Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.69 (BMT)
 2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to explore the influence of purified donor regulatory T cells (T(Reg) cells) infused after allogeneic bone marrow transplantation (allo-BMT) on GVHD and hematopoietic reconstitution of mice, an allo-BMT model of C(57)BL/6-->BALB/c mice was established. CD4(+)CD25(+)T(Reg) cells were purified through bead-magnetic activated cells separated from donor mice peripheral blood. The recipient mice were randomly divided into three groups: CD4(+)CD25(+) T cells, CD4(+)CD25(-) T cells and RPMI 1640 culture medium. These cells and RPMI 1640 were infused into recipient mice by caudal veins at about 6 to 8 hours after allo-BMT respectively. Incidence of GVHD, pathological lesion of liver, spleen, small intestine, survival time and hematopoietic reconstitution in the recipients were observed after allo-BMT. The results showed that the time for WBC > 1.0 x 10(9)/L was (8.14 +/- 3.26) days, (17.62 +/- 5.71) days, (19.81 +/- 6.77) days and the time for Plt > 20.0 x 10(9)/L was (5.29 +/- 1.34) days, (8.97 +/- 3.44) days, (9.52 +/- 3.92) days in T(Reg) positive cell group, T(Reg) negative cell group and the blank control group respectively, and the recovery times of WBC and Plt in T(Reg) positive cell group were faster than that in T(Reg) negative cell group and the blank control group (P < 0.05). The scores of GVHD were (1.33 +/- 0.58), (1.80 +/- 0.27), (1.93 +/- 0.45) in three groups of mice at about 15 days after allo-BMT, respectively, the GVHD in T(Reg) positive cell group was slighter than that in T(Reg) negative cell group and the blank control group (P < 0.05). It was found that GVHD pathologic manifestations of the liver, spleen and small intestine in T(Reg) positive cell group were slighter in a certain extent than those in other two groups at about (25 - 30) days after allo-BMT. The mean survival time in three groups was (41.45 +/- 17.88) days, (18.75 +/- 14.39) days and (25.67 +/- 16.84) days after allo-BMT, respectively, which in the T(Reg) positive cell group was significantly longer than that in other two groups (P < 0.05). It is concluded that donor-T(Reg) cell infusion can mitigate the GVHD so as to reach hematopoietic reconstitution and prolong survival time after allo-BMT in mice.
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PMID:[Influence of donor T(reg) cells on GVHD and hematopoietic reconstitution after allogeneic bone marrow transplantation in mice]. 1760 63

Syngeneic graft-vs.-host disease (SGVHD) develops in rodents following the treatment of lethally irradiated, bone marrow (BM) reconstituted animals with a short course of the immunosuppressive agent cyclosporine A (CsA). Using an in vivo depletion approach, we recently demonstrated that CD4(+), but not CD8(+), T cells participated in inducing SGVHD. Studies were therefore undertaken to adoptively transfer SGVHD into lethally irradiated, syngeneic BM reconstituted secondary recipients. Whole T cell populations as well as purified CD4(+)T cells isolated from SGVHD, but not normal or transplant control, animals mediated the transfer of SGVHD into secondary recipients. These cells have an apparent specificity for enteric bacterial antigens. The pathologic process that developed was identical to that observed in the animals with de novo SGVHD after syngeneic BMT and CsA therapy. It was shown that a radiation-sensitive mechanism prevented the transfer of SGVHD into normal, nonirradiated secondary recipients. The ability to reproducibly transfer SGVHD into secondary recipients will enhance our ability to study regulatory mechanisms that are altered during CsA therapy and permit the development of murine CsA-induced SGVHD.
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PMID:Adoptive transfer of murine syngeneic graft-vs.-host disease by CD4+ T cells. 1772 53

Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4(+) but not CD8(+) T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFalpha but not IFNgamma levels. Transfer of Tnf(-/-) T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8(+) T cells resulted in enhanced GVT response, which was dependent on donor CD8(+) T cell-derived IFNgamma. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4(+) T cells from the graft or by inhibiting TNFalpha.
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PMID:Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation. 1853 2

The objective of this study was to investigate the function and mechanism of hyperbaric oxygen (HBO) in antagonizing acute graft-versus-host disease (aGVHD) and improving the rate of survival. The lethally irradiated C57BL/6 recipients were injected with bone marrow and lymphocyte of spleen from BALB/c donors and were treated with HBO, cyclosporine A (CsA) and methotrexate (MTX). T lymphocytes and subsets, adhesion molecules and cytokines were detected by flow cytometry, ELISA and RT-PCR respectively. The results showed that the survival rate in HBO group was much higher than that in allogenetic bone marrow transplantation (allo-BMT) group and CsA + MTX group; the numbers of CD3(+), CD4(+), CD8(+), CD4(+)CD11a(+), CD4(+)CD18(+), CD8(+)CD11a(+), CD8(+)CD18(+) lymphocytes in spleen were decreased markedly by HBO and CsA + MTX (p < 0.05); the levels of IL-2 and TNFalpha mRNA and their serum concentrations in HBO group were much lower than those in allo-BMT group but were higher than those in CsA + MTX group; the levels of IL-4 and IL-10 mRNA in HBO group were much higher than those in allo-BMT group and CsA + MTX group. It is concluded that HBO has more remarkable advantage in improving the rate of survival than CsA + MTX, its mechanism of anti-aGVHD is tightly correlated with the transform of T cell and its subsets and the expression of adhesion molecules and cytokines.
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PMID:Effect of hyperbaric oxygen on acute graft-versus-host disease after allogeneic bone marrow transplantation. 1854 42

CD4(+) interleukin-17 (IL-17)(+) T cells (Th17 cells) have been implicated in allograft rejection of solid organs and several autoimmune diseases. However, the functional role of Th17 cells in the development of acute graft-versus-host disease (GVHD) has not been well-characterized. We detected significant numbers of alloreactive CD4(+) donor T cells expressing IL-17, IL-17F, or IL-22 in the lymphoid organs of recipients of an allogeneic bone marrow transplant. We found no differences in GVHD mortality or graft-versus-tumor (GVT) activity between wild type (WT) and IL-17(-/-) T-cell recipients. However, upon transfer of murine IL-17(-/-) CD4(+) T cells in an allogeneic BMT model, GVHD development was significantly delayed behind recipients of WT CD4(+) T cells, yet overall GVHD mortality was unaffected. Moreover, recipients of IL-17(-/-) CD4(+) T cells had significantly fewer Th1 cells during the early stages of GVHD. Furthermore, we observed a decrease in the number of IFN-gamma-secreting macrophages and granulocytes and decreased production of proinflammatory cytokines (interferon [IFN]-gamma, IL-4, and IL-6) in recipients of IL-17(-/-) CD4(+) T cells. We conclude that IL-17 is dispensable for GVHD and GVT activity by whole T cells, but contributes to the early development of CD4-mediated GVHD by promoting production of proinflammatory cytokines.
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PMID:IL-17 contributes to CD4-mediated graft-versus-host disease. 1893 41

We examined the effects of intra-BM-BMT (IBM-BMT) plus adult thymus transplantation (ATT) from the same donor after 5.5 Gy sublethal irradiation (SubLI) or low-dose (3 x 10(6)) BM cell injection (LDBMCI). With SubLI, BALB/c mice that had received 1 x 10(7) bone marrow cells by IBM-BMT plus ATT from B6 mice showed 73% donor chimerism, whereas those treated with IBM-BMT alone showed 45% chimerism. In the LDBMCI with 7Gy irradiation, IBM-BMT plus ATT resulted in a 90% survival rate with 90% chimerism, whereas IBM-BMT alone resulted in a 55% survival rate with 44% chimerism. Although the number of CD4 T cells was higher in IBM-BMT plus ATT than in IBM-BMT alone, the percentages of FoxP3+/CD4+ T cells and lymphocyte functions in the former were almost identical to those in the latter. When treated with IBM-BMT plus donor lymphocyte infusion (DLI), the mice showed a reduced survival time as a result of GVHD, with low numbers of FoxP3+CD4 T cells under either condition, although 100% chimerism was induced. These results suggest that IBM-BMT plus ATT is effective in reconstituting the recipients with donor-derived cells even after SubLI or LDBMCI.
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PMID:Allogeneic intra-BM-BMT plus adult thymus transplantation from same donor has benefits for long-term survival even after sublethal irradiation or low-dose BM cell injection. 1907 14

Keratinocyte growth factor (KGF) protects mice from acute graft-vs-host disease and graft rejection by cytoprotective and yet incompletely understood immunological mechanisms. Recently, we showed that administration of KGF induces selective peripheral expansion of CD4(+)Foxp3(+) regulatory T cells (Treg). In this study, we set out to assess whether the peripheral expansion of Treg accounts for the immunomodulatory effects of KGF after bone marrow (BM) transplantation. To exclude potentially confounding cytoprotective and thymopoietic effects of KGF, we applied KGF to congenic wild-type mice that served as T cell provider mice for T and B cell-deficient RAG-1(-/-) mice that were subsequently transplanted with allogeneic BM. Treatment of congenic T cell provider mice with KGF significantly improved engraftment and reduced graft rejection in BMT recipients. CD4(+)Foxp3(+) Treg remained increased for 4 wk, while expansion of congenic CD3(+) T cells was inhibited. To assess a causal relationship between expansion of Treg and improved BM engraftment, congenic Scurfy mice, which lack Foxp3(+) Treg, served as T cell provider mice and were treated with KGF. KGF-treatment of Scurfy mice did not affect engraftment nor did it inhibit the expansion of congenic T cells. These data demonstrate that administration of KGF to the T cell provider mice improves engraftment of allogeneic BM through a CD4(+)Foxp3(+) Treg-dependent mechanism.
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PMID:Keratinocyte growth factor improves allogeneic bone marrow engraftment through a CD4+Foxp3+ regulatory T cell-dependent mechanism. 1949 58

We present long-term outcomes of BXSB mice after non-myeloablative bone marrow transplants using major histocompatability complex (MHC)-matched cells. Groups differed in sources of donor lymphocytes or mesenchymal stromal cells (MSC). Unfractionated marrow cells from green fluorescent protein (GFP) transgenic (Tg) mice (BMT group) or from RAG1-/- B6 mice (RAG group) were injected intravenously (i.v.) into irradiated (550 cGy) hosts. As a source of mesenchymal cells, bone chips from GFP-Tg were injected intraperitoneally alone (MSC group) or along with i.v. bone marrow cells (BMT + MSC group). Controls were untreated mice (UnTx) or mice exposed to radiation only (Rad Cont). At 62 weeks post-transplant, surviving mice were harvested for histopathology, flow cytometry and real time polymerase chain reaction (RT-PCR). The mice from BMT + MSC group had the best outcomes for survival rates (71.4% vs. 43.8%), renal scores (2.9% vs. 28.8% glomerular sclerosis) and percent splenic monocytes (4.2 vs. 11.3%) compared with mice from Rad Cont. Improvement in RAG and BMT groups was less prominent but were comparable with one another. Although MSC alone were not sufficient to control the renal pathology, it limited the expansion of CD4(-)CD8(-) T cell populations without a change in Foxp3 expression. The results suggest the importance of the innate immune system in disease pathogenesis and a role for MSC in immunomodulation.
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PMID:Long-term follow-up after non-myeloablative transplant of bone and marrow in BXSB mice. 1957 6

Co-stimulatory molecules expressed on T cells critically regulate donor T-cell activation and are implicated in acute GVHD after allogeneic BMT. We here investigated the role of interaction between B7-related protein-1 (B7RP-1) and ICOS in murine acute GVHD model that received T cell-depleted BM cells and splenocytes. Administration of blocking anti-B7RP-1 mAb significantly reduced the lethality and symptoms in acute GVHD. A significant hypo-responsiveness of splenocytes to host alloantigen was observed in the recipient mice treated with anti-B7RP-1 mAb. Moreover, acute GVHD was significantly reduced in the recipients of T cells composed of ICOS-deficient CD8 T cells and WT CD4 T cells compared with that in the recipients of T cells composed of WT CD8 T cells and ICOS-deficient CD4 T cells. These results suggested that B7RP-1/ICOS co-stimulatory signal plays a role in the activation of alloantigen-reactive donor T cells, particularly in CD8 T cells, in murine acute GVHD model, and that the blockade of B7RP-1/ICOS interaction may be useful for selectively manipulating allo-reactive T cells in the recipients with acute GVHD.
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PMID:Contribution of B7RP-1/ICOS co-stimulation to lethal acute GVHD. 2013 24

In order to explore the influence of purified donor regulatory T cells (Treg) infused after allogeneic bone marrow transplantation (allo-BMT) on GVHD and GVL effect in mice, an EL4 leukemia allo-BMT model of BALB/c-->C57BL/6 mice was established. The CD4(+)CD25(+)T cells were purified by positive selection using MACS. The recipients were injected with CD4(+)CD25(+)T cells or CD4(+)CD25(-)T cells within 4 hours respectively along with allo-BMT. Survival time, clinical GVHD score or histopathological features were observed after allo-BMT. The results showed that the mean survival time in leukemia control group was (17.9 +/- 0.7) days and all mice died of leukemia. The mean survival times in transplantation control group and CD4(+)CD25(-)T group were (23.2 +/- 1.6) and (22.3 +/- 1.9) days. Histopathological analysis in several target organs (skin, liver and small intestine) confirmed the presence of severe GVHD. The mean survival time in Treg group was (47.3 +/- 6.5) days. 70% of recipients were alive until day 60 without features of GVHD or tumor progression. Clinical GVHD scores in Treg group significantly decreased as compared to transplantation control group and CD4(+)CD25(-)T group (p < 0.05). It is concluded that allo-BMT combined with injection of donor CD4(+)CD25(+)Treg cells can efficiently prevent recipients from lethal GVHD with preserving GVL effect during allo-BMT.
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PMID:[Influence of donor Treg cells on GVHD and GVL effects after allogeneic bone marrow transplantation in mice]. 2013 43


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