Non ablative bone marrow transplantation

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation)...

Tissue homeostasis demands regulatory feedback, suggesting that hematopoietic stem cell (HSC) activity is controlled in part by HSC progeny. Yet, cell extrinsic HSC regulation has been well characterized only in niche cells of non-hematopoietic origin. Here we identify feedback regulation of HSCs by megakaryocytes (Mks), which are mature hematopoietic cells, through production of thrombopoietin (Thpo), a cytokine pertinent for HSC maintenance. Induced ablation of Mk cell population in mice perturbed quiescent HSCs in bone marrow (BM)...

The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery...

BACKGROUND: The role of Kupffer cell interleukin (IL)-1 in non-alcoholic steatohepatitis development remains unclear. AIMS: To evaluate the role of Kupffer cell IL-1α, IL-1β or IL-1 receptor type-1 (IL-1R1) in steatohepatitis. METHODS: C57BL/6 mice were irradiated and transplanted with bone marrow-derived cells from WT, IL-1α-/-, IL-1β-/- or IL-1R1-/- mice combined with Kupffer cell ablation with Gadolinium Chloride, and fed atherogenic diet...

SCID is a fatal syndrome caused by mutations in at least 13 different genes. It is characterized by the absence of T cells. Immune reconstitution can be achieved through nonablative related donor BMT. However, the first transplant may not provide sufficient immunity. In these cases, booster transplants may be helpful. A prospective/retrospective study was conducted of 49 SCID patients (28.7% of 171 SCIDs transplanted over 30 years) who had received booster transplants to define the long-term outcome, factors contributing to a need for a booster and factors that predicted success...

The mouse thymus supports T-cell development, but also contains non-T-cell lineages such as dendritic cells, macrophages, and granulocytes that are necessary for T-cell repertoire selection and apoptotic thymocyte clearance. Early thymic progenitors (ETPs) are not committed to the T-cell lineage, as demonstrated by both in vitro and in vivo assays. Whether ETPs realize non-T-cell lineage potentials in vivo is not well understood and indeed is controversial. In the present study, we investigated whether ETPs are the major precursors of any non-T-lineage cells in the thymus...

PURPOSE: Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B and sometimes NK cell function. Non-ablative HLA-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T cell development in the recipients, leading to a high rate of long-term survival. However, the development of B cell function has been more problematic. We report here results of analyses of B cell function in 125 SCID recipients prior to and long-term after non-ablative BMT, according to their molecular type...

PURPOSE: This study evaluated the usefulness of 3-Tesla magnetic resonance (MR) spectroscopy in patients with non-Hodgkin's lymphoma (NHL) undergoing bone marrow transplantation (BMT). MATERIALS AND METHODS: Twelve NHL patients who were candidates for BMT underwent three MR examinations of the lumbosacral spine: before ablative therapy for BMT, 15±4 days and 54±24 days after BMT. The MR study was supplemented by spectroscopic analysis. The lipid content was calculated and expressed as a percentage of lipid signal intensity relative to total signal intensity [fat fraction (FF)]...

The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3(+) Treg cells both in the spinal cord and peripheral lymphoid organs...

Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth...

Tumor growth and metastasis are determined by the complex interplay of factors, including those intrinsic to tumor cells and extrinsic factors associated with the tumor microenvironment. Our previous work demonstrated key roles for CD34 in the maintenance of vascular integrity and eosinophil and mast cell homing. Since both of these functions affect tumor development, we characterized the effect of CD34 ablation on tumor growth using the B16F1 melanoma model. Intriguingly, we found that CD34 plays a biphasic role in tumor progression...

The stem cell factor (SCF)/Kit system has served as a classic model in deciphering molecular signaling events in the hematopoietic compartment, and Kit expression is a most critical marker for hematopoietic stem cells (HSCs) and progenitors. However, it remains to be elucidated how Kit expression is regulated in HSCs. Herein we report that a cytoplasmic tyrosine phosphatase Shp2, acting downstream of Kit and other RTKs, promotes Kit gene expression, constituting a Kit-Shp2-Kit signaling axis. Inducible ablation of PTPN11/Shp2 resulted in severe cytopenia in BM, spleen, and peripheral blood in mice...

Allogeneic bone marrow transplantation is a common method used to study the contribution of myeloid and lymphoid cell populations in murine models of disease. The method requires lethal doses of radiation to ablate the bone marrow. Unintended consequences of radiation include organ injury and inflammatory cell activation. The goal of our study was to determine the degree to which bone marrow transplantation alters lungs and to develop a system to protect the lungs during radiation. C57BL/6 mice were subjected to total body irradiation with 900cGy and then transplanted with bone marrow from green fluorescent protein (GFP) expressing mice...

The objective of this study was to examine the pharmacodynamic basis for the potent preclinical and clinical anti-leukemic activity of CPX-351, a nano-scale liposome formulation of cytarabine and daunorubicin co-encapsulated at a synergistic 5:1 molar ratio. A bone marrow-engrafting CCRF-CEM leukemia model in Rag2-M mice was utilized to correlate the therapeutic and myelosuppressive properties of CPX-351 with bone marrow delivery and drug uptake in leukemia cells relative to normal bone marrow cell populations...

Cytotoxic antineoplastic therapy is widely used in the clinic as a treatment for malignant diseases. The treatment itself, however, leads to long-term depletion of the adaptive immune system, which is more pronounced in older patients, predominantly due to thymic atrophy. We and others have previously shown that withdrawal of sex steroids is able to regenerate the aged thymus and enhance recovery from autologous and allogeneic hematopoietic stem cell transplant. In this study we have examined the effects of sex steroid ablation (SSA) on the recovery of lymphopoiesis in the bone marrow (BM) and thymus following treatment with the chemotherapeutic agent cyclophosphamide (Cy) in middle-aged and old mice...

Emerging evidence indicates that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to angiogenesis-mediated growth of certain tumors in mice and human. EPCs regulate the angiogenic switch via paracrine secretion of proangiogenic growth factors and by direct luminal incorporation into sprouting nascent vessels. While the contributions of EPCs to neovessel formation in spontaneous and transplanted tumors and to the metastatic transition have been reported to be relatively low, remarkably, specific EPC ablation in vivo has resulted in severe angiogenesis inhibition and impaired primary and metastatic tumor growth...

The Cleveland Clinic blood and marrow transplant program has routinely performed 'backup' autologous harvests in unrelated recipients with hematological malignancies in remission, lymphoma without marrow involvement and CML in chronic phase. We reviewed all adult or cord unrelated donor (URD) transplants performed from January 1995 through September 2008 to evaluate the value of this procedure. Of 130 patients who had backup harvests, 15 (11%) had their backup harvests re-infused, all for graft failure. No patients undergoing fully ablative preparation and unmanipulated or T-depleted grafts from well-matched adult donors required infusion of backup marrow...

Magnetic resonance imaging of cells labeled with superparamagnetic iron oxide (SPIO) could be a valuable tool for tracking transplanted cells in living organisms. Human bone marrow-derived mesenchymal stem cells (hBMMSC) were labeled with a novel polyvinyl pyrrolidone (PVP)-coated SPIO. Prussian blue staining and electron microscopy revealed that almost all of the cells were efficiently labeled with PVP-SPIO nanoparticles. There were no signs of cytotoxicity, even at concentrations of up to 1600 microg Fe/ml of the nanoparticles, and the labeled cells were successfully visualized by in vitro cellular MRI...

Hematopoietic stem cells (HSCs) reside in association with bone marrow (BM) sinusoidal vessels in vivo, but the function of BM endothelial cells (ECs) in regulating hematopoiesis is unclear. We hypothesized that hematopoietic regeneration following injury is regulated by BM ECs. BALB/c mice were treated with total body irradiation (TBI) and then infused with C57Bl6-derived endothelial progenitor cells (EPCs) to augment endogenous BM EC activity. TBI caused pronounced disruption of the BM vasculature, BM hypocellularity, ablation of HSCs, and pancytopenia in control mice, whereas irradiated, EPC-treated mice displayed accelerated recovery of BM sinusoidal vessels, BM cellularity, peripheral blood white blood cells (WBCs), neutrophils, and platelets, and a 4...

Gastric antral vascular ectasia (GAVE), though a rare disorder, causes up to 4% of non-variceal upper GI bleeding. This paper gives an overview of studies examining clinical presentation and pathophysiology, and reviews the current evidence for invasive and non-invasive treatments. GAVE is often associated with systemic illnesses, such as cirrhosis of the liver, autoimmune connective tissue disorders, bone marrow transplantation and chronic renal failure. The pathophysiological changes leading to GAVE have not been fully explained and remain controversial...