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)

To study the effects of major histocompatibility complex (MHC) class II expression on T-cell development, we have investigated T-cell immune reconstitution in two MHC class II-deficiency patients after allogeneic bone marrow transplantation (allo-BMT). Our study showed that the induction of MHC class II antigen expression on BM graft-derived T cells in these allo-BMT recipients was hampered upon T-cell activation. This reduction was most striking in the CD8(+) T-cell subset. Furthermore, the peripheral T-cell receptor (TCR) repertoire in these graft-derived MHC class II-expressing CD4(+) and in the CD8(+) T-cell fractions was found to be restricted on the basis of TCR complementarity determining region 3 (CDR3) size profiles. Interestingly, the T-cell immune response to tetanus toxoid (TT) was found to be comparable to that of the donor. However, when comparing recipient-derived TT-specific T cells with donor-derived T cells, differences were observed in TCR gene segment usage and in the hydropathicity index of the CDR3 regions. Together, these results reveal the impact of an environment lacking endogenous MHC class II on the development of the T-cell immune repertoire after allo-BMT.
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PMID:Incomplete T-cell immune reconstitution in two major histocompatibility complex class II-deficiency/bare lymphocyte syndrome patients after HLA-identical sibling bone marrow transplantation. 1038 32

Human lymphocytes remain among the most promising target cells for gene therapy. Gene-modified lymphocytes have been used successfully to treat adenosine deaminase (ADA)-deficient patients and to control GvHD after allogeneic BMT. Because activation and proliferation of T cells are necessary for efficient retrovirus-mediated gene transfer and subsequent selection of transduced cells, mononuclear cells (MNC) from steady-state and G-CSF-stimulated peripheral blood were activated by short exposure to the mitogen PHA, the anti-CD3 antibody OKT3, or both in the presence of different concentrations of recombinant IL-2. Using OKT3 (10 or 30 ng/ml) and IL-2 (100 U/ml), T cells expanded efficiently during a 14-day culture period. Cell expansion was similar under serum-free conditions. The immunophenotypic profile over time showed a marked increase in CD8+ cells, leading to a reversed CD4/CD8 ratio of 1:2 and a slight increase in CD56+ cells. Supernatant-based centrifugal transduction of primary human T lymphocytes was compared with supernatant transduction on the extracellular matrix protein fibronectin. Transduction with cell-free retrovirus-containing supernatant in tissue culture flasks coated with human plasma fibronectin led to significantly higher transduction efficiencies (20% +/- 7.5%) than centrifugal transduction in uncoated culture flasks (13.6% +/- 5.1%)(p = 0.041). To both rapidly characterize transduced cells and isolate these from residual nontransduced but biologically equivalent cells, an amphotropic Moloney murine leukemia virus (MoMuLV)-based retroviral vector containing the intracytoplasmically truncated human low-affinity nerve growth factor receptor (deltaLNGFR) cDNA as a marker gene was used. FACS sorting of T cells after transduction resulted in >90% LNGFR+ cells and was much faster than enrichment of transduced cells through growth in G418-selection medium. These results show that supernatant-based retroviral gene transfer into primary human T lymphocytes can be enhanced by fibronectin. Ectopic expression of a cell surface protein can be used to rapidly and conveniently quantitate transduction efficiency through FACS analysis and to efficiently enrich transduced cells through FACS sorting.
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PMID:Expansion and fibronectin-enhanced retroviral transduction of primary human T lymphocytes for adoptive immunotherapy. 1063 78

Natural killer (NK) and T cell development was studied after allogeneic and autologous BMT. We determined the phenotypic expression and lytic ability of these subpopulations after BMT. Following T cell-depleted (TCD) BMT, the number of CD16+ and CD56+ cells peaked at 39 and 46 days, respectively, and constituted the majority of peripheral blood lymphocytes (PBL). Coexpression of CD3 and CD16 was <10% up to 14.5 weeks after transplant. Following allogeneic non-T cell-depleted (NTCD) BMT, the number of CD16+ and CD56+ cells peaked at 6 weeks. CD3 expression was normal (70%-80%), % CD8+ cells was high (40%), and % CD4+ cells was low (20%). Following autologous BMT (ABMT), % CD3+ T cells was 80%, of which 70% expressed the CD8 marker. In contrast, CD4 expression was low (20%). CD16+ cells appeared 2.5-3 weeks after ABMT but with low frequency (20%), at which point 20%-30% of the CD3+ cells coexpressed CD16. A positive correlation was found between CD16 expression and cytotoxic capability. In conclusion, a marked difference was observed in NK and T cell-associated markers following TCD BMT, NTCD BMT, and ABMT. Following NTCD or ABMT, but not TCD BMT, a high percentage of cells co-express CD16 and CD3, which may indicate the possibility of a common NK and T cell progenitor.
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PMID:Natural killer (NK) and T cell-associated surface marker expression following allogeneic and autologous bone marrow transplantation (BMT). 1073 73

Flow cytometry laboratory plays an integral part in the evaluation of a BMT patient. Its role starts at the time of clinical presentation to assure most accurate and reproducible disease diagnosis and subclassification. This can only be achieved if the flow cytometrist is fully qualified in the diagnosis of hematolymphoid neoplasia and is able to correlate each and every case with morphologic data. Flow cytometric report, therefore, includes a standing diagnosis and goes beyond the sole description of an abnormal/atypical population. Following initial diagnosis, generated data are carefully stored and are retrieved for review whenever needed particularly during the evaluation of the remission status, response to chemotherapy, relapse, staging and detection of residual disease in marrow and apheresis product. Our laboratory performs leukemia/lymphoma assessment of approximately 150-200 samples a month in addition to 3-8 weekly apheresis procedures, 25-30 post-BMT immune monitoring samples and other isoteric assessments including CD4 counts for HIV population, HLA B27 evaluation, platelet/leukocyte antibodies, reticulated platelets, immunodeficiency disorders etc. This multidisciplinary center allowed us to develop a substantial expertise in the field, which hopefully benefits our patient, clinicians and fellow cytometrists. We are please to share our expertise at this distinguished forum.
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PMID:Flow cytometric assessment of bone marrow transplant patient. 1082 94

To study the impact of an MHC class II-negative environment on T cell immune reconstitution, we have analyzed the phenotypical and functional characteristics of FACS-sorted cultured CD4(+) and CD8(+) T cells in two Bare Lymphocyte Syndrome (BLS) patients before and after allo-BMT. A similar analysis was performed in two MHC class II expressing pediatric leukemia patients after treatment with an allo-BMT who were included in our study as control. It was observed that CD4(+) T cells displayed cytolytic alloreactivity in both BLS patients prior to and within the first year after allo-BMT, whereas such cells were absent at a later time-point, in the donors and pediatric leukemia controls. In addition, reduced MHC class II expression was observed in CD8(+) T cells of both recipients early after allo-BMT, irrespective of the T cell chimerism pattern. Lack of endogenous MHC class II expression in BLS patients, therefore, results in aberrant T cell selection within the first year after allo-BMT, analogous to T cell selection before transplantation. These T cell selection processes seem to be normalized at a later time point after allo-BMT probably due to migration and integration of graft-derived MHC class II-positive antigen presenting cells to sites of T cell selection.
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PMID:T cell immune reconstitution after allogeneic bone marrow transplantation in bare lymphocyte syndrome. 1105 33

To understand the nature of long-term Th immune responses, we investigated in the present study the TCRBV gene repertoire of CD4(+) T cells specific for the recall antigen tetanus toxoid (TT) in recipients of an allogeneic bone marrow transplantation (allo-BMT) at several time points after transplantation and in their BM donors. We observed that the TCR repertoire of TT-specific CD4(+) Th cells was heterogeneous, and differed between allo-BMT recipients and their respective donors. Some individuals, however, used similar TCR-complementarity-determining region (CDR) 3 motifs that could reflect recognition of and selection by similar promiscuous epitopes of TT. Longitudinal analysis of this TT-specific T cell response revealed that T cells with completely identical TCR were present at several time points after the first analysis in allo-BMT recipients, most probably reflecting long-term stability of at least part of the antigen-specific TCR repertoire. Similar stability of the TT-specific TCR repertoire in time was also noted in the allo-BMT donors. These observations reveal that within a given individual the dominant antigen-specific T cell clones persist in time in an otherwise diverse TT-specific CD4(+) T cell immune response.
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PMID:Longitudinal analysis of T cells responding to tetanus toxoid in healthy subjects as well as in pediatric patients after bone marrow transplantation: the identification of identical TCR-CDR3 regions in time suggests long-term stability of at least part of the antigen-specific TCR repertoire. 1128 90

Lymphoproliferative disease induced by EBV (EBV-LPD) is a complication of allogeneic transplantation caused by T-cell immunodeficiency. EBV-LPD responds poorly to conventional treatment modalities. Recently, adoptive transfer of EBV-specific, HLA-class I-restricted CTL lines was shown to be effective both as prophylaxis and as treatment of EBV-LPD. The CTL lines are produced by in vitro selection of EBV-specific memory T cells contained in MNC of EBV-seropositive individuals by repeated stimulation with irradiated EBV-transformed cells. The non-EBV-reactive and potentially alloreactive cells remain unactivated. Twenty-one CTL lines were initiated. All were successfully generated and shown to be HLA-restricted and EBV-specific as well as CD8/CD4 and CD45RO positive T cells. The majority of the CTL lines were generated from BMT donors, but two CTL lines were obtained from solid organ transplant recipients receiving immunosuppression. Evidence of probable in vivo efficacy is presented. Development of efficient adoptive T-cell strategies for EBV-positive malignancies could serve as a model for treatment of other viral or malignant disorders.
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PMID:Generation of EBV-specific CTLs suitable for adoptive immunotherapy of EBV-associated lymphoproliferative disease following allogeneic transplantation. 1206 70

The cytokine receptor common gamma chain (gamma c) plays a pivotal role in multiple interleukin signaling, and gamma c gene mutations cause an X-linked form of SCID (X-SCID). Recently, gamma c gene transfer into the autologous X-SCID BM achieved appreciable lymphocyte reconstitution, contrasting with the limited success in previous gene therapy trials targeting hematopoietic stem cells. To understand the mechanisms underlying this success, we examined the repopulating potential of the wild-type (WT) BM cells using an X-SCID mouse model. Limited numbers of WT cells were infused into non-ablated WT and X-SCID hosts. Whereas no appreciable engraftment was observed in WT recipients, donor-derived lymphocytes repopulated well in X-SCID, reaching 37% (10(6)cells given) and 53% (10(7) cells given) of the normal control value 5 months post BMT. A lineage analysis showed a predominance of the donor-derived lymphocytes (CD4(+) T, CD8(+) T, B and NK cells) in X-SCID while the donor-derived granulocytes and monocytes engrafted poorly. These results showed a selective advantage of WT cells in X-SCID, and that the advantage was restricted to lymphocytes. In human gene therapy for X-SCID, an analogous growth advantage would greatly enhance the repopulation of lymphocytes derived from a very small number of gamma c gene-supplemented precursors.
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PMID:Selective growth advantage of wild-type lymphocytes in X-linked SCID recipients. 1213 50

Approaches using reduced conditioning regimens have been developed to obtain minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However, many aspects remain under-evaluated and few data are available about immune and dendritic cell (DC) reconstitution after these highly immunosuppressive regimens. We present here our data in 20 patients receiving allogeneic bone marrow transplantation (allo-BMT) using a reduced preparative regimen. We evaluated in the first 3 months following allo-BMT, several immunological parameters including DC subsets, and compared these to historical results obtained in a group of myeloablative allo-BMT patients. We found an early recovery of leukocytes, CD8+ and NK lymphocytes. We also found a trend towards an improved B cell recovery. These results are somewhat in contrast to the altered immune recovery observed in the myeloablative setting. In addition, we found a significant early circulating DC recovery. Circulating blood DCs were also found to be of full donor origin as assessed by FISH in sex-mismatched pairs. Nevertheless, naive CD4 + CD45RA + T cells were found to be profoundly reduced following such regimens.Collectively, these data further enhance the overall benefits of reduced intensity regimens and the need for a stringent biological monitoring for assessment of the potential advantages of reduced intensity allo-BMT in comparison with conventional allo-BMT.
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PMID:Recovery of lymphocyte and dendritic cell subsets following reduced intensity allogeneic bone marrow transplantation. 1224 78

As recently reported, children having T cell-depleted peripheral blood stem cell transplantation (PBSCT) might be at increased risk for the development of drug resistance. To investigate if delayed immune recovery was a potential risk factor, the recovery of the CD3(+), CD4(+), CD8(+) and CD19(+) cells was related retrospectively to genotypic detected resistance development in three pediatric patients with ganciclovir (GCV)-resistant human cytomegalovirus (HCMV)-infection out of 79 receiving allogeneic PBSCT. Selected control groups consisted of HCMV-seronegative patients without any infection (A, n = 8), asymptomatic infected patients with viral leuko- and plasmaDNAemia (B, n = 4) and patients with HCMV-disease (pneumonia) (C, n = 3). Patient No. 1 with very early resistance development exhibited a rapid immune recovery with higher T cell counts than in group A. Immune recovery of patient No. 2 was delayed, as also observed in groups B and C. Patient No. 3 showed an immune recovery comparable to group A. Resistance developed before (No. 2) or during (Nos 1 and 3) the recovery of the relevant CD3(+), CD4(+), CD8(+) lymphocytes. GCV-resistance development did not necessarily coincide with delayed immune recovery, but appeared in all three cases in the early phase of immune recovery (range: day +44 to day +95). Therefore, children seem to be at special risk for resistance development in the early phase after transplantation before immune cells have recovered. These results suggest that GCV treatment of an HCMV infection in the early posttransplant phase of children after T cell-depleted PBSCT/BMT should promote more stringent resistance screening.
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PMID:Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery. 1236 55


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