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)

Because the phenomenon of in vitro lysis of lymphoma cells by spleen natural killer (NK) cells bears genetic and effector cell resemblances to genetic resistance to bone marrow transplantation, they were compared for additional known unique characteristics of the latter phenomenon. Like GR to BMT, NK cell activity first appeared abruptly at about 3 weeks of post-natal age; was radioresistant to 1 100 R whole body irradiation, but was quantitatively diminished by higher exposures or delay of test post-irradiation; was suppressed by pretreatment with either cyclophosphamide, carrageenan, silica particles, anti-bone marrow serum or anti-thymus serum. The many unique identical characteristics of these two effector mechanisms indicates that they represent two manifestations of the same basic phenomenon of natural immunity. This is in accord with other data indicating that GR to BMT is directed at Hh antigens which, like TL antigens, may in some mouse strains appear on both leukemic cells and normal hemopoietic cells.
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PMID:Apparent identity of mechanisms of genetic resistance to marrow transplantation and natural killer cell activity. 38 73

Bone marrow (BM) chimera mice were established by injecting BM cells from B10 H-2 congenic or recombinant mice (Mls-1b) into lethally irradiated AKR (Mls-1a) mice in order to elucidate what type of cells were responsible for intrathymic clonal elimination of self-reactive V beta 6+T cells that are reactive to Mls-1a plus I-E products. When I-E+ mice were donors, V beta 6+ SP thymocytes were not eliminated. However, in chimeras where B10 (I-Ab, I-E-) or B10.A(4R)(I-Ak, I-E-) mice were donors, variable proportions of V beta 6+ SP cells were observed. These differences appeared to be attributable to the difference in affinity between class II antigens expressed on BM derived cells and Mls-1a on recipient cells. When AKR mice were reconstituted with BM cells from both B10 and AKR mice, V beta 6+ SP thymocytes were eliminated according to frequencies of the AKR derived cells. These findings collectively indicate that the BM derived thymic stromal cells are essential for the clonal elimination of V beta 6+ cells. However, in GVHR chimeras prepared by injecting of both BM cells and splenic T cells from the same donor mice, V beta 6+ cells were not eliminated at all any periods after BMT. Significantly high number of V beta 6+ SP thymocytes seen 1 week after BMT were shown to be the splenic T cellsinjected with BM cells or their descendants. By contrast, the proportions of the V beta 6+ SP cells in GVHR chimeras 5 weeks after BMT fell within the same range as those of normal donor mice. These V beta 6+ cells were derived from BM precursors. These results reveal that acute GVHR in the thymus results in abrogation of clonal elimination of self reactive T cells in the thymus.
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PMID:[A study on clonal elimination of auto-reactive thymocytes in bone marrow chimera mice]. 151 55

We have recently demonstrated that mixed xenogeneic chimerism and donor-specific tolerance can be produced across a species barrier using a nonmyeloablative conditioning regimen (1). This regimen involves pretreatment of B10 mice with mAbs against CD4+, CD8+, Thy1+, and NK1+ cells, followed by a low dose (3 Gy) of whole-body irradiation and a higher dose (7 Gy) of local irradiation to the thymus and administration of T cell-depleted (TCD) F344 strain rat BMC. Although initial mixed chimerism and de novo maturation of donor rat T cells can be demonstrated in such animals, chimerism is gradually lost, and is no longer detectable by 6 months following BMT (1). When rat skin was grafted onto such animals 4 months following BMT, however, donor-specific skin graft survival was markedly prolonged, while non-donor type rat skin grafts were rapidly rejected (1). These results suggested that a state of donor-specific T cell tolerance existed, and that loss of chimerism was not due to a T cell-mediated immune mechanism. In order to evaluate the possibility that a humoral mechanism might mediate delayed loss of xenogeneic bone marrow grafts, we have now examined sera at various times for the presence of antibody against donor cells. Groups of animals not receiving the complete tolerizing mAb pretreatment regimen produced antidonor lymphocytotoxic antibody in response to BMT and skin grafting. Flow cytometric studies demonstrated high levels of IgM and of IgG of all subclasses against rat BMC and spleen cells in these control mice immunized by BMT. In contrast, such antibodies were not detectable in sera from animals receiving BMT following pretreatment with the tolerance-inducing mAb regimen. Furthermore, the tolerant animals did not develop cytotoxic antibodies or high levels of IgM or IgG against donor BMC after loss of hematopoietic chimerism. Donor-type skin grafts were eventually rejected, but rejection of these and repeat skin grafts did not lead to a cytotoxic antibody response. Low levels of rat BMC-binding IgM antibody were also detected in sera of tolerant mice, but the intensity of staining of rat BMC was lower than that of control animals receiving conditioning without BMT. These results suggest that a state of tolerance exists among cells responsible for T cell-dependent IgG antibody subclasses and natural IgM antibodies in animals receiving BMT following this nonmyeloablative conditioning regimen.
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PMID:Humoral tolerance in xenogeneic BMT recipients conditioned by a nonmyeloablative regimen. 158 75

This report investigates the effects of cyclosporine on the reconstitution of T lymphocytes after syngeneic bone marrow transplantation and its role in the development of a novel T cell-mediated autoimmune disease, syngeneic graft versus host disease. We analyzed the effect of CsA treatment on T lymphocyte differentiation during reconstitution after bone marrow transplantation and correlated the maturation of CD4+ and CD8+ T cell subsets with the onset of syngeneic GVHD. Administration of CsA following syngeneic bone marrow transplantation leads to a developmental arrest of mature CD4+ and CD8+ T lymphocytes in the thymus and a marked reduction in cells expressing the alpha beta T cell receptor. The reduction of CD4+ and CD8+ T cell subsets is also reflected in the peripheral lymphoid compartment with an altered CD4/CD8 ratio. Functional assessment of the cells revealed that CD8+ cells respond normally to mitogenic signalling whereas CD4+ cells exhibit marginal proliferative responses. Both subsets of T lymphocytes respond to syngeneic B lymphoblasts, comparable to the response of T lymphocytes from non-CsA-treated syngeneic BMT recipients, suggesting that autoreactive cells are produced despite CsA treatment. Following discontinuation of CsA, T cell differentiation in the thymus is rapidly restored to normal. However, concurrent with the onset of syngeneic GVHD, a compensatory insurgence of CD4+ T helper cells is observed.
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PMID:Effect of cyclosporine on T lymphocyte development. Relationship to syngeneic graft-versus-host disease. 189 96

The effects of cyclosporin A (CsA) on the generation of NK cells were studied using syngeneic bone marrow transplanted mice subsequently treated with CsA (BMT/CsA mice). In contrast to a severe reduction in T cells that was reported previously, these mice exhibited a marked enhancement of splenic NK activity. The enhanced NK activity was mediated by NK1.1+, Thy-1- cells as assessed by antibody plus complement treatment, and was concomitant with an absolute increase in the numbers of NK1.1+ cells as assessed by flow cytometry. Because the depletion of host-derived, mature NK cells by injection of anti-asialo GM1 antibody before bone marrow reconstitution did not affect the enhancement of NK activity, CsA appeared to augment the generation of NK cells from bone marrow precursors. To investigate a possible relationship between the enhancement of NK activity and the maturational arrest of T cells in the thymus induced by CsA, mice were thymectomized, followed by irradiation, bone marrow reconstitution, and CsA treatment. These mice exhibited as strong enhancement of splenic NK activity as BMT/CsA mice, suggesting that the CsA-induced effect on NK cells is distinct from its effect on T cell development in the thymus. Taken together, these results are the first demonstration of the positive effect of CsA on NK cell generation and may be of importance in clinical bone marrow transplantation.
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PMID:Effect of cyclosporin A on lymphopoiesis. III. Augmentation of the generation of natural killer cells in bone marrow transplanted mice treated with cyclosporin A. 199 36

Thymulin, a peptide secreted by human thymic epithelial cells, circulates in peripheral blood. Levels of plasma thymulin (FTS-Zn) activity were analyzed in 21 patients with lethal combined immunodeficiency disorders who were treated with transplantation of HLA-haplotype-mismatched parental bone marrow depleted of T cells by differential agglutination with soybean agglutinin and E-rosetting (SBA-E-BMT). Among these 21 infants, 15 were patients with severe combined immunodeficiency (SCID) and 6 had combined immunodeficiency (CID) with Omenn's syndrome or CID with T cell predominance (CIDTP). In contrast to normal infants who possess high levels of plasma thymulin activity, 20 of the 21 patients demonstrated undetectable or low plasma thymulin levels for their age at admission prior to transplantation. Following SBA-E-BMT, however, thymulin became detectable in the plasma of 17 of 18 evaluable patients and reached normal or near-normal levels between 21 and 125 days posttransplant. In patients in whom the timing of engraftment could be established by emergence of donor lymphocytes, thymulin appeared in the plasma at approximately the same time as lymphoid chimerism was detected, and in all patients who were engrafted and immunologically reconstituted, the increment in thymulin levels preceded development of immune functions. These studies support the concept that normal marrow-derived cells in the graft can provide a stimulus necessary for induction of thymic epithelial secretory function in patients with thymic dysplasia. Further, immunologic reconstitution in these patients was not seen following SBA-E-BMT unless and until recovery of thymus function had been observed.
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PMID:Evidence that appearance of thymulin in plasma follows lymphoid chimerism and precedes development of immunity in patients with lethal combined immunodeficiency transplanted with T cell-depleted haploidentical marrow. 236 51

A boy with combined immunodeficiency having low natural killer (NK)-cell activity received thymopoietin pentapeptide (TP-5) treatment, transplanted with T cell-depleted HLA-haploidentical bone marrow (BMT) cells from his father and with thymus tissue from an infant at different times during the first year of life. He showed a marked increase in large granular lymphocytes (LGL) both during the treatment with TP-5 and after BMT. The LGL generated following TP-5 injection had a T3+Leu11- surface phenotype and low NK activity. In contrast, the LGL appearing after BMT showed T3-, Leu7+, and/or Leu11+ surface phenotypes, had high NK- and K-cell activities, and were lymphokine-activated killer (LAK)-cell precursors. These killer activities were assigned to the Leu7-Leu11+ subset and proved to be of recipient origin. LGL proliferation following BMT was accompanied by neutropenia, which was improved in association with a reduction in the number of LGL and the appearance of T cells of BMT donor origin following thymus transplantation. This suggested the inhibition of granulopoiesis by the LGL and an in vitro study revealed that the Leu7+Leu11- subset of LGL suppressed the growth of granulocyte/macrophage colony-forming units. These results indicated that phenotypically different LGL could be generated by different treatments and that the LGL showing NK activity were distinct from those regulating granulopoiesis. It was also suggested that the generation of LGL was controlled by T cells.
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PMID:Phenotypical and functional heterogeneity of the large granular lymphocytes increased after various treatments in a patient with combined immunodeficiency. 264 8

We examined the binding of polyomavirus large (L-T)-, middle (M-T)-, and small-tumor antigens to DNA cellulose. At pH 6.0, the majority of L-T bound to calf thymus DNA cellulose, while little or no small tumor antigen was retained under these conditions. Unexpectedly, a small but reproducible proportion of M-T bound to both native and denatured DNA cellulose. M-T encoded by polyomavirus mutant dl 8, which expressed shortened L-T and M-T, bound to DNA, indicating that the deleted sequences are not required for DNA binding. Also, M-T from transformed BMT-1 rat cells, which synthesize exclusively this polyomavirus tumor antigen, bound to DNA, indicating that its binding is not due to association with other polyomavirus-encoded proteins. Using the DNA fragment immunoassay, we found that, under conditions in which L-T bound specifically to DNA fragments containing viral regulatory sequences, no viral DNA fragments were bound by M-T. The existence of distinct subpopulations of M-T that differ in their DNA-binding properties was indicated by rebinding experiments in which M-T that had bound to DNA cellulose rebound very efficiently, while that which had not been originally retained by DNA cellulose rebound poorly. Furthermore, the M-T-pp60 c-src complex did not bind to DNA cellulose. These data suggest that polyomavirus M-T is heterogeneous, consisting of populations of molecules that differ in their interactions with DNA cellulose.
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PMID:A subclass of polyomavirus middle tumor antigen binds to DNA cellulose. 300 44

We examined the effect of a maximum tolerated, split-dose chemotherapy protocol of cyclophosphamide, cisplatin, and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) on neutrophil and lymphocyte subpopulations in the peripheral blood leukocytes (PBLs), thymus, bone marrow, and spleen. It was found that this protocol of polychemotherapy, modeled after the induction protocol used with autologous bone marrow transplantation (AuBMT) for breast cancer, suppressed both B- and T-cell populations and T-cell function at times when the absolute neutrophil count had returned to normal or supernormal numbers. We observed an organ- and phenotype-specific T- and B-cell recovery to normal levels following chemotherapy. However, despite normalization of cellularity and phenotype frequency, splenic lymphocytes remained unable to respond to normally concanavalin A (ConA). This polychemotherapy protocol in mice with an extensive experimental metastasis mammary tumor burden, was a dose lethal to 20% of the test group, which could be overcome with treatment by BMT and rHu interleukin (IL)-7. Furthermore, therapy with the T-cell augmenting agent rHu IL-7 had additive therapeutic activity and significantly prolonged survival beyond that of chemotherapy and BMT although it did not cure any mice with a heavy tumor burden. In summary, these studies demonstrate an organ-specific and selective polymorphonuclear neutrophil and T- and B-cell reconstitution following multidrug, split-dose chemotherapy on tissue and PBL populations, and a chronic depression in T-cell function, which when modified can result in significant therapeutic activity.
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PMID:T-cell reconstitution by molecular, phenotypic, and functional analysis in the thymus, bone marrow, spleen, and blood following split-dose polychemotherapy and therapeutic activity for metastatic breast cancer in mice. 750 77

Induction of a graft-vs-host reaction in irradiated (BALB/c X C57BL/6)F1 mice (CBF1 mice) with bone marrow cells (BMC) plus spleen cells of BALB/c mice leads to bone marrow transplantation--GVHD (BMT-GVHD). BMT-GVHD is characterized by liver disease, splenomegaly, and hypergammopathy. In addition, we found that increased serum IgE and IgG1 levels were correlated with BMT-GVHD such as liver disease and splenomegaly. The allotype of increased IgE levels in BMT-GVHD was IgEa of donor origin, not IgEb of host origin. We also found that in the thymus of murine BMT-GVHD, the CD4+ CD8+ double-positive T cells were decreased, but the CD4+ CD8- or CD4- CD8+ single-positive T cells were increased. Interestingly, double-positive T cells appeared in the spleen, suggesting that abnormal T cell differentiation existed in murine BMT-GVHD. When the recipients were treated with anti-IL-4 Ab (11B11), the increase of IgE and IgG1 was markedly reduced and liver disease and splenomegaly were also prevented. Moreover, abnormal T cell differentiation and maturation were suppressed. These observations suggest that IL-4 plays an important role in immunoregulation or pathogenesis of allogeneic effects, and 11B11 prevents immunodysfunction including T cell differentiation in the thymus or the spleen and autoimmune symptoms in murine BMT-GVHD.
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PMID:Anti-IL-4 antibody prevents graft-versus-host disease in mice after bone marrow transplantation. The IgE allotype is an important marker of graft-versus-host disease. 787 41


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