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)

Autoantigen-specific CD4+ T cells have been implicated as the causative cell type in: multiple sclerosis, rheumatoid arthritis, autoimmune uveitis, diabetes mellitus, inflammatory bowel disease and graft-versus-host disease. The pathology of a number of experimentally induced autoimmune diseases is also mediated by autoantigen-specific CD4+ T cells. Ideally, treatment of CD4+ T-cell-mediated diseases would eliminate the autoantigen-specific cells, while sparing the remainder of the T-cell repertoire. We have developed an effective therapy that deletes the autoreactive T cells at the site of autoimmune tissue destruction. This approach uses an antibody directed against a cell-surface protein (OX-40, also known as CD134) that is selectively upregulated on activated autoantigen-specific T cells within the inflamed tissue.
 ...
PMID:Antibodies to OX-40 (CD134) can identify and eliminate autoreactive T cells: implications for human autoimmune disease. 954 94

CD134 (OX40) is a member of the tumor necrosis factor family which is expressed by activated T lymphocytes. CD134 expression on T cells was monitored during the first 35 days post-transplant in 14 patients, receiving either an HLA-identical sibling bone marrow transplant (BMT), a matched unrelated transplant (MUD-BMT) or an autologous peripheral blood progenitor cell transplant (PBPCT). The sibling and unrelated grafts were partially depleted of T cells. CD134 expression on CD4+ T cells peaked between 7 and 14 days after BMT, with a mean peak value of 45% of CD4+ cells (range 26-70%) over all three patient groups. The observed pattern of CD4+ CD134+ expression, an increase during the first 2 weeks post-BMT followed by a gradual decline towards values of 15-40%, was similar in all groups. No difference in the kinetics of CD134 expression by CD4+ T cells was observed between the patients that did or did not develop graft-versus-host disease (GVHD), nor did the clinical effect of any treatment given for GVHD correlate with alterations in CD134 expression by CD4+ T cells. Absolute CD4+,CD134+ T cell numbers showed a more rapid increment after autologous PBPCT than after sibling or MUD transplants. We conclude that expression of CD134+ by CD4+ T lymphocytes cannot serve as a surrogate marker for allo-reactivity. CD134+ expression may reflect lymphocyte regeneration, rather than alloreactivity.
 ...
PMID:Expression of T cell activation antigen CD134 (OX40) has no predictive value for the occurrence or response to therapy of acute graft-versus-host disease in partial T cell-depleted bone marrow transplantation. 1037 67

Expression of CD134 (OX40) on activated CD4(+) T cells has been observed in acute graft-versus-host disease (GVHD) after human and rat allogeneic bone marrow transplantation (BMT). We investigated the role of interaction between CD134 and CD134 ligand (CD134L) in a murine model of acute GVHD by using a newly established monoclonal antibody (mAb) against murine CD134L. Acute GVHD was induced by transfer of bone marrow cells and spleen cells into lethally irradiated recipients in a parent (C57BL/6) to first filial generation (C57BL/6 crossed with DBA/2) BMT. Administration of anti-CD134L mAb significantly reduced the lethality of acute GVHD and other manifestations of the disease, such as loss of body weight, hunched posture, diarrhea, and patchy alopecia. The survival rate 80 days after BMT in mice treated with the mAb was about 70%, whereas all mice treated with control antibodies died within 43 days. Histologic examinations revealed that inflammatory changes in target organs such as the liver, gut, and skin were also ameliorated in mice treated with the mAb compared with control mice. An in vitro assay of T-cell proliferation showed a marked hyporesponsiveness to host alloantigen in samples from mice treated with anti-CD134L mAb. In addition, low levels of interferon gamma and transiently elevated levels of interleukin 4 and IgE in serum samples were found in mice treated with anti-CD134L mAb. These results suggest that CD134-CD134L interactions have an important role in the pathogenesis of acute GVHD.
 ...
PMID:Blockade of CD134 (OX40)-CD134L interaction ameliorates lethal acute graft-versus-host disease in a murine model of allogeneic bone marrow transplantation. 1073 18

Intravenous immunoglobulin (IVIg) was shown to decrease the severity of acute graft-versus-host disease (aGVHD) in recipients of allogeneic bone marrow transplants. To investigate the mechanisms involved in the protective effect of IVIg, we have used the parent-into-F1 model in which parental lymphocytes are transferred into semi-syngeneic non-irradiated F1 rats. Here we report that IVIg, as well as F(ab')(2) fragments of IVIg, protected (Lewis x Brown-Norway) F1 rats against aGVHD induced by a single injection of Lewis lymphocytes. IVIg was given as five consecutive daily injections, starting on the day preceding that of the transfer of Lewis cells. Protection was associated with a decreased ability of lymphocytes to spontaneously proliferate and to produce NO and IFN-gamma, in the absence of an increased production of IL-10. We further demonstrate that protection was associated with a decrease in CD4(+) T cells bearing the activation marker CD134 in vivo, and with an enhanced apoptosis of activated CD4(+) T cells by IVIg, in vitro. Our observations suggest that the prevention of aGVHD by IVIg in this model is mediated by the induction of apoptosis of activated alloreactive CD4(+)CD134(+) donor T cells. The results further emphasize the role of normal immunoglobulin in modulating alloantigen immune responsiveness.
 ...
PMID:Normal IgG protects against acute graft-versus-host disease by targeting CD4(+)CD134(+) donor alloreactive T cells. 1153 77

There is no reliable laboratory indicator of the onset of chronic graft-versus-host disease (cGVHD). This study looks at whether the expression of OX40, a member of the tumor necrosis factor receptor family, is related to the development of cGVHD in patients who underwent allogeneic hematopoietic stem cell transplantation. Peripheral blood mononuclear cells from 22 patients after day 100 were subjected to multicolor flow cytometry. The percentages of both OX40+CD4+ and OX40+CD8+ T cells were significantly higher in patients with cGVHD than those without (P <.0001 and P =.001, respectively). Serial analyses showed that OX40+CD4+ T cells elevated before the onset of cGVHD and closely correlated with the therapeutic response. The expression of CD25, CD69, and HLA-DR was partially detectable on OX40+ T cells. These results indicate that serial measurement of OX40+ T cells is useful for predicting the onset as well as the therapeutic response of cGVHD and raise a possibility that the OX40/gp34 system is involved in the pathogenesis of cGVHD.
 ...
PMID:Correlation of peripheral blood OX40+(CD134+) T cells with chronic graft-versus-host disease in patients who underwent allogeneic hematopoietic stem cell transplantation. 1169 7

OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40(-/-) donor or OX40L(-/-) recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4(+) and CD8(+) T cells isolated during GVHD, the major effects of OX40 ligation were on CD4(+) and not CD8(+) T-cell-mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription-6(-/-) (Stat-6(-/-)) (Th2-defective) or Stat-4(-/-) (Th1-defective) major histocompatibility complex (MHC)-disparate splenocytes, indicating that the GVHD-ameliorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L(-/-) versus OX40L(+/+) T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD.
 ...
PMID:Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. 1252 97

CD134 (OX40) is expressed on activated CD4(+) donor T cells in allogeneic stem cell transplant recipients with acute graft-versus-host disease. The data presented here reveal that differential expression of CD25 by CD4(+) CD134(+) T cells allows separation of these activated cells into 2 phenotypically and functionally distinct alloreactive T-cell subsets. These subsets exhibit distinct tissue associations, with CD4(+) CD134(+) CD25(-) T cells preferentially found in lymphoid tissues and CD4(+) CD134(+) CD25(+) T cells located in lymphoid tissues and inflamed extralymphoid tissues. The CD25(-) T-cell subset exhibited potent proliferative responses to both concanavalin A and allogeneic host leukocytes. By contrast, the CD25(+) T-cell subset proliferated minimally in response to either treatment and inhibited alloantigen-induced proliferation of the CD25(-) subset. Proliferative unresponsiveness associated with the CD25(+) T-cell subset did not extend to cytokine secretion. When stimulated with alloantigen, both CD4(+) CD134(+) T-cell subsets responded by secreting interferon-gamma and interleukin (IL)-10, and neither T-cell subset produced detectable levels of IL-2 or IL-4. Three-day treatment of the CD25(+) T-cell subset with IL-2 restored the proliferative responsiveness of these cells to host alloantigens, suggesting that the proliferative unresponsiveness associated with this T-cell subset reflected a requirement for IL-2. The preferential tissue associations and distinct functional properties associated with these separable alloreactive CD4(+) CD134(+) T-cell subsets suggest that they participate differentially in clinical graft-versus-host disease.
 ...
PMID:CD25 expression distinguishes functionally distinct alloreactive CD4 CD134 (OX40) T-cell subsets in acute graft-versus-host disease. 1511 29

Graft-versus-host disease (GVHD) is still a major complication after allogeneic stem cell transplantation. In murine models, freshly isolated or ex vivo expanded CD4(+)CD25(high) regulatory T cells (Treg) are able to ameliorate GVHD while maintaining graft-versus-leukaemia reactions. However, in the human setting, prospective studies of this population and its interaction with activated non-regulatory CD134(+) (OX40) lymphocytes during post-transplant follow-up are lacking. In this study, we prospectively quantified CD4(+)CD25(high) and activated CD134(+) lymphocytes in 119 peripheral blood samples from 35 consecutive patients who underwent allogeneic bone marrow transplantation (BMT). Fifty-five samples obtained less than 100 d after allogeneic BMT, were not statistically different regarding CD4(+)CD25(high) Treg or CD134(+) lymphocytes compared with those obtained from patients with (n = 35) or without (n = 20) acute GVHD. Chronic GVHD was associated with a small, but not statistically significant, increase in the number of Treg (9.9 vs. 6.7 x 10(6)/L). However, the CD134/CD25(high) ratio was significantly higher during chronic GVHD (cGHVD) when compared with either patients without cGVHD (67.7 +/- 40.3 vs. 4.0 +/- 0.9, P < 0.01) or cGVHD after treatment (67.7 +/- 40.3 vs. 3.7 +/- 0.8, P < 0.01). Our findings suggest that the suppressive activity of CD4(+)CD25(high) Treg could be abrogated in vivo during cGVHD by CD134 expression in a much higher number of activated donor T lymphocytes. In addition to CD4(+)CD25(high)ex vivo expansion protocols, OX40 blocking might be crucial to optimize the use of Treg to prevent GVHD.
 ...
PMID:Kinetic of regulatory CD25high and activated CD134+ (OX40) T lymphocytes during acute and chronic graft-versus-host disease after allogeneic bone marrow transplantation. 1532 22

OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor family that is transiently expressed on T cells after T-cell receptor (TCR) ligation. Both naive and activated CD4(+)CD25+ regulatory T cells (T reg's) express OX40 but its functional role has not been determined. Since glucocorticoid-induced tumor necrosis factor receptor (GITR), a related TNF receptor family member, influences T reg function, we tested whether OX40 might have similar effect. Triggering either GITR or OX40 on T reg's using agonist antibodies inhibited their capacity to suppress and restored effector T-cell proliferation, interleukin-2 (IL-2) gene transcription and cytokine production. OX40 abrogation of T reg suppression was confirmed in vivo in a model of graft-versus-host disease (GVHD). In a fully allogeneic C57BL/6>BALB/c bone marrow transplantation, GVHD was lethal unless T reg's were cotransferred with the bone marrow and effector T cells. Strikingly, T reg suppression of GVHD was abrogated either by intraperitoneal injection of anti-OX40 or anti-GITR monoclonal antibodies (mAbs) immediately after transfer, or by in vitro pretreatment of T reg's with the same mAbs before transfer. Cumulatively, the results suggest that in addition to controlling memory T-cell numbers, OX40 directly controls T reg-mediated suppression.
 ...
PMID:Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. 1559 Nov 18

OX40 (CD134), a member of the tumor necrosis factor receptor superfamily, is expressed on activated T cells, including CD4(+)CD25(+) T regulatory (Treg) cells. To investigate the kinetics of OX40-OX40L in graft-versus-host disease (GVHD), OX40 mRNA transcript levels were temporally examined in peripheral blood mononuclear cells (PBMCs) from patients undergoing either allogeneic (allo) bone marrow transplantation (alloBMT) or autologous (auto) BMT with the induction of autoGVHD by cyclosporine (CsA) treatment posttransplant. Real-time quantitative PCR analysis revealed that OX40 mRNA expression decreased significantly in PBMCs from patients with either alloGVHD or autoGVHD compared with healthy individuals. No differences were detected between patients developing alloGVHD and those who did not develop this posttransplant complication. On the other hand, a decrease in OX40 mRNA levels correlated directly with the development of autoGVHD. Moreover, the upregulation of OX40 gene expression coincided with the resolution of autoGVHD. Interestingly, expression of OX40 by CD4(+) T lymphocytes after stimulation with autoantigen (Ag) was significantly (>700-fold) increased with a concomitant increase in expression of the Foxp3 regulatory gene. Expression of OX40 was increased (maximum 11-fold) after allo-Ag via mixed-lymphocyte reaction response. CsA suppressed the upregulation of OX40 expression after allo-Ag in a dose-dependent manner. Taken together, these results suggest that the decrease in OX40 expression posttransplant includes the defective reconstitution of Treg cells, and the active inhibition of gene transcription by CsA.
 ...
PMID:Regulation of OX40 gene expression in graft-versus-host disease. 1580 46


1 2 3 Next >>