UMLS:C0018133 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0018133 (graft-versus-host disease)
18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-18 (IL-18) is a unique cytokine that modulates both T(H)1/T(H)2 responses, but its ability to modulate diseases through induction of T(H)2 cytokines is unclear. It has been shown to play an important role in allogeneic bone marrow transplantation (BMT). Because immune responses of allogeneic BM donors may affect acute graft-versus-host disease (GVHD), we investigated the effect of pretreating BM transplant donors with IL-18 on the severity of acute GVHD using a well-characterized experimental BMT model (BALB/c-->B6). Pretreatment of allogeneic BM transplant donors with IL-18 significantly improved survival (80% vs 0%; P <.001), and reduced clinical, biochemical, and pathologic indices of acute GVHD in BM transplant recipients. IL-18 pretreatment was associated with reduced interferon gamma (IFN-gamma) and greater IL-4 secretion by donor T cells after BMT. Acute GVHD mortality was reduced when IL-18 was administered to donors deficient in IFN-gamma and signal transducer and activator of transcription 4 (STAT4) but not STAT6 signaling molecules, suggesting a critical role for STAT6 signaling in IL-18's protective effect. IL-18 treatment did not alter donor CD8(+) cytotoxic T-lymphocyte (CTL) activity and preserved graft-versus-leukemia (GVL) effects after allogeneic BMT (70% vs 10%; P <.01). Together these data illustrate that pretreatment of donors with IL-18 prior to allogeneic BMT attenuates acute GVHD in a STAT6-dependent mechanism while preserving GVL effects.
...
PMID:Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. 1243 81

Transferring DBA/2 spleen cells into (C57BL/10xDBA/2) F1 (referred to as BDF1) mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th(2) cytokines, hypergammaglobulinemia, and immune complex-mediated glomerulonephritis that resembles systemic lupus erythematosus. DNA motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (CpG ODN) induces Th(1) cytokine production in mice. This study examines the effect of administering CpG ODN to mice undergoing chronic GVHD, based on the premise that altering Th(1)/Th(2) activity might beneficially impact on disease progression.GVHD BDF1 mice injected with DBA/2 spleen cells were treated with weekly intraperitoneal injection of 50 microg CpG ODN. This treatment significantly suppressed the production of IgG anti-DNA autoantibody and reduced the development of glomerulonephritis. Serum IgG2a titers were higher in the CpG ODN than in non-CpG control group, whereas IgG1 titers were unchanged. As predicted, IFN-gamma levels were significantly higher in the CpG ODN-treated group, while IL-4 levels were lower, resulting in a shift in the Th(1)/Th(2) cytokine ratio. Results suggest that CpG ODN administration may be of therapeutic benefit in chronic GVHD.
...
PMID:Therapeutic effect of CpG motifs on the development of chronic graft-versus-host disease in mice. 1244 Nov 43

The authors report two cases of hypereosinophilia as the major presenting sign of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Tissue biopsies of the skin, salivary gland, gut, and liver showed evidence of acute GVHD (aGVHD). In one case, further investigations have been performed. Elevated levels of interleukin (IL)-5 and soluble IL-2 receptor were found in the blood, and skin biopsy specimens demonstrated high levels of IL-5 messenger ribonucleic acid (mRNA). In contrast, skin biopsy specimens from other patients with aGVHD but without eosinophilia were negative for IL-5 mRNA. The authors also demonstrated the presence of IL-4 and interferon(IFN)-gamma mRNA within the same skin biopsy specimen, suggesting that this case of aGVHD was mediated by both Th1 and Th2 cell type. These two patients were treated by glucocorticoids with resolution of the hypereosinophilia and the symptoms of GVHD. The authors briefly discuss the possible mechanisms of this hypereosinophilia with respect to aGVHD.
...
PMID:Hypereosinophilia as a presenting sign of acute graft-versus-host disease after allogeneic bone marrow transplantation. 1249 2

To detect effects of B7 co-stimulation on cytokines, especially on IL-2 mRNA and transcription factors NF-kappa B and AP-1, antiB7-1 McAb, antiB7-2 McAb and C TLA-4 Ig were added into mixture lymphocyte reaction (MLR) system to block B7/C D28 signal transduction, IL-2 mRNA and IL-4 mRNA were determined by using competitive PCR and IFN-gamma mRNA by using semi-quantitative PCR. MHC class II molecules and B7 transfectants were used to stimulate CD28(+) T cell, effects of B7 on NF-kappa B and AP-1 were detected by DNA-protein binding assay. The results showed that IL-2, IL-4 and IFN-gamma mRNA were significantly lower when blockade of B7-2 in MLR than blockade of B7-1. Synergistic effects could be seen with combination of two or three antibodies. One to six hours after MLR, tDR7 alone induced NF-kappa B binding activity; cotransfecting B7 no significantly difference at early time point. After 6 hours, induction of tDR7 was decreased whereas B7 prolonged the induction of NF-kappa B till 72 hours. tDR7 alone also upregulated AP-1 binding activity, on the contrary to NF-kappa B, co-transfecting B7-1 and B7-2 decreased AP-1 binding activity within 24 hours. But during 48 - 72 hours, B7 also prolonged the AP-1 binding activity. It is concluded that after MLR, B 7 increased IL-2 secretion by decreasing the degradation of IL-2 mRNA and upregulating IL-2 transcription factors. B7 also induced several kinds of cytokines secretion. Effects of B7-1 and B7-2 had no significant difference on transcription factors. It is suggested that the different functions between B7-1 and B7-2 maybe related to the difference of cell expression and kinetics. To study the molecular mechanism of B7 mediated T cell immune tolerance can help us to design a better clinic schema to prevent transplantation rejection and GVHD.
...
PMID:[The identical effects of B7-1 and B7-2 on regulation of human IL-2 gene transcription factors NF-kappa B and AP-1]. 1251 11

To investigate the mechanisms underlying the issue that bone marrow mesenchymal stem cells (MSC) could trigger low responsiveness of allogeneic T lymphocytes against alloantigens, phenotypes of T cells were analysed with flow cytometry before and after coculture of allogeneic T lymphocytes with MSC. Further, expression of cytokines including IL-4, IFN-gamma and TGF-beta1 was evaluated by RT-PCR and ELISA as well. The results showed that CD8(+) subpopulation was increased and CD25(+) subset was decreased in proportion after coculture of allogeneic T lymphocytes with MSC for 2 weeks. RT-PCR assay showed that MSC expressed TGF-beta1 but not IL-4 and IFN-gamma, and the result was further proved by ELISA assay showing that the secretion of TGF-beta1 reached to 1 ng/ml in 72 hours. It was concluded that allogeneic MSC suppressed T cells activation by alteration of T cell subpopulations. The suppressive effect was at least in part due to the secretion of TGF-beta1. The results indicate that MSC pretreatment might be useful in the prevention of GVHD in HLA-mismatched bone marrow transplantation and further donors for hematopoietic stem cells could be selected from greater potentials.
...
PMID:[Mesenchymal stem cells suppress allogeneic T cell responses by secretion of TGF-beta1]. 1251 58

The 4-aminoquinolines, chloroquine and hydroxychloroquine, are established, with a 52% response rate, as therapy for human steroid-refractory GVHD after BMT. Chloroquine affects numerous mechanisms that play a role in GVHD, including inhibition of major histocompatibility complex (MHC) class II antigen presentation, cytokine production, and antigen-presenting cell activation by bacterially derived CpG oligodeoxynucleotides (ODNs). Using an MHC-disparate murine model, we evaluated the effect of chloroquine treatment on the development of acute GVHD. We assessed the effect of chloroquine on the immunostimulatory responses induced by CpG ODNs after BMT. We also evaluated the impact of chloroquine on cytokine-producing populations known to affect GVHD, including CD4+ and CD8+ T-cell and CD3(+)/NK1.1(+) natural killer T-cell (NKT cell) populations. Twelve (86%) of 14 mice receiving phosphate-buffered saline solution (PBS) developed lethal GVHD; only 4 (29%) of 14 mice receiving chloroquine 20 mg/kg 3 times per week developed lethal GVHD (P < .01). Chloroquine significantly suppressed CpG ODN-induced splenic proliferation and interleukin 6 (IL-6) production associated with GVHD. Chloroquine suppressed CD8+ T-cell production of IL-2 and IL-4 associated with GVHD in this model and maintained an early expansion (day 7) of splenic NKT cells. These results indicate that the 4-aminoquinolines are effective in therapy for or prevention of acute GVHD secondary to MHC disparities. Chloroquine actions may include inhibition of CpG ODN augmentation of GVHD. Other mechanisms involved may include suppression of CD8+ T-cell production of IL-2 and IL-4 and an increase in NKT cells associated with GVHD inhibition by chloroquine.
...
PMID:Chloroquine prevention of murine MHC-disparate acute graft-versus-host disease correlates with inhibition of splenic response to CpG oligodeoxynucleotides and alterations in T-cell cytokine production. 1252 76

CD4 T cells regulate immune responses that cause chronic graft rejection and graft versus host disease but their target antigens remain virtually unknown. We developed a new method to identify CD4 T cell-stimulating antigens. LacZ-inducible CD4 T cells were used as a probe to detect their cognate peptide/MHC II ligand generated in dendritic cells fed with Escherichia coli expressing a library of target cell genes. The murine H46 locus on chromosome 7 was thus found to encode the interleukin 4-induced IL4i1 gene. The IL4i1 precursor contains the HAFVEAIPELQGHV peptide which is presented by A(b) major histocompatibility complex class II molecule via an endogenous pathway in professional antigen presenting cells. Both allelic peptides bind A(b) and a single alanine to methionine substitution at p2 defines nonself. These results reveal novel features of H loci that regulate CD4 T cell responses as well as provide a general strategy for identifying elusive antigens that elicit CD4 T cell responses to tumors or self-tissues in autoimmunity.
...
PMID:Second class minors: molecular identification of the autosomal H46 histocompatibility locus as a peptide presented by major histocompatibility complex class II molecules. 1256 21

We have evaluated recovery of CD56 positive and other cell types following allogeneic stem cell transplantation and have found that the recovery of CD56 positive cells was faster than other lymphoid cells after allogeneic stem cell transplantation, while the recovery of CD4 positive cells was markedly delayed. Chimerism analysis showed that mixed chimerism was often observed in younger (<30 years old) patients. Mixed chimerism in older (> or =30 years old) patients was associated with rejection and relapse, while this was not found in younger patients. Among the chimerism of various cell populations, donor-derived CD56-positive cells are important in early engraftment when determined in allogeneic nonmyeloablative stem cell transplantation (allo-NST), regardless of the proportion of donor-derived CD3-positive cells. Complementarity-determining region three (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies (Vbeta) showed that high level of diversity in TCR Vbeta repertoire is important for a late rejection and skewed TCR Vbeta repertoire is correlated with the occurrence of graft-versus-host disease (GVHD) especially chronic GVHD. Expression of inhibitory natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral CD3-negative and -positive cells were increased in parallel with GVHD. Interestingly, these cells appeared to control GVHD, while preserving graft-versus-leukemia (GVL) effect. Analysis of cytokine gene expression in peripheral blood mononuclear cells showed that type 1 helper T cells (Th1)-derived cytokines increased in severe GVHD, while Th2-derived cytokines such as IL-4, IL-10 and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress GVHD, although Th1 cells augment GVHD. Taken together, evaluation of immune reconstitution and tolerance in patients receiving allogeneic stem cell transplantation from the various viewpoints is essential and useful to obtain better clinical outcome.
...
PMID:Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation. 1262 23

Although in utero transplantation (IUT) has resulted in donor-specific tolerance to posnatal solid organ transplantation, the mechanisms of this tolerance remain poorly understood. Our recent findings demonstrate that under specific conditions prenatal injection of allogeneic cells may lead to allosensitization instead of tolerance. These laboratory observations were supported by clinical findings as well, and therefore suggested that, depending on the conditions of prenatal transplantation, tolerance or immunity may develop. The present study explored the role of CD4 cells, cytokines, and I-E superantigen in developing tolerance vs. immunity after in utero transplantation. Sixteen animals survived IUT (40-60% survival rate) and were free from any signs of graft-versus-host disease (GVHD). Mice were considered tolerant when their antidonor and antihost CTL responses were similar, sensitized when antidonor responses were significantly higher than antihost and anti-third-party responses, and nontolerant when antidonor responses in transplanted and control mice were similar. The TH1 --> TH2 shift was associated with tolerance and TH2 --> TH1 shift with allosensitization. Our results showed that tolerant BALB/c (H-2d, I-E+) --> CS7BL/6 (H-2b, I-E-) (2/7) mice showed higher IL-4 (p < 0.05) in antidonor MLR, and partial deletion of recipient I-E-reactive T cells (CD3Vbeta11) (p < 0.045). On the other hand, nontolerant animals (5/7) demonstrated high production of IFN-gamma (p < 0.05) without deletion of CD3Vbeta11 T cells. In C57CBL/6 (H-2b, I-E-) --> C3H (H-2k, I-E+) mice CD3Vbeta11 T cells do not play any role in tolerance induction because they are deleted in the C3H background. Tolerant mice (4/9) showed an overproduction of IL-4 (p < 0.05) in antidonor MLR whereas allosensitized animals (5/9) demonstrated high level of IFN-gamma (p < 0.05). Suppressor cells seem to play no role in tolerant C57BL/6 --> C3H as demonstrated by suppressor assay. Hence, a shift from TH1 --> TH2 or TH2 --> TH1 cytokines may determine whether tolerance or immunity develops.
...
PMID:Tolerance and immunity following in utero transplantation of allogeneic fetal liver cells: the cytokine shift. 1269 67

Adoptive T-cell therapy using CD3/CD28 co-stimulation likely requires in vivo generation of antigen specificity. Because CD28 promotes TH1/TC1 (T1) or TH2/TC2 (T2) differentiation, costimulation may generate donor T1 or T2 cells capable of differentially mediating allogeneic graft-versus-tumor (GVT) effects and graft-versus-host disease (GVHD). Costimulation under T1 or T2 conditions indeed generated murine TH1/TC1 cells secreting interleukin-2/interferon-gamma (IL-2/IFN-gamma) or TH2/TC2 cells secreting IL-4/IL-5/IL-10. In vivo, allogeneic T1 cells expanded, maintained T1 secretion, and acquired allospecificity involving IFN-gamma and IL-5. In contrast, allogeneic T2 cells expanded less and maintained T2 secretion but did not develop significant allospecificity.Allogeneic, but not syngeneic, T1 cells mediated a GVT effect against host-type breast cancer cells, as median survival time (MST) increased from 25.6 +/- 2.6 (tumor controls) to 69.2 +/- 5.9 days (P < 1.2 x 10(-9)). This T1-associated GVT effect operated independently of fasL because T1 cells from gld mice mediated tumor-free survival. In contrast, allogeneic T2 cells mediated a modest, noncurative GVT effect (MST, 29 +/- 1.3 days; P <.0019). T1 recipients had moderate GVHD (histologic score, 4 of 12) that contributed to lethality after bone marrow transplantation; in contrast, T2 recipients had minimal GVHD (histologic score, 1 of 12). CD3/CD28 co-stimulation, therefore, generates T1 or T2 populations with differential in vivo capacity for expansion to alloantigen, resulting in differential GVT effects and GVHD.
...
PMID:CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects. 1285 80

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>