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)

The peripheral blood regeneration of natural killer (NK) cells was studied before and on 5 occasions during the first 6 weeks after autologous bone marrow transplantation (auto-BMT) in 10 patients with hematological malignancies and solid tumors. The number of NK cells (relative as well as absolute), enumerated by their lack of CD3 and their expression of CD56 recovered after a severe decline 1 week posttransplant to increase beyond pretransplantation levels during the next 2 weeks. Similar patterns were seen for the average NK activity against K562 as well as LAK cell lytic activity against Daudi but without the overshoot at weeks 2-3. Moreover, the fraction, but not the absolute numbers, of NK cells was found to correlate to the lytic NK activity. In contrast, no phenotypic marker was correlated to LAK activity. Immunophenotypic studies using three-color flow cytometry revealed that during the first 2 weeks after auto-BMT the phenotype of NK cells changed towards an immature phenotype (decreased CD45RA and CD11a) 1 week after transplant to an activated (increase in CD25, HLA-DR and CD11c) after 2-4 weeks. However, when the absolute number of selected phenotypically defined NK cell subsets(CD45RA, CD45RB, CD11a, CD11c, CD2, CD25, HLA-DR and fibronectin expressing CD56+,CD3- NK cells) were compared to the cytotoxic activity for each patient, we were not able to show any correlations except between the activation-related antigens CD25 and HLA-DR on the one hand, and NK lysis on the other, and only 3 weeks after auto-BMT. We conclude that NK cell function recovers quickly following auto-BMT concomitantly with the emergence of a transiently altered phenotype which increased expression of activation-related antigens.
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PMID:Natural killer cells in peripheral blood after autologous bone marrow transplantation: a combined phenotypic and functional study. 883

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

We have previously identified donor-derived Thy1+ alphabeta T-cell receptor (TCR)+ CD4+ CD8- regulatory T-cells that suppress GVH reactivity induced by donor leukocyte infusion (DLI) after BMT. These cells develop in the recipient thymus and may play a role in the maintenance of donor-host tolerance after allogeneic BMT. In the present study, we sought to further characterize the T-cells responsible for the regulatory cell activity in our model. Lethally irradiated recipient AKR mice (H-2k) received transplants of BM from CD25-deficient (-/-) C57BL/6 mice (H-2b). Recipients of CD25-deficient BM developed more severe GVHD after DLI than did recipients of normal BM, a result that indirectly suggests that CD4+ CD25+ regulatory T-cells are important to the suppression of GVH reactivity after allogeneic BMT. GVHD was accompanied by mortality, body weight loss, and elevated percentages of T-cells from the DLI in the peripheral blood in mice that received CD25-deficient BM compared to mice that received normal BM. Both CD40-CD40L and CD28-B7 costimulatory pathways have been implicated in the generation of CD25+ regulatory T-cells. Therefore, we tested whether deficiency in either of these pathways affected the activity of donor BM-derived regulatory T-cells. The absence of CD40L did not affect the regulatory T-cells (ie, recipient mice were still protected from DLI-induced GVHD). In contrast, use of marrow from CD28-deficient mice resulted in complete loss of suppression of GVH reactivity. Thus, CD28 but not CD40L was critical for the generation and/or activation of immunoregulatory T-cells that suppressed GVHD induced by DLI. Together, the results of these experiments suggest that CD4+ CD25+ regulatory T-cells suppress GVH reactivity after BMT and that CD28 expression is indispensable for the generation of these cells.
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PMID:CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. 1243 47

To explore the feasibility of using CD25 monoclonal antibody (Basiliximab) in T-cell undepleted allo-BMT with graft from haplotype-matched related donor for acute GVHD prophylaxis. Twenty-eight patients with leukemia received allo-BMT from HLA two or three loci mismatched related donors. The donors were given G-CSF (Lenograstim) 250 micro g/d for 7 doses prior to marrow harvest. CSA, MTX, ATG and mycophenolate mofetil (MMF) were combined for GVHD prophylaxis. ATG 5 mg/(kg.d) was infused from day 4 to day 1 before transplantation and MMF was administered from day 7. In the study group, the patients received additional CD25 monoclonal antibody for aGVHD prophylaxis. CD25 20 mg each by 30 min intravenous infusion on 2 hours before transplantation and day 4 after transplantation was administered while no application of CD25 in the controls. The outcomes of transplantation were compared between the stud y and control groups. The results showed that the median number of CD34(+) cell in graft was 5.9 x 10(6)/kg in the control group and 7.9 x 10(6)/kg in the study group. The median number of CD3(+) cell was 48 x 10(6)/kg and 52 x 10(6)/kg respectively (P > 0.05). All patients showed 100% donor-typed hematopoietic cells after transplantation by cytogenetic evidence. Five out of fifteen patients in the control group experienced II - IV acute GVHD. While none of thirteen in the study group developed the II - IV acute GVHD. However, none in both groups developed extensive cGVHD. The median follow-up duration was 8 (3-15) months in the study group and 26 (15-36) months in control. In the study group, one patient died from transplant related mortality (CMV infection); no one relapsed; and 12/13 patients survived in disease-free situation within the period of follow-up. In the control group, six patients died from transplant related mortality (3 GVHD, 2 infection and 1 relapsed) and 9/15 patients survived in disease-free situation. The one-year probabilities of disease-free survival (DFS) in two groups were significantly different (P < 0.05). It is concluded that the transplant from haploidentical donors used CD25 antibody is effective and feasible in preventing acute severe GVHD and improving DFS. The major histocompatibility barrier in the haploidentical related allo-BMT could be crossed by donors primed with G-CSF and GVHD prophylaxis with CD25 antibody in the hosts.
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PMID:[A clinical study of haploidentical and G-CSF primed bone marrow transplantation by using CD25 for aGVHD prophylaxis]. 1251 46

Positively selected CD34(+) hematopoietic stem cells from unrelated donors (UD-HSCT) have been successfully transplanted, but little is known about immune reconstitution in this setting. Here we report a prospective comparison of immune reconstitution in recipients of UD-HSCT and of unmanipulated bone marrow from matched sibling donors (MSD-BMT). T-cell reconstitution occurred more than 100 days later in the UD-HSCT than in the MSD-BMT group. The first T cells after UD-HSCT were almost exclusively CD45RO(+) HLA-DR(+), whereas early-emerging T cells after MSD-BMT more frequently expressed CD62L, CD28, and CD25. In both groups, numbers of CD45RA(+) naive T cells increased after 180 days. After UD-HSCT, the T-cell-receptor (TCR)-repertoire was severely skewed and showed significantly reduced diversity during the first year, but only minor abnormalities were seen after MSD-BMT. TCR-diversity increased simultaneously with the number of naive T cells. In both groups, we observed transient expansions of gammadelta T cells. B cells were reconstituted more rapidly in UD-HSCT than in MSD-BMT recipients, whereas the rapidity of NK-cell reconstitution was similar in the two groups. In summary, T-cell reconstitution was slower after UD-HSCT than after MSD-BMT because of the delayed recovery of early memory-type T cells with reduced TCR-diversity, whereas naive T-, NK-, and B cells were reconstituted similarly in the two groups.
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PMID:A prospective comparison of immune reconstitution in pediatric recipients of positively selected CD34+ peripheral blood stem cells from unrelated donors vs recipients of unmanipulated bone marrow from related donors. 1290 Jul 74

Allogeneic bone marrow transplantation (alloBMT) is the only curative therapy for chronic myelogenous leukemia (CML). This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI) producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma), and unstimulated (in vivo) lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR), of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2) on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.
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PMID:Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation. 1476 74

To evaluate longtime survival after matched unrelated donor (MUD) transplantation a group of patients (n = 10) with intensified GVHD prophylaxis were compared to patients receiving matched sibling (MSD) transplantation (n = 10); all transplantations were done between 1989 and 1995 in the same institution. A murine monoclonal antibody against CD25 was assessed in addition to standard GVHD prophylaxis for reducing GVHD in children with advanced leukemia after MUD BMT (group I). We compared the incidence of GVHD, relapse and survival under prophylaxis with either anti-CD25 (group I, n = 10) or MSD BMT without anti-CD25 (group II, n = 10) with respect to known risk factors of transplant related morbidity, mortality and outcome. 3/10 leukemia patients in both groups were in CR3 or in relapse at time of transplant. Whereas incidence of acute GVHD grade III and IV was significantly higher in group I compared to group II (0.4 vs. 0.0), no differences in engraftment, or chronic GVHD were seen between both groups. In addition, overall (0.5 vs. 0.6) and leukemia free survival (0.5 vs. 0.6) was not different after 8 respectively 10 years from transplant. Murine anti-CD25 therapy may have contributed to matching outcome of MUD vs. MSD marrow transplants in children with advanced leukemia. In conclusion, the use of anti-CD25 in modulation of CD25+ regulatory and effector T cells in allo- and leukemia recognition merrits further exploration of its potential to improve both tolerance and leukemia control. Since the outcome of children with leukemia that received intensified GVHD prophylaxis in MUD BMT was similar to children with MSD transplants, MUD BMT has to be considered as an equivalent therapeutic option for patients, who have no HLA-identical sibling donor.
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PMID:Long-time survival after unrelated bone marrow transplantation in children and adolescents and targeted therapy with CD25 blockade to prevent GVHD. 1517 62

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.
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PMID:Regulation of OX40 gene expression in graft-versus-host disease. 1580 46

Haploidentical donors are available for most patients who need allografts but do not have matched donors. However, GVHD, rejection, delayed immune reconstitution, and infections have been significant barriers. We designed a haploidentical BMT protocol focusing on prevention of GVHD and rejection. A total of 53 leukemic patients underwent haploidentical G-CSF-primed BMT without ex vivo T-cell depletion. GVHD prophylaxis consisted of antithymocyte globulin, cyclosporine, methotrexate, and mycophenolate mofetil. In all, 38 patients (the CD25 group) received additional anti-CD25 monoclonal antibody basiliximab. The results were compared to 15 patients who did not receive basiliximab. All patients achieved trilineage engraftment with full-donor chimerism. The incidence of acute II-IV GVHD was 11% in the CD25 group vs 33% in the control group (P=0.046). The overall incidence of extensive chronic GVHD was 15%. T, B, and NK cells recovered within 12 months post transplant. The disease-free survival at 2 years was 53% with a median follow-up of 31 months. In conclusion, G-CSF primed haploidentical BMT along with sequential immunosuppressive agents as described here deserves further study.
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PMID:Anti-CD25 monoclonal antibody (basiliximab) for prevention of graft-versus-host disease after haploidentical bone marrow transplantation for hematological malignancies. 1596 93

Recently, we have shown that anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity against the host are endowed with marked veto activity and can facilitate bone marrow (BM) allografting without graft-versus-host disease. We also demonstrated synergism between rapamycin (RAPA) and the veto cells. CD4(+)CD25(+) T-regulatory (Treg) cells are suppressor cells that can enhance alloengraftment. We investigated whether donor Tregs would be synergistic with veto CTLs and RAPA in augmenting alloengraftment or, conversely, would suppress veto CTL effects. Lethally irradiated C3H mice were transplanted at day 2 after irradiation with Balb-nude BM. Graft rejection was induced by purified host-type T cells infused 1 day prior to BMT. The addition of Tregs led to moderate enhancement of engraftment. RAPA at different doses was synergistic with Tregs. The addition of veto CTLs to Tregs enabled reducing the effective RAPA dose fourfold. Combining all three agents was necessary to overcome rejection at low-dose RAPA. Chimerism analysis at 5 to 9 months revealed a significant presence of host-type cells coexisting with the predominant donor T cells, suggesting that tolerance had been attained. The synergistic effects between Tregs, veto CTLs, and RAPA offer an attractive approach for facilitating alloengraftment.
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PMID:Overcoming T cell-mediated rejection of bone marrow allografts by T-regulatory cells: synergism with veto cells and rapamycin. 1672 86


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