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)

We have recently made the paradoxical observation that a single injection of recombinant murine interleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving fully major histocompatability complex (MHC)-mismatched bone marrow and spleen cells. We have now examined the mechanism of this effect of IL-12 on acute GVHD. By day 4 post-BMT, IL-12-treated mice showed marked reductions in splenic donor CD4(+) and CD8(+) T cells compared with GVHD controls. Expression of the early activation markers IL-2R alpha chain (CD25) and CD69 on splenic donor CD4(+) cells was considerably higher at early time points (36 and 72 hours post-BMT) in IL-12-treated mice compared with GVHD controls. However, the later, GVHD-associated increase in CD25 and very late antigen-4 (VLA-4) expression on donor T cells was greatly depressed in IL-12-protected mice compared with GVHD controls. The marked GVHD-associated expansion of host-reactive T helper cells by day 4 was also completely inhibited in the IL-12-treated group. Expression of Fas was increased on donor CD4 cells of IL-12-treated mice compared with those of controls on days 3 through 7 post-BMT. Furthermore, the ability of IL-12 to protect against GVHD was at least partially dependent on the ability of donor cells to express functional Fas molecules. We conclude that IL-12 treatment at the time of BMT markedly perturbs the activation of alloreactive donor CD4(+) T cells that play a critical role in the pathogenesis of acute GVHD. We hypothesize that these perturbations culminate in Fas-dependent apoptosis of donor T cells, thus impeding their expansion and their GVHD-promoting activity.
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PMID:Interleukin-12 inhibits graft-versus-host disease through an Fas-mediated mechanism associated with alterations in donor T-cell activation and expansion. 955 88

One of the main goals in allogeneic bone marrow transplantation is the abrogation of graft-versus-host disease with the preservation of antileukaemia and antiviral activity. We have established a novel system for the selective removal of alloreactive lymphocytes from donor grafts while retaining an effective allogeneic response to third-party stimulator cells. Initial feasibility studies were done with unrelated HLA-mismatched pairs and then extended into the matched setting. Mononuclear cells from HLA-matched donors were cocultured with irradiated recipient cells prestimulated with cytokines (gamma-IFN and TNF-alpha) in a modified mixed lymphocyte culture (MLC). Alloreactive donor lymphocytes were identified by expression of CD69, an early activation marker and selectively removed by paramagnetic bead sorting. The remaining 'non-alloreactive' lymphocytes were tested in proliferative assays against the original matched recipient and to a third-party donor. A mean depletion of proliferative capacity to 11.5 +/- 9.9% of the original matched recipient response was achieved while the residual third-party response was largely preserved at 77.8 +/- 20.9% which should translate into improved immune reconstitution and preservation of antiviral activity. The non-alloreactive lymphocytes could also possess functional antileukaemia activity. Moreover, the alloreactive cells are easily recoverable in this selective T cell depletion strategy for cryopreservation and ready for immediate access as therapeutic donor lymphocyte infusions in cases of frank relapse post transplant.
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PMID:Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis. 1037 75

Development of acute graft-versus-host disease (aGVHD) following HLA-identical sibling bone marrow transplantation (BMT) remains a serious complication. A selective depletion of T cells has proved to be effective in preventing aGVHD but is associated with relapse and increased incidence of infection. As aGVHD is directed mainly against epithelial tissues we examined whether it would be feasible to selectively deplete T cells reactive with epithelial cells whilst preserving other specificities. Donor T cells which express HLA-DR, CD25, CD69 and CD71 activation markers after cocultivation with patient keratinocytes were depleted using magnetic cell separation techniques. Depletion of major as well as minor histocompatibility antigen activated T cells revealed a significant (P = 0.004 and P = 0.031, respectively) 10-fold decrease in the frequency of donor T lymphocyte precursors reactive with patient keratinocytes. The frequency reactive with third-party and patient peripheral blood mononuclear cells, including leukaemia cells, remained unchanged, supporting the notion that aGVHD and graft-versus-leukaemia (GVL) may be separable. This alloantigen-specific depletion may be used in matched unrelated as well as HLA-identical sibling BMT for reducing aGVHD whilst conserving GVL.
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PMID:Selective depletion of major and minor histocompatibility antigen reactive T cells: towards prevention of acute graft-versus-host disease. 1052 38

Hydroxychloroquine (HCQ), a lysosomotropic amine, is an immunosuppressive agent presently being evaluated in bone marrow transplant patients to treat graft-versus-host disease. While its immunosuppressive properties have been attributed primarily to its ability to interfere with antigen processing, recent reports demonstrate HCQ also blocks T-cell activation in vitro. To more precisely define the T-cell inhibitory effects of HCQ, the authors evaluated T-cell antigen receptor (TCR) signaling events in a T-cell line pretreated with HCQ. In a concentration-dependent manner, HCQ inhibited anti-TCR-induced up-regulation of CD69 expression, a distal TCR signaling event. Proximal TCR signals, including inductive protein tyrosine phosphorylation, tyrosine phosphorylation of phospholipase C gamma1, and total inositol phosphate production, were unaffected by HCQ. Strikingly, anti-TCR-crosslinking-induced calcium mobilization was significantly inhibited by HCQ, particularly at the highest concentrations tested (100 micromol/L) in both T-cell lines and primary T cells. HCQ, in a dose-dependent fashion, also reduced a B-cell antigen receptor calcium signal, indicating this effect may be a general property of HCQ. Inhibition of the calcium signal correlated directly with a reduction in the size of thapsigargin-sensitive intracellular calcium stores in HCQ-treated cells. Together, these findings suggest that disruption of TCR-crosslinking-dependent calcium signaling provides an additional mechanism to explain the immunomodulatory properties of HCQ.
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PMID:Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties. 1082 29

Donor T cells support both engraftment and immune reconstitution after allogeneic BMT. Moreover, they may exert potent anti-tumor effects (graft-versus-leukemia, GVL), which are used for adoptive immunotherapy. On the other hand, infusion of allogeneic T cells is frequently associated with the manifestation of immune reactions against healthy tissue, which may lead to life-threatening graft-versus-host disease (GVHD). To overcome this problem, we developed a new strategy for the exclusive depletion of alloreactive cells from donor leukocytes. We activated donor T cells by co-cultivation with a stroma layer of recipient cells and analyzed activation kinetics of CD3+, CD4+ and CD8+ T cells. Based on these data, activated cells were then depleted based on expression of activation-induced antigens using magnetic cell sorting (MACS). Alloreactivity of donor T cells was remarkably decreased after depletion of cells expressing either CD25 or CD69, as was shown in suitable in vitro assays. The lowest level of alloreactivity was found when both CD25- and CD69-positive cells were depleted. Importantly, depleted cell fractions preserved reactivity against third-party cells. In summary, we found that MACS-based ex vivo depletion of alloreactive cells may be a suitable way to prevent GVHD and therefore improve allogeneic BMT and adoptive immunotherapy.
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PMID:Depletion of alloreactive donor T cells using immunomagnetic cell selection. 1093 86

After non-T-cell-depleted allogeneic hematopoietic stem cell transplantation (HSCT), both alloreactive and homeostatic signals drive proliferation of donor T cells. Host-reactive donor T cells, which proliferate on alloantigen stimulation, are responsible for the life-threatening graft-versus-host disease. Non-host-reactive donor T cells, which proliferate in response to homeostatic signals, contribute to the beneficial peripheral T-cell reconstitution. The elimination of alloreactive T cells is a major therapeutic challenge for HSCT and would greatly benefit from their specific identification. After T-cell transfer in lymphopenic recipients, the present results show that alloreactive T cells rapidly divided; up-regulated CD69, CD25, and CD4 molecules; and down-regulated CD62L. In contrast, nonalloreactive T cells started to divide later and did not up-regulate CD69, CD25, and CD4. Thus, these 2 cell populations can be effectively discriminated. This should facilitate the specific depletion of alloreactive T cells in allogeneic HSCT.
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PMID:Division rate and phenotypic differences discriminate alloreactive and nonalloreactive T cells transferred in lethally irradiated mice. 1846 12

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.
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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

Graft-versus-host disease (GvHD) is a multistep immune process involving lymphocyte activation, proliferation and target cell killing. We have devised a novel method for the selective depletion of alloreactive cells from haematopoietic stem cell grafts which retains a pool of immunocompetent lymphocytes possessing antiviral activity with the potential to hasten immune reconstitution. The method is based upon the expression of the activation antigen CD69 on responding donor lymphocytes in a cytokine-modified mixed lymphocyte culture (mMLC) and depletion of these cells by paramagnetic bead sorting. We have previously demonstrated the in vitro efficacy of this system for the removal of alloreactive cells in both human leucocyte antigen-mismatched and -matched settings. Here, we describe a non-obese diabetic/severe combined immunodeficient murine model of aggressive GvHD in which we have tested its in vivo efficacy. Murine recipients of infusions of non-manipulated major histocompatibility complex class I and class II mismatched donor T cells suffered rapid onset of acute, and generally fatal, GvHD. This model is akin to aggressive clinical transfusion-related GvHD. Recipients of lymphocyte infusions depleted of CD69+ alloreactive donor cells ex vivo and monitored for 10 weeks post infusion demonstrated significantly improved survival (71.4% compared with 12.5% in the non-manipulated group) and the absence of clinical GvHD despite the presence of circulating donor lymphocytes.
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PMID:Alloantigen-specific T-cell depletion in a major histocompatibility complex fully mismatched murine model provides effective graft-versus-host disease prophylaxis in the presence of lymphoid engraftment. 1210 Jan 33

Preconditioning with the nonmyeloablative regimen total lymphoid irradiation (TLI) before hematopoietic cell transplantation facilitates the establishment of mixed chimerism and protects against graft-versus-host disease. We reported that the development of mixed chimerism requires interleukin (IL)-4 and is associated with increased host anti-donor TH2 cells, but the effect of TLI on the differentiation of immunocompetent donor cells has not been investigated. To examine the extent to which TLI preconditioning influences donor T cells, we measured responses of transgenic CD4+cells specific for ovalbumin peptide (OVA-Tg) following in vivo and in vitro antigen stimulation in a TLI-preconditioned environment. OVA-Tg cells that were adoptively transferred into TLI-preconditioned mice that express cross-reactive antigens produced more IL-4 and less interferon-gamma and IL-2 than controls when stimulated with OVA peptide one week later. OVA-Tg primed in vitro with spleen from TLI-preconditioned mice generated more TH2 and fewer TH1 cells when stimulated in recall enzyme-linked immunosorbent spot (ELISPOT) assays with OVA peptide. Naive OVA-Tg up-regulated CD69 and CD25 normally following stimulation with OVA peptide in the presence of spleen from TLI-preconditioned mice, but proliferated less and secreted less IL-2 than controls. Surprisingly, naive OVA-Tg secreted IL-4 in primary cultures that were stimulated with OVA peptide in the presence of spleen from TLI-preconditioned mice. This response depends on CD4+cells from TLI-spleen, which constitutively produce IL-4 and are composed primarily of CD4+-natural killer T (TNK) cells. Thus, TLI preconditioning enriches for IL-4-secreting and TNK-like CD4+cells that may function in the protection from graft-versus-host disease by redirecting the differentiation of immunocompetent donor CD4+cells toward TH2 and away from pathogenic TH1 cells.
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PMID:Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4-producing CD4+-TNK cells and skews differentiation of immunocompetent donor CD4+ cells. 1240 8

To analyze the relation of early immune reconstitution with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (all-HSCT), the changes of CD3(+), CD4(+), CD8(+), CD25(+) and CD69(+) cells in peripheral blood from 26 patients with hematologic malignancies were assayed by flow cytometry within 2 months after allo-HSCT. All patients achieved hematopoietic reconstitution, and grade I and II - IV GVHD were developed in 9 and 5 patients, respectively. CD25(+) cells were increased in patients aGVHD at week 2 after transplantation and the peak value was appeared at week 3. The increase of CD25(+) cells was preceded the occurence of clinical signs of aGVHD. The maximal levels of CD25(+) cells increase correlated significantly with the severity of aGVHD. The increase of CD25(+) cells was declined along with remission of aGVHD signs. Our results suggest that analyzing immune reconstitution after allo-HSCT could predict occurence of aGVHD, and CD25(+) cell increase prior occurence of aGVHD is predictive marker for aGVHD.
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PMID:[Study on Relation of Early Immune Reconstitution with Acute Graft-Versus-Host Disease] 1257 78


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