Browsing by keyword "*Bone Marrow Transplantation"
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Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasiaTherapy-related myelodysplasia (MDS) is a fatal marrow disorder distinct from primary MDS. We examined the efficacy of bone marrow transplantation (BMT) as a treatment for patients with therapy-related MDS. Eighteen patients with therapy-related MDS and twenty-five patients with primary MDS received an allogeneic, syngeneic, or unrelated donor BMT. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, FK-506, or T cell depletion. Conditioning regimens consisted of cyclophosphamide/total body irradiation, with and without cytosine arabinoside, busulfan/cyclophosphamide, and cyclophosphamide/etoposide/carmustine. For patients with therapy-related MDS, the median age was 32 years and the actuarial disease-free survival was 24% (95% confidence interval 6, 42%) with a median follow-up of 3 years. For patients with primary MDS, the median age was 36 years and the actuarial disease-free survival at 3 years was 43% (95% confidence interval 22, 64%). Four of the therapy-related patients and two of the primary patients have relapsed. Three patients experienced graft failure; all three had received T cell-depleted marrow and two had marrow fibrosis. Our results suggest that patients with therapy-related MDS can be successfully transplanted. Transplantation should be considered early in the disease, since long-term disease-free survival is achievable.
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Cells capable of bone production engraft from whole bone marrow transplants in nonablated miceAllogeneic and autologous marrow transplants are routinely used to correct a wide variety of diseases. In addition, autologous marrow transplants potentially provide opportune means of delivering genes in transfected, engrafting stem cells. However, relatively little is known about the mechanisms of engraftment in transplant recipients, especially in the nonablated setting and with regard to cells not of hemopoietic origin. In particular, this includes stromal cells and progenitors of the osteoblastic lineage. We have demonstrated for the first time that a whole bone marrow transplant contains cells that engraft and become competent osteoblasts capable of producing bone matrix. This was done at the individual cell level in situ, with significant numbers of donor cells being detected by fluorescence in situ hybridization in whole femoral sections. Engrafted cells were functionally active as osteoblasts producing bone before being encapsulated within the bone lacunae and terminally differentiating into osteocytes. Transplanted cells were also detected as flattened bone lining cells on the periosteal bone surface.
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Engraftment of a clonal bone marrow stromal cell line in vivo stimulates hematopoietic recovery from total body irradiationWhether bone marrow stromal cells of donors contribute physiologically to hematopoietic stem cell reconstitution after marrow transplantation is unknown. To determine the transplantability of nonhematopoietic marrow stromal cells, stable clonal stromal cell line (GB1/6) expressing the a isoenzyme of glucose-6-phosphate isomerase (Glu6PI-a, D-glucose-6-phosphate ketol-isomerase; EC 5.3.1.9) was derived from murine long-term bone marrow cultures and made resistant to neomycin analogue G418 by retroviral gene transfer. GB1/6 cells were fibronectin+, laminin+, and collagen-type IV+ and collagen type I-; these GB1/6 cells supported in vitro growth of hematopoietic stem cells forming colony-forming units of spleen cells (CFU-S) and of granulocytes, erythrocytes, and macrophage/megakarocytes (CFU-GEMM) in the absence of detectable growth factors interleukin 3 (multi-colony-stimulating factor), granulocyte/macrophage colony-stimulating factor, granulocyte-stimulating factor, or their poly(A)+ mRNAs. The GB1/6 cells produced macrophage colony-stimulating factor constitutively. Recipient C57BL/6J (glucose-6-phosphate isomerase b) mice that received 3-Gy total-body irradiation and 13 Gy to the right hind limb were injected i.v. with GB1/6 cells. Engrafted mice demonstrated donor-originating Glu6PI-a+ stromal cells in marrow sinuses in situ 2 mo after transplantation and a significantly enhanced hematopoietic recovery compared with control irradiated nontransplanted mice. Continuous (over numerous passages) marrow cultures derived from transplanted mice demonstrated G418-resistant, Glu6PI-a+ stromal colony-forming cells and greater cumulative production of multipotential stem cells of recipient origin compared with cultures established from irradiated, nontransplanted control mice. These data are evidence for physiological function in vivo of a transplanted bone marrow stromal cell line.
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Improved hematopoiesis in anemic Sl/Sld mice by splenectomy and therapeutic transplantation of a hematopoietic microenvironmentThe ability of a clonal hematopoiesis-supportive bone-marrow stromal cell line GBlneor to engraft and alter the microenvironment-induced anemia of Sl/Sld mice was studied. Prior to stromal cell transplantation, Sl/Sld mice received 1 Gy total body irradiation (TBI) and 13 Gy to the right hind limb. Two months after intravenous (IV) injection of 5 x 10(5) GBlneor cells, 54.4% +/- 17.0% donor origin (G418r) colony-forming cells were recovered from the right hind limb of Sl/Sld mice. Long-term bone marrow cultures (LTBMCs) established from GBlneor-transplanted mice produced 189.5 CFU-GEMM-forming progenitors/flask over 10 weeks compared with 52.7 +/- 6.2 CFU-GEMM forming progenitors/flask from irradiated nontransplanted Sl/Sld mice. A partial correction of macrocytic anemia was detected 2 months after GBlneor transplantation in splenectomized, irradiated Sl/Sld mice (HgB 7.2 +/- 0.4 g/dL; MCV 68.3 +/- 7.0 fL) compared to splenectomized, irradiated, nontransplanted Sl/Sld mice (HgB 5.5 +/- 1.1 g/dL; MCV 76 +/- 8.5 fL) or control Sl/Sld mice (HgB 5.4 +/- 0.5 g/dL; MCV 82.4 +/- 1.3 fL). Mean RBC volume distribution analysis showed a 2.5-fold increase in percentage of peripheral blood RBCs with MCV less than or equal to 45 fL and confirmed reduction of the MCV in splenectomized-GBlneor-transplanted mice compared to control Sl/Sld mice. A hematopoiesis-suppressive clonal stromal cell line derived from LTBMCs of Sl/Sld mice (Sldneor) engrafted as effectively (43.5% +/- 1.2% G418r CFU-F/limb) as did GBlneor cells (38.3% +/- 0.16% G418r CFU-F/limb) to the irradiated right hind limbs of C57Bl/6 mice. LTBMCs established after 2 or 6 months from Sldneor-transplanted mice showed decreased hematopoiesis (182 +/- 12 [2 months] and 3494.3 +/- 408.1 [6 months] CFU-GEMM forming progenitors/flask over 10 weeks) compared to those established from GBlneor-transplanted mice (5980 +/- 530 [2 months] and 7728 +/- 607, [6 months] CFU-GEMM progenitors forming/flask). Thus, transplantation of clonal bone-marrow stromal cell lines in vivo can stably transfer their physiologic properties to normal or mutant mice.
