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

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Query: EC:2.1.1.69 (BMT)
2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we examined changes in the expression of CD45RA, CD31, and CD29 on total CD4 and CD8 lymphocytes in patients who had received CD6 T cell-depleted allogeneic marrow and received no immune suppressive drugs after engraftment in order to identify defects in reconstitution of immunoregulatory T cells after allogeneic BMT. Results following allo-BMT were compared with normal controls and patients following autologous BMT. We showed that CD4+CD45RA+, CD4+CD29+ (CD29high), and CD4+CD31+ cells were markedly decreased during the first 24 months after allo- and auto-BMT. CD8+CD45RA+ cells recovered to normal levels within the first month after auto-BMT, while after allo-BMT, the CD8+CD45RA+ cells were at slightly low levels during the first month, but gradually increased to normal levels by 12 months post-BMT. CD8+CD29+ cells were increased during the first 12 months both after allo- and auto-BMT although during the first month, a decreased percentage of CD8+CD29+ cells was observed in allo-BMT patients. More important, CD4+CD29+, CD8+CD29+, and CD8+S6F1+ cells were significantly increased in patients with moderate-to-severe acute GVHD (grades II-IV) compared with those with or without mild acute GVHD (grade I), suggesting that CD4 helper-inducer (CD4+CD29high) and CD8 killer-effector (CD8+CD29highS6F1+) cells play an important role in the pathophysiology of acute GVHD.
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PMID:The phenotype and reconstitution of immunoregulatory T cell subsets after T cell-depleted allogeneic and autologous bone marrow transplantation. 791 Sep 87

Immunological reconstitution after allogeneic bone marrow transplantation in man is characterized by a decreased lymphocyte transformation response to various mitogens and antigens during a period of from months to years. One reason for the decreased proliferative capability could be an inverted CD4/CD8 ratio; however, the present investigation demonstrates that this is not the only explanation for the immunodeficiency, since the CD4 as well as the CD8 subset, when studied in isolation, have qualitative defects, as evidenced by a reduced response of both subsets to stimulation with PHA, anti-CD2 and anti-CD3 MABs. The reason for the qualitative defect is unknown but a distorted composition of the CD4+ as well as the CD8+ T-cell subsets is suggested by the present investigations. We also observed that the PHA response was almost completely reconstituted one year after BMT, while the PWM response was still severely affected. The present study suggests that T-cell subsets which differ in their capacity to respond to PHA and PWM have different kinetics of reconstitution after BMT.
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PMID:Defective T-cell stimulatory pathways in patients after allogeneic bone marrow transplantation (BMT) in man. 836 24

Clinical application of approaches to inducing transplantation tolerance that involve bone marrow reconstitution will require achievement of engraftment without major toxicity to the recipient. These requirements are likely to vary according to the type of histoincompatibility between donor and recipient. We have attempted to determine the minimal conditioning required to achieve lasting mixed allogeneic chimerism and tolerance in the presence of a class I MHC disparity by evaluating the host elements that resist alloengraftment. We based our approach on a regimen that was shown to induce mixed chimerism in fully MHC-mismatched strain combinations. Recipient B10.AKM (KkIkDq) mice were treated with 7 Gy thymic irradiation (TI) and 3 Gy whole body irradiation (WBI) and received either anti-CD8 mAb alone or anti-CD4 plus anti-CD8 mAbs before transplantation of K locus-disparate B10.MBR (KbIkDq) marrow. All (27 of 27) animals receiving both mAbs showed lasting multi-lineage mixed chimerism and donor-specific tolerance. In contrast, five of 22 (23%) recipients pre-treated with anti-CD8 mAb alone in the same experiments failed to develop lasting multilineage mixed chimerism, suggesting that the CD4 T cell subset also participates in resistance to class I-mismatched marrow engraftment. We next attempted to determine whether or not host non-T cell elements resist allogeneic engraftment by comparing the minimum number of syngeneic vs allogeneic BMC required to achieve lasting multilineage mixed chimerism. Titrated numbers (10(6) to 10(7)) of B10.MBR (KbIkDq) bone marrow cells were administered to B10.AKM recipients treated with anti-CD4 and -CD8 mAbs, 3 Gy WBI and 7 Gy TI. All recipients of each marrow dose developed lasting multilineage mixed chimerism and showed specific tolerance to B10.MBR skin grafts. The level of donor-type repopulation in recipients of each dose was not lower than that observed in similarly irradiated recipients in an Ly5 congenic, otherwise syngeneic, BMT system. Together, our results suggest that CD4+ T cells contribute to resistance to K locus class I-mismatched marrow allografts and that resistance is mediated only by CD4 and CD8 T cells, with no role for non-T cell host elements.
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PMID:Alloresistance to K locus class I-mismatched bone marrow engraftment is mediated entirely by CD4+ and CD8+ T cells. 886 36

Matched related cord blood transplantation (CBT) has been successfully used to rescue patients undergoing myeloablative therapy. However, few data are available on the kinetics of hematological and immunological reconstitution of CBT recipients. We have investigated the hematological engraftment and immune recovery following related CBT in three patients, with acute lymphoblastic leukemia, aged 10, 9 and 7 years and with a body weight of 31, 40 and 25 kg, respectively. All patients engrafted and none experienced acute or chronic graft-versus-host disease. The time needed to achieve granulocyte recovery was 13, 26 and 29 days, respectively and platelet recovery occurred in 28, 49 and 51 days. All patients presented a marked increase of HbF, the values observed being much greater than those documented in patients given marrow transplantation and comparable with those observed in normal children in the first year of age. The recovery of T cell immunity, as well as that of natural killer subpopulations, mimicked that described in BMT recipients, a quicker return of CD8+ T cells determining the characteristic inversion of CD4/CD8 ratio. An impressive increase in the percentage and absolute number of B lymphocytes, apparently not related to viral infections, was demonstrable in all three cases. These data suggest that CBT recipients can experience a slight delay in hematological recovery when compared with patients given BMT. The reconstitution of erythropoiesis seems to recapitulate the ontogenetic pattern and the kinetics of recovery of the immune system reproduce that observed after BMT with the peculiarity of B cell expansion in peripheral blood.
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PMID:Hematopoietic and immune recovery after transplantation of cord blood progenitor cells in children. 897 78

Ex vivo production of interleukin 10 (IL-10) and interferon-gamma (IFN-gamma) was investigated in patients with (n = 5) or without (n = 5) chronic graft-versus-host disease (cGVHD) after allogeneic BMT. Patients were matched for time after transplantation and type of transplant. Anti-CD3-induced IL-10 production in MNCs isolated from patients with cGVHD (range/median: 26-650 pg/10(6) MNC; 400 pg/10(6) MNC) was significantly reduced compared to patients without cGVHD (646-2662 pg/10(6) MNC; 1314 pg/10(6) MNC; P < 0.05) or healthy controls (679-6361 pg/10(6) MNC; 3054 pg/10(6) MNC, P < 0.01). In vitro inhibition of IL-10 by an anti-IL-10 monoclonal antibody enhanced the release of IFN-gamma by anti-CD3-stimulated MNCs from 354 +/- 34 pg/10(6) MNCs to 899 +/- 61 pg/10(6) MNCs. Thus, low IL-10 production may cause high IFN-gamma release. In anti-CD3-activated MNCs obtained from patients with cGVHD IFN-gamma production was significantly increased (324-3331 pg/10(6) MNC; 1849 pg/10(6) MNC) compared to healthy donors (127-900 pg/10(6) MNC; 305 pg/10(6) MNC P < 0.01). In addition, median IFN-gamma release by anti-CD3-activated MNCs obtained from patients without cGVHD (464 pg/10(6) MNC) was about five-fold lower than in patients with cGVHD. In contrast to cytokine production, the differential leukocyte count (percentages of monocytes, T cells and CD4/CD8 ratio) was essentially the same both in patients with or without cGVHD. Thus, a different activation of Th-1 and Th-2 cells by anti-CD3 may be responsible for the deviant cytokine productions in patients with cGVHD. In conclusion, we observed significantly decreased IL-10 production in patinets with cGVHD and an increased median IFN-gamma secretion, which may contribute to the altered cytokine production after allogeneic BMT leading to cGVHD. Thus, supplementing IL-10 may become a new strategy for preventing cGVHD.
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PMID:Decreased interleukin 10 and increased interferon-gamma production in patients with chronic graft-versus-host disease after allogeneic bone marrow transplantation. 915 46

Bone marrow transplantation was performed with a conditioning regimen including antithymocyte globulin (ATG) for 8 patients with HLA-compatible unrelated donors or HLA mismatched donor. Administration of ATG was halted due to side effects in only 1 case, but the other cases were had no adverse reaction. During administration of ATG, platelet counts did not decrease rapidly, but platelet infusion was not effective in some cases. As compared between patients with conventional allogeneic BMT, autologous BMT or peripheral blood stem cell transplantation and those with ATG administration, no obvious difference was seen between the two groups in lymphocyte counts, CD3, CD4, CD8 and CD20 positive cells. No patient with ATG saffered graft failure or acute GVHD. However, cytomegalovirus infection was observed more frequently than in patients without ATG. In hematological malignancy, relapse was more frequent than in patients without ATG.
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PMID:[Antithymocyte globulin as conditioning regimen for bone marrow transplantation]. 942 35

T cell repertoire alterations occurring after allogeneic BMT and related emergence of aGVHD has not been directly demonstrated. CD4, CD8 and Vbeta usage of T cells infiltrating spleen, lymph nodes and liver was compared in lethally irradiated F1(DBA/2 x B10.D2) recipients which develop (GVHD mice) or not (long survivor:LS mice) aGVHD across minor histocompatibility antigens (mHAgs) and Mtv-6 and Mtv-7 encoded super-antigens (SAgs) barriers according to experimental conditions. The early expansion in GVHD mice of CD4Vbeta6+ and of CD4Vbeta3+ T cell subsets specific for Mtv-7 and Mtv-6 SAgs, respectively, is abolished in LS protected mice. By contrast, CD8+ T cells infiltrate lymph nodes, the liver but not the spleen of LS as in GVHD mice. Vbeta subset overexpression is frequent in all T cell phenotypes in GVHD but only among CD8+ T cells in LS mice. Predominant Vbeta pattern subpopulation is unique to each mouse. Overexpressed Vbeta subpopulation sequencing clearly indicates that expansion results from a very limited number of clones. Association of a given Vbeta segment with different Jbeta for each mouse suggests that the response is directed towards many different antigens. The data emphasize that Mtv-SAg and mHAgs CD4+ T cells are of crucial importance during GVHD and that there is no relationship between CD8+ T cell repertoires and pathological status.
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PMID:Relative importance of CD4+ and CD8+ T cell repertoires in the development of acute graft-versus-host disease in a murine model of bone marrow transplantation. 954 62

The prophylactic use of T cell depletion (TCD) strategies for the prevention of graft-versus-host disease (GVHD) following allogeneic stem cell transplantation remains widespread. Initial reports of high incidence of graft rejection after TCD BMT led to a move away from this approach but improved conditioning regimens have reduced this risk substantially. The use of TCD has also been associated with higher relapse risk post-BMT although the success of donor leukocyte infusion (DLI) as treatment for relapse has reduced this problem, especially in chronic myeloid leukaemia (CML). Currently the use of TCD BMT is increasing particularly due to the relative increase in BMT from non-related donors for whom TCD is the optimal GVHD prophylaxis. However, doubts remain over the long-term effect on the reconstituted immune system of recipients of TCD BMT, particularly in adult recipients. In this study we have undertaken a detailed sequential analysis in 23 patients who received allo-grafts from HLA-identical sibling donors after high-dose chemo/radiotherapy for acute or chronic leukaemia. Of these patients, 11 received non-manipulated grafts, five received 'partially TCD' (PTCD) and a further seven received 'fully TCD' (FTCD) bone marrow. T cell depletion was performed ex vivo by Campath-1M plus autologous serum as a source of complement. Partial TCD describes grafts with a T cell reduction of 1-2 log. Full TCD refers to grafts with a reduction of >2.5 log. The decision regarding the optimal degree of TCD was clinical and was based upon the perceived relative risk of relapse based upon the disease and remission status. All patients were monitored for up to 12 months post-BMT with regard to reconstitution of T and NK cell subsets. T cell depletion at either level was associated with a slower recovery of CD4 cells. This was most marked in the FTCD recipients and lasted throughout the period of study. CD8 cell recovery was also slower in the TCD recipients but this normalised throughout the 12 months post-BMT. The ratio of CD45RA+:CD45RO+ increased in all recipients after month 3. This suggests that a degree of extra-thymic T cell maturation can occur in recipients of allogeneic BMT. NK cell recovery was more rapid in the TCD recipients and these differences were maintained throughout the first year.
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PMID:The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia. 957 7

BMT was carried out on a patient with DiGeorge syndrome who suffered recurrent infections after birth. At 13 months of age, 8.0 x 10(8)/kg of bone marrow nuclear cells were infused from an HLA-identical sibling using only anti-thymocyte globulin to prevent rejection. Donor DNA was not detected on microsatellite polymorphism by PCR. At 19 months of age, a second BMT from the same donor was carried out using busulfan and cyclophosphamide as conditioning. DNA examination of bone marrow showed chimerism at day 18 and complete donor origin at day 28. Seven months post-BMT, the numbers of CD3-, CD4- and CD8-positive cells were in the normal range. BMT is thus an effective therapy for DiGeorge syndrome.
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PMID:Complete-type DiGeorge syndrome treated by bone marrow transplantation. 982 24

Human severe combined immunodeficiency (SCID) can be caused by defects in Janus kinase 3 (JAK3)-dependent cytokine signaling pathways. As a result, patients are at high risk of life-threatening infection. A JAK3 -/- SCID mouse model for the human disease has been used to test whether transplant with retrovirally transduced bone marrow (BM) cells (JAK3 BMT) could restore immunity to an influenza A virus. The immune responses also were compared directly with those for mice transplanted with wild-type BM (+/+ BMT). After infection, approximately 90% of the JAK3 BMT or +/+ BMT mice survived, whereas all of the JAK3 -/- mice died within 29 days. Normal levels of influenza-specific IgG were present in plasma from JAK3 BMT mice at 14 days after respiratory challenge, indicating restoration of B cell function. Influenza-specific CD4(+) and CD8(+) T cells were detected in the spleen and lymph nodes, and virus-specific CD8(+) effectors localized to the lungs of the JAK3 BMT mice. The kinetics of the specific host response correlated with complete clearance of the virus within 2 weeks of the initial exposure. By contrast, the JAK3 -/- mice did not show any evidence of viral immunity and were unable to control this viral pneumonia. Retroviral-mediated JAK3 gene transfer thus restores diverse aspects of cellular and humoral immunity and has obvious potential for human autologous BMT.
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PMID:Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency. 987 1


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