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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To measure the ability of human hematopoietic stem cells (HSCs), the SCID-repopulating cell (SRC) assay has been widely used. Conventionally, human HSCs are transplanted into a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse via a tail vein. However, those cells must go through various obstacles until they reach the mouse marrow environment, which could explain the generally low homing efficiency in this system. Thus, the capability of HSCs may not be studied accurately by this intravenous transplantation method. In our attempt to reveal actual SRC potential, ie, self-renewal and multilineage differentiation in recipient bone marrow, we introduced cells into mouse marrow directly (intrabone marrow [iBM]) to minimize the effect of factors that may interfere with the homing of HSCs and compared the results obtained by intravenous and iBM methods. When cord blood CD34(+)CD38(-) cells were transplanted in NOD/SCID mice by iBM, a 15-fold higher frequency of SRC, 1 in 44 CD34(+)CD38(-) cells, was achieved compared with 1 in 660 by the intravenous method. Furthermore, the iBM transplant showed high levels of engraftment in the secondary transplantation. Pretreatment of CD34(+) cells with antibodies that block either very late antigen 4 (VLA-4) or VLA-5 reduced engraftment partially, whereas blockage of both molecules resulted in complete inhibition of engraftment, which suggests that VLA-4 and VLA-5 are involved in different processes in engraftment or have complementary roles. Our results indicate that the iBM injection strategy is a more sensitive and direct way to measure the capability of human SRCs and is useful to investigate the interaction of HSCs and marrow environment in vivo.
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PMID:A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow. 1241 Dec 99

Immune-mediated elimination of tumor cells by donor T cells recognizing recipient minor H antigens contributes to the curative potential of allogeneic HCT. The importance of the allogeneic response to a successful outcome is clearly illustrated by the results of stem cell transplant for malignancy after nonmyeloablative conditioning. Remarkably little is understood about the molecular nature of minor H antigens and this has impeded efforts to determine the role of specific disparities in graft versus tumor reactions or to manipulate T cell responses to augment antitumor activity without exacerbating GVHD. The isolation of minor H antigen-specific CD8+ and CD4+ T cell clones from recipients of allogeneic HCT has provided the reagents to characterize their expression on leukemic progenitors and to identify the genes encoding these antigens. Using cDNA expression cloning, genetic polymorphisms in the human IFI-75, Uty, KIAA0020, and UGT2B17 genes have been identified to encode new minor H antigens presented by HLA A3, B8, A2, and A29 respectively. Two of these genes are preferentially expressed in hematopoietic cells including leukemic progenitors suggesting it may be possible to augment T cell responses to promote a selective graft versus leukemia effect. A third gene, UGT2B17 is highly expressed in liver and GI tract and may be a target for GVHD in these organs. The studies to identify the molecular nature of minor H antigens have provided insights into the complexities of the graft versus host response associated with allogeneic HCT, but the challenge for the future will be to develop strategies that can selectively induce durable graft versus tumor effects without GVHD. A critical issue in developing specific immunotherapy to augment GVL responses is to determine which minor H antigens are expressed on leukemic stem cells. Studies using transplantation of human AML into SCID mice have identified a putative leukemic stem cell which is contained in the CD34+ CD38- subset of the blast population and is present in very low frequency (<1/200,000) in blood or bone marrow from AML patents. We have examined the ability of minor H antigen-specific CTL to prevent engraftment of human AML in NOD/SCID mice. These studies show that engraftment of leukemias derived from individuals encoding the minor H antigen can be specifically prevented demonstrating that AML stem cells express minor H antigens and are targets for CTL. One approach to determine directly which minor H antigens can be selectively targeted to induce a GVL effect without GVHD is to adoptively transfer T cell clones of defined specificity and function to patients who relapse after HCT. Studies of this approach are now in progress in acute leukemia and have provided important insights into potential obstacles of T cell therapy for relapsed leukemia after HCT.
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PMID:Minor histocompatibility antigens--targets of graft versus leukemia responses. 1243 Sep 18

Cyclic ADP-ribose (cADPR) is a potent and universal intracellular calcium mobilizer, recently shown to behave as a new hemopoietic cytokine stimulating the in vitro proliferation of both committed and uncommitted human hemopoietic progenitors (HP). Here, we investigated the effects of cADPR on engraftment of hemopoietic stem cells (HSC) into irradiated NOD/SCID mice. Two different protocols were used: i) a 24 h in vitro priming of cord blood-derived mononuclear cells (MNC) with micromolar cADPR, followed by their infusion into irradiated mice (both primary and secondary transplants); and ii) co-infusion of MNC with CD38-transfected, cADPR-generating, irradiated murine 3T3 fibroblasts. We demonstrated a dual effect of cADPR on human HP in vivo: i) enhanced proliferation of committed progenitors, responsible for improvement of short-term engraftment; ii) expansion of HSC, with increased long-term human engraftment into secondary recipients and a significantly higher expansion factor of CD34+ progenitors in mice co-infused with MNC and CD38+ 3T3 fibroblasts. These results hold promise for the possible therapeutic use of cADPR, and of cADPR-producing stroma, to achieve long-term expansion of human HSC, that is, those HP capable of self-renewal and responsible for repopulation of the bone marrow.
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PMID:Cyclic ADP-ribose generation by CD38 improves human hemopoietic stem cell engraftment into NOD/SCID mice. 1247 90

Sublethally irradiated NOD/SCID mice were transplanted with hematopoietic progenitor cells obtained from the marrow of patients with myelodysplastic syndromes (MDS). Engraftment of MDS cells, as determined by flow cytometry, was delayed compared to marrow from normal donors. Human CD38(+)CD34(-) cells were prominent in marrows and spleens of MDS chimeras. CD34(+)CD38(-), CD34(+)CD38(+) and T cells were also easily detected. Human myeloid cells (CD33(+); CD15(+)) were present in low proportions. No clonal precursors were identified by fluorescent in situ hybridization (FISH) or by molecular analysis of polymorphic X-linked markers in mice with documented engraftment of human cells more than 2 months after transplantation. These data indicate that human cells present in murine MDS chimeras, at the levels of sensitivity of our assays, were derived from residual normal cells in human MDS marrow, and suggest that the NOD/SCID environment was not conducive to the expansion of clonal MDS precursors. This model may allow identification of factors relevant for sustaining or expanding clonal precursors.
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PMID:NOD/SCID mice transplanted with marrow from patients with myelodysplastic syndrome (MDS) show long-term propagation of normal but not clonal human precursors. 1262 Feb 94

The development of culture systems that facilitate ex vivo maintenance and expansion of transplantable hematopoietic progenitor cells (HPC) is vital to stem cell transplantation. The use of a monolayer of stromal cells on which to grow HPC in direct contact allows high efficiency ex vivo expansion of HPC. Here, we report an establishment of three murine embryonic fibroblast stromal cell lines from adherent cells of day-12 mouse embryos. Among them, HYMEQ-5 was most efficient in supporting long-term maintenance of human umbilical cord blood (CB) CD34(+) cells. Human CB CD34(+) cells cultured on HYMEQ-5 in the presence of stem cell factor (SCF), thrombopoietin, and flk-ligand (FL) showed high expansion of CD34(+)CD38(-) cells and highly proliferative potential-colony forming cells (HPP-CFC). Direct cell-to-cell contact between CD34(+) cells and HYMEQ-5 was important for this expansion. RT-PCR analysis showed that HYMEQ-5 produced FL, SCF, interleukin-6, and macrophage colony-stimulating factor (M-CSF). Expanded CB CD34(+) cells efficiently reconstituted hematopoiesis in nonobese diabetic/severe combined immunodeficient disease (NOD/SCID) mice. These findings suggest that HYMEQ-5 provides a milieu that supports long-term human hematopoiesis as well as ex vivo expansion of human CB CD34(+) HPC. This cell line may facilitate elucidation of the mechanism of cellular interactions between HPC and stromal cells.
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PMID:Establishment of mouse embryonic fibroblast cell lines that promote ex vivo expansion of human cord blood CD34+ hematopoietic progenitors. 1266 35

Ex vivo expansion of hematopoietic stem cells (HSCs) has been investigated as a means of enhancing engraftment of transplantation therapies, but current ex vivo expansion methods typically result in a loss of functional stem cell activity. Factors that can selectively expand human HSCs remain elusive. Recently we have isolated three functionally distinct human brain microvascular endothelial cells (HBMVECs) that differ greatly in their ability to support in vitro proliferation of human umbilical cord blood (UBC) CD34+CD38-cells. Using these distinct HBMVEC populations, we have devised a cell-based functional cloning assay to identify a molecule(s) capable of facilitating expansion of HSCs in vitro. A gene encoded for IGFBP-3 (insulin-like growth factor binding protein-3) has been identified. IGFBP-3 mRNA and protein are differentially expressed in distinct HBMVEC populations. In vitro cell proliferation assay and CD34+CD38- immunophenotype analysis showed that the addition of an exogenous IGFBP-3 to cultures of purified CD34+/-CD38-Lin- cells (CD2/CD3/CD14/CD16/CD19/CD24/CD56/CD66b/GlyA depleted) enhanced proliferation of primitive hematopoietic cells with CD34+CD38- phenotype, suggesting that IGFBP-3 is capable of expanding primitive human blood cells. These expanded primitive blood cells were illustrated to maintain ability to generate functional progenitors. IGFBP-3 belongs to a family of high-affinity IGFBPs, which binds to IGFs and modulates their actions. IGFBP-3 appears to have intrinsic bioactivity that is independent of IGF binding. We are currently exploring the underlying mechanism by which IGFBP-3 modulates proliferation of primitive hematopoietic cells, and the potential of IGFBP-3 to expand pluripotent human repopulating cells capable of hematopoietic reconstitution of irradiated NOD/SCID recipients.
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PMID:Functional cloning of IGFBP-3 from human microvascular endothelial cells reveals its novel role in promoting proliferation of primitive CD34+CD38- hematopoietic cells in vitro. 1272 26

There have been controversies about CD34 and CD38 expression by human cord blood (CB) stem cells. Using the newborn NOD/SCID/beta2-microglobulin-null mouse assay that we recently developed, we examined the in vivo engrafting capability of human CB cells. Almost all of the 4-5 months engrafting cells were found in CD34(+) population. The capability of secondary reconstitution was found only in the CD34(+) cells. When the CD34(+) CB cells were separated into CD38(-) and CD38(+) subpopulations and tested for engraftment, the majority of the engrafting cells were detected in the CD38(-) subpopulation. These findings are consistent with the results from studies of murine stem cells and strongly indicate that the phenotype of human CB stem cells is CD34(+) CD38(-).
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PMID:Human cord blood long-term engrafting cells are CD34+ CD38-. 1275 Jul 10

Nectins are recently described adhesion molecules that are widely expressed on many tissues, including the hematopoietic tissue. Nectin 1 (CD111) is expressed on a higher proportion of mobilized peripheral blood (mPB) than cord blood (CB) CD34+ cells, and of CD34+/CD38+ cells when compared with CD34+/CD38- cells. We studied functional properties of human CB and mPB CD34+ cells that express low or high levels of CD111. CD34+/CD111(dim) cells contain a higher proportion of cells in G0/G1 phase than CD34+/CD111(bright) cells. CD34+/CD111(bright) cells contain more erythroid progenitors: CFU-E, than their counterparts, which on the opposite contain more HPP-CFC. Limiting dilution analyses demonstrate a higher frequency of immature progenitors: cobblestone-area colony-forming cells, CD34+/CD111(dim) than in CD34+/CD111(bright) cells. In vitro differentiation assays demonstrate a higher frequency of B-, T- and dendritic-cell precursors, but less NK-cell precursors in CD34+/CD111(dim) cells. Evaluation of engraftment in NOD-SCID mice shows that SCID repopulating cells are more frequent among mPB CD34+/CD111(dim) cells. Liquid culture of CD34+/CD111(dim) cells with erythropoietin shows that CD111 expression increases simultaneously with CD36, following CD71 and before glycophorin A expression. In conclusion, immature human hematopoietic progenitors express low levels of CD111 on their surface. During erythroid differentiation CD34+ cells acquire higher levels of the CD111 antigen.
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PMID:Functional characterization of human CD34+ cells that express low or high levels of the membrane antigen CD111 (nectin 1). 1276 81

A novel cell line, SACHI, was established from a pericardial effusion developed during the course of primary plasma cell leukemia (PCL). The cell line SACHI cells were the same as the infiltrating plasma cells with regard to surface markers (CD38(+)CD19(-)PCA-1(+)VLA-5(-)CD56(-)TdT(+)) and immunoglobulin gene rearrangements. Analysis of SACHI cells showed a complex hypertriploid (karyotype mode 70-73) including 7p32, 14q32, and Xq24 structural abnormalities, which were found also in the original leukemia cells. Dual-color fluorescence in situ hybridization revealed that the c-MYC gene was juxtaposed with a constant region of IgG (Cgamma) on 14q32. The split Cgamma locus was fused near the MAFB gene on chromosome 20. The SACHI cells had increased amounts of c-MYC and MAFB transcripts. Injection of SACHI cells into NOD/SCID mice generated leukemic plasmacytosis with invasion to liver, spleen, and bone marrow. This cell line may be useful for therapeutic testing as well as analyzing the molecular pathogenesis of PCL.
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PMID:A xeno-transplantable plasma cell leukemia line with a split translocation of the IgH gene. 1281 Feb 53

The human hematopoietic stem cell compartment is comprised of repopulating CD34(+) and CD34(-) cells. The interaction between these subsets with respect to their reconstitution capacity in vivo remains to be characterized. Here, lineage-depleted (Lin(-)) human CD34(+) and CD34(-) hematopoietic cells were isolated from human male and female umbilical cord blood (CB) and transplanted into immune-deficient NOD/SCID EMV(null) mice, thereby allowing the use of human and Y-chromosome-specific DNA sequences to discriminate human reconstitution contributed by CD34(+) vs CD34(-) repopulating stem cells. Although cultured human CB CD34(-)Lin(-) cells transplanted alone possessed only minimal repopulating capacity, with 15% of mice achieving low levels of engraftment, transplantation of cocultured male CD34(-)Lin(-) cells with female CD34(+)Lin(-) cells demonstrated human repopulation with a contribution from CD34(-)Lin(-)-derived progeny in 80% of the recipients. After coculture and transplantation, male CD34(-)Lin(-) cells gave rise to primitive CD34(+)CD38(-) cells isolated in vivo, which demonstrated clonogenic progenitor function into multiple lineages. Taken together, our study indicates that the presence of CD34(+)Lin(-) cells in coculture enhanced the low repopulating function of human CD34(-)Lin(-) cells in vivo. We propose that CD34(+)Lin and CD34(-)Lin cells represent phenotypically distinct, but related cell types that exhibit unique and previously unappreciated functional interaction.
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PMID:Coculture and transplant of purified CD34(+)Lin(-) and CD34(-)Lin(-) cells reveals functional interaction between repopulating hematopoietic stem cells. 1288 51


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