High-dose therapy in lymphomas: a review of the current status of allogeneic and autologous stem cell transplantation in Hodgkin's disease and non-Hodgkin's lymphoma.
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Autologous stem cell transplantation has proven to be beneficial in selected patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). In patients with HD, transplantation appears to increase event-free survival in patients who fail to enter complete remission with initial therapy. When a patient relapses after a complete remission, transplantation is probably the best option and particularly so if the remission lasted less than 1 year. Transplantation as part of primary therapy for very high-risk patients may be beneficial, but is not standard therapy at this time. For patients with diffuse large-cell NHL, transplantation can be considered standard therapy for relapsed patients if they have chemotherapy-sensitive disease. The use of transplantation for high-risk patients in complete remission is promising, but definite recommendations cannot be made at this time. For follicular lymphomas, selected patients seem to benefit and studies are ongoing. Finally, the use of allogeneic stem cell transplantation can be useful in a select group of younger patients. (+info)
Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis.
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Systemic activation and proliferation of CD8(+) T cells result in T cell accumulation in the liver, associated with T cell apoptosis and liver injury. However, the role of Ag and APC in such accumulation is not clear. Bone marrow chimeras were constructed to allow Ag presentation in all tissues or alternatively to restrict presentation to either bone marrow-derived or non-bone marrow-derived cells. OVA-specific CD8(+) T cells were introduced by adoptive transfer and then activated using peptide, which resulted in clonal expansion followed by deletion. Ag presentation by liver non-bone marrow-derived cells was responsible for most of the accumulation of activated CD8(+) T cells. In contrast, Ag presentation by bone marrow-derived cells resulted in less accumulation of T cells in the liver, but a higher frequency of apoptotic cells within the intrahepatic T cell population. In unmodified TCR-transgenic mice, Ag-induced T cell deletion and intrahepatic accumulation of CD8(+) T cells result in hepatocyte damage, with the release of aminotransaminases. Our experiments show that such liver injury may occur in the absence of Ag presentation by the hepatocytes themselves, arguing for an indirect mechanism of liver damage. (+info)
CD34- blood-derived human endothelial cell progenitors.
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A subset of adult peripheral blood leukocytes functions as endothelial cell progenitors called angioblasts. They can incorporate into the vasculature in animal models of neovascularization and accelerate the restoration of blood flow to mouse ischemic limbs. Earlier reports suggested that CD34-expressing (CD34+) but not CD34+ cell-depleted (CD34-) leukocytes can differentiate into endothelial cells (EC) in vitro and in vivo. Recent findings suggest that CD14+ cells, which are typically CD34-, also have angioblast-like properties in vitro. To determine the identity of angioblasts, the potential of CD34+, CD34-, CD34- CD14+, and CD34- CD14- cells to produce EC was compared. We show that a subset of monocyte (CD34- CD14+)-enriched cells can take on an EC-like phenotype in culture, but that the EC-like cells also express dendritic cell antigens. These findings suggest that monocytes differentiate into macrophages, dendritic cells, or EC depending on environmental cues. The data also demonstrate that angioblasts are more abundant in the blood than previously thought. Finally, we demonstrate that CD34- and CD34- CD14+ cells incorporate into the endothelium of blood vessels in mouse ischemic limbs. However, incorporation of these cells requires co-injection with CD34+ cells, indicating that leukocyte-leukocyte interactions may play a critical role in governing angioblast behavior in vivo. (+info)
Amniotic membrane grafts, "fresh" or frozen? A clinical and in vitro comparison.
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BACKGROUND/AIMS: The use of "fresh" (hypothermically stored) and frozen amniotic membrane (AM) was compared in a patient with cicatricial pemphigoid with stem cell failure. The viability of both "fresh" and frozen AM epithelial cells was assessed after storage. METHODS: AM was stored at either +4 degrees C ("fresh") or at -80 degrees C (frozen). A "fresh" graft was applied to the cornea following superficial keratectomy. Subsequently, a further frozen graft was applied to the same eye. Viability of the stored AM epithelium was assessed by investigating membrane integrity and mitochondrial activity. RESULTS: In both cases the cornea re-epithelialised and visual acuity improved. Improvement, however, was not sustained. CONCLUSION: Although both procedures led to an improvement in visual acuity, "fresh" tissue performed no better than frozen in promoting re-epithelialisation. The authors suggest that logistical, safety, and cost considerations outweigh any benefits of using "fresh" as opposed to frozen graft material. (+info)
Segregation of human neural stem cells in the developing primate forebrain.
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Many central nervous system regions at all stages of life contain neural stem cells (NSCs). We explored how these disparate NSC pools might emerge. A traceable clone of human NSCs was implanted intraventricularly to allow its integration into cerebral germinal zones of Old World monkey fetuses. The NSCs distributed into two subpopulations: One contributed to corticogenesis by migrating along radial glia to temporally appropriate layers of the cortical plate and differentiating into lamina-appropriate neurons or glia; the other remained undifferentiated and contributed to a secondary germinal zone (the subventricular zone) with occasional members interspersed throughout brain parenchyma. An early neurogenetic program allocates the progeny of NSCs either immediately for organogenesis or to undifferentiated pools for later use in the "postdevelopmental" brain. (+info)
A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia.
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The hematopoietic stem cell underlying acute myeloid leukemia (AML) is controversial. Flow cytometry and the DNA-binding dye Hoechst 33342 were previously used to identify a distinct subset of murine hematopoietic stem cells, termed the side population (SP), which rapidly expels Hoechst dye and can reconstitute the bone marrow of lethally irradiated mice. Here, the prevalence and pathogenic role of SP cells in human AML were investigated. Such cells were found in the bone marrow of more than 80% of 61 patients and had a predominant CD34(low/-) immunophenotype. Importantly, they carried cytogenetic markers of AML in all 11 cases of active disease examined and in 2 out of 5 cases in complete hematological remission. Comparison of daunorubicin and mitoxantrone fluorescence emission profiles revealed significantly higher drug efflux from leukemic SP cells than from non-SP cells. Three of 28 SP cell transplants generated overt AML-like disease in nonobese diabetic--severe combined immunodeficient mice. Low but persistent numbers of leukemic SP cells were detected by molecular and immunological assays in half of the remaining mice. Taken together, these findings indicate that SP cells are frequently involved in human AML and may be a target for leukemic transformation. They also suggest a mechanism by which SP cells could escape the effects of cytostatic drugs and might eventually contribute to leukemia relapse. (Blood. 2001;98:1166-1173) (+info)
Quantitative effects of Nf1 inactivation on in vivo hematopoiesis.
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The NF1 tumor-suppressor gene is frequently inactivated in juvenile myelomonocytic leukemia, and Nf1 mutant mice model this myeloproliferative disorder (MPD). Competitive repopulation assays were performed to quantify the proliferative advantage of Nf1(-/-) hematopoietic cells in vivo. Nf1 mutant stem cells demonstrated a growth advantage that was greatest in myeloid lineage cells and least pronounced in T lymphocytes. Surprisingly, although low numbers of Nf1-deficient cells consistently outcompeted wild-type cells, levels of chimerism were stable over months of observation, and MPD was not observed unless threshold numbers of mutant cells were injected. These data showing that normal competitor cells can strongly modulate the growth of mutant populations in vivo have general implications for modeling cancer in the mouse. In particular, strains in which cancer-associated mutations are expressed in fields of target cells may not accurately model early events in tumorigenesis because they eliminate the requirement for a mutant clone to outcompete resident normal cells. (+info)
Effective cryopreservation of human embryonic stem cells by the open pulled straw vitrification method.
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BACKGROUND: Human embryonic stem (ES) cells originate from the inner cell mass of the blastocyst, and retain in culture the properties of pluripotent cells of the early embryo. The study aim was to determine whether the open pulled straw (OPS) vitrification method, which is highly effective for the cryopreservation of embryos, might be also efficient for human ES cells. METHODS AND RESULTS: All human ES cell clumps that were vitrified by the OPS method could be recovered upon thawing, and gave rise to ES cell colonies after plating. Vitrified colonies were significantly smaller and showed an increased level of background differentiation compared with control colonies. However, these unwanted effects could be overcome by additional cultivation of the colonies for 1 and 2 days respectively. The vitrified human ES cells were cultivated for prolonged periods and retained the properties of pluripotent cells, including a normal karyotype, expression of the transcription factor Oct-4 and surface markers that are characteristic to human ES cells. When grafted into SCID mice, the vitrified cells gave rise to teratomas containing derivatives of all three embryonic germ layers. CONCLUSIONS: Vitrification by the OPS method is reliable and effective for the cryopreservation of human pluripotent embryonic stem cells. (+info)