokine expression in PBSCT recipients in the first year. Engraftment of neutrophils and monocytes stabilized early but NK cells, B cells and CD4+ T cell numbers were significantly (P < 0.05) low with persistently reversed CD4:CD8 ratios. NK function remained low throughout the first year. The quantitative decrease in CD4+ T cells resulted in significantly decreased proliferation in response to mitogens and alloHLA antigens. Yet, a qualitative analysis of T cell function measured by Ca++ influx after T cell activation with antiCD3 as well as T-dependent polyclonal Ig secretion by mitogen-stimulated B cells was preserved even early post transplant. TNF alpha mRNA was detected in almost all recipients in the first year. IL-10 mRNA was detected in 77%, IL-2 in 22% and IFN gamma in 44% of recipients in the first 6 months. Only 30% expressed IL-10 in the second 6 months post transplant while expression of IL-2 and IFN gamma was detected in 38% and 46% respectively. Thirty-seven percent of PBSCT recipients developed grades II-IV acute GVHD but 72% went on to develop chronic extensive GVHD at a median of 120 days. Sixty-two percent developed CMV viremia and 5.4% developed overt CMV disease in the first year post PBSCT. Lymphocyte engraftment is quantitatively delayed but CD4 functions are preserved while NK numbers and function are compromised post PBSCT. IL-10 expression decreases after the first 6 months post transplant while TNF alpha is continually expressed. The balance between quantitative lymphocyte reconstitution and qualitative lymphocyte functions as well as changes in lymphokine patterns may influence infection and GVHD and thus the clinical outcome post PBSCT.
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PMID:Immune reconstitution following allogeneic peripheral blood stem cell transplants. 1010 May 77

Cyclosporin A (CsA) has been used clinically to induce graft-versus-host disease following autologous bone marrow transplantation in an attempt to destroy residual leukemia cells and reduce relapse. To analyze the antitumor potential of murine syngeneic graft-versus-host disease (SGVHD), C3H/HeN mice were lethally irradiated, reconstituted with T cell-depleted syngeneic bone marrow (ATBM) and treated with CsA for 21 days. Graft-versus-leukemia activity was assessed by challenging groups of olive oil-treated control ATBM (OO-ATBM) and CsA-treated (CsA-ATBM) mice 1 week after CsA therapy with graded doses of the syngeneic 38C13 B cell lymphoma. Following CsA treatment, up to 70% of CsA-ATBM developed SGVHD and more than 70% of the animals injected with 500 38C13 cells exhibited long-term survival (MST >80 days). In contrast, none of the OO-ATBM control mice developed SGVHD, and more than 75% of these mice died following injection of 500 38C13 tumor cells (MST = 34 days). Long-term survivors were not resistant to tumor challenge suggesting that tumor-specific immunity did not develop. Finally, class II negative 38C13 cells cultured in IL-4 or IL-10 were not inducible for MHC class II molecules, demonstrating that class II-independent antitumor mechanisms exist in SGVHD mice.
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PMID:Rejection of an MHC class II negative tumor following induction of murine syngeneic graft-versus-host disease. 1010 May 80

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