scholarly journals Efficacy and Toxicity of Long-Term Administration of 2′,3′-dideoxycytidine in the LP-BM5 Murine-Induced Immunodeficiency Model

1995 ◽  
Vol 6 (3) ◽  
pp. 153-161 ◽  
Author(s):  
G. Brandi ◽  
A. Casabianca ◽  
G.F. Schiavano ◽  
L. Rossi ◽  
A. Fraternale ◽  
...  

The LP-BM5 murine retrovirus-induced immunodeficiency model was used to evaluate the efficacy and toxicity of long-term 2′,3′-dideoxycytidine (DDC) therapy. A mean plasma drug concentration of 0.2 + 0.02 μm of DDC for 3 months was found to reduce splenomegaly, lymphoadenopathy and hypergammaglobulinemia in infected mice. However, DDC also reduced spleen weight in control mice and spleen haemopoiesis in both infected and uninfected animals. In the bone marrow the most prominent feature of DDC treatment was a marked reduction of megakariocytes, while in the liver an hepatocellular vacuolation was evident in uninfected animals. DDC reduced, but did not prevent, LP-BM5 integration in lymph node DNA and Pr 60gag expression in spleen lymphocytes and bone marrow cells. Furthermore, DDC reduced the mitochondrial DNA content and restored the mitogen proliferation of T cells but not that of B cells in infected mice. Thus, DDC appears to be of some, but limited, efficacy in murine AIDS, with a toxicity profile involving more cell types than previously thought.

Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3025-3031 ◽  
Author(s):  
Fulu Liu ◽  
Jennifer Poursine-Laurent ◽  
Daniel C. Link

Abstract The mechanisms that regulate hematopoietic progenitor cell (HPC) mobilization from the bone marrow to blood have not yet been defined. HPC mobilization by granulocyte colony-stimulating factor (G-CSF), cyclophosphamide (CY), or interleukin-8 but not flt-3 ligand is markedly impaired in G-CSF receptor–deficient (G-CSFR–deficient) mice. G-CSFR is expressed on mature hematopoietic cells, HPCs, and stromal cells, which suggests that G-CSFR signals in one or more of these cell types was required for mobilization by these agents. To define the cell type(s) responsible for G-CSF–dependent mobilization, a series of chimeric mice were generated using bone marrow transplantation. Mobilization studies in these chimeras demonstrated that expression of the G-CSFR on transplantable hematopoietic cells but not stromal cells is required for CY- or G-CSF–induced mobilization. Moreover, in irradiated mice reconstituted with both wild type and G-CSFR–deficient bone marrow cells, treatment with CY or G-CSF resulted in the equal mobilization of both types of HPCs. This result held true for a broad spectrum of HPCs including colony-forming cells, CD34+lineage− and Sca+ lineage−cells, and long-term culture initiating cells. Collectively, these data provide the first definitive evidence that expression of the G-CSFR on HPCs is not required for their mobilization by G-CSF and suggest a model in which G-CSFR–dependent signals act in trans to mobilize HPCs from the bone marrow.


Blood ◽  
2000 ◽  
Vol 95 (10) ◽  
pp. 3025-3031 ◽  
Author(s):  
Fulu Liu ◽  
Jennifer Poursine-Laurent ◽  
Daniel C. Link

The mechanisms that regulate hematopoietic progenitor cell (HPC) mobilization from the bone marrow to blood have not yet been defined. HPC mobilization by granulocyte colony-stimulating factor (G-CSF), cyclophosphamide (CY), or interleukin-8 but not flt-3 ligand is markedly impaired in G-CSF receptor–deficient (G-CSFR–deficient) mice. G-CSFR is expressed on mature hematopoietic cells, HPCs, and stromal cells, which suggests that G-CSFR signals in one or more of these cell types was required for mobilization by these agents. To define the cell type(s) responsible for G-CSF–dependent mobilization, a series of chimeric mice were generated using bone marrow transplantation. Mobilization studies in these chimeras demonstrated that expression of the G-CSFR on transplantable hematopoietic cells but not stromal cells is required for CY- or G-CSF–induced mobilization. Moreover, in irradiated mice reconstituted with both wild type and G-CSFR–deficient bone marrow cells, treatment with CY or G-CSF resulted in the equal mobilization of both types of HPCs. This result held true for a broad spectrum of HPCs including colony-forming cells, CD34+lineage− and Sca+ lineage−cells, and long-term culture initiating cells. Collectively, these data provide the first definitive evidence that expression of the G-CSFR on HPCs is not required for their mobilization by G-CSF and suggest a model in which G-CSFR–dependent signals act in trans to mobilize HPCs from the bone marrow.


2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Hirohiko Ise ◽  
Kumiko Matsunaga ◽  
Marie Shinohara ◽  
Yasuyuki Sakai

Mesenchymal stem cells (MSCs) in bone marrow and adipose tissues are expected to be effective tools for regenerative medicine to treat various diseases. To obtain MSCs that possess both high differentiation and tissue regenerative potential, it is necessary to establish an isolation system that does not require long-term culture. It has previously been reported that the cytoskeletal protein vimentin, expressed on the surfaces of multiple cell types, possesses N-acetylglucosamine- (GlcNAc-) binding activity. Therefore, we tried to exploit this interaction to efficiently isolate MSCs from rat bone marrow cells using GlcNAc-bearing polymer-coated dishes. Cells isolated by this method were identified as MSCs because they were CD34-, CD45-, and CD11b/c-negative and CD90-, CD29-, CD44-, CD54-, CD73-, and CD105-positive. Osteoblast, adipocyte, and chondrocyte differentiation was observed in these cells. In total, yields of rat MSCs were threefold to fourfold higher using GlcNAc-bearing polymer-coated dishes than yields using conventional tissue-culture dishes. Interestingly, MSCs isolated with GlcNAc-bearing polymer-coated dishes strongly expressed CD106, whereas those isolated with conventional tissue-culture dishes had low CD106 expression. Moreover, senescence-associated β-galactosidase activity in MSCs from GlcNAc-bearing polymer-coated dishes was lower than that in MSCs from tissue-culture dishes. These results establish an improved isolation method for high-quality MSCs.


2018 ◽  
Vol 22 (5-6) ◽  
pp. 22-24
Author(s):  
Yu. Bahmut ◽  
O. S. Ivanov ◽  
G. V. Tsapko

The hematopoietic system is a population of many cells that perform certain functions in the body. The pharmaceutical industry creates new drugs from the group of nonsteroidal anti-inflammatory drugs, but the “gold” standard remains the drug Diclofenac Sodium. In some conditions, a person is forced to take the drug for a long time, and sometimes all life. The mechanism of the drug effect on the bone marrow cells under the condition of long-term administration remains unclear. In the process of analyzing the literature, it has been established that the use of the drug has a toxic effect on the blood cells and blood-forming organs. Gradually, the toxic effect is reduced, but the long-term effect of the drug on the rat organism contributes to the inhibition of the development of erythrocyte and myelocytic sprouts of the bone marrow. A period of up to 10 days is optimal for use, and then it is worthwhile to look for a drug that is safer for the body.


Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4136-4142 ◽  
Author(s):  
I Kawashima ◽  
ED Zanjani ◽  
G Almaida-Porada ◽  
AW Flake ◽  
H Zeng ◽  
...  

Using in utero transplantation into fetal sheep, we examined the capability of human bone marrow CD34+ cells fractionated based on Kit protein expression to provide long-term in vivo engraftment. Twelve hundred to 5,000 CD34+ Kit-, CD34+ Kit(low), and CD34+ Kit(high) cells were injected into a total of 14 preimmune fetal sheep recipients using the amniotic bubble technique. Six fetuses were killed in utero 1.5 months after bone marrow cell transplantation. Two fetuses receiving CD34+ Kit(low) cells showed signs of engraftment according to analysis of CD45+ cells in their bone marrow cells and karyotype studies of the colonies grown in methylcellulose culture. In contrast, two fetuses receiving CD34+ Kit(high) cells and two fetuses receiving CD34+ Kit- cells failed to show evidence of significant engraftment. Two fetuses were absorbed. A total of six fetuses receiving different cell populations were allowed to proceed to term, and the newborn sheep were serially examined for the presence of chimerism. Again, only the two sheep receiving CD34+ Kit(low) cells exhibited signs of engraftment upon serial examination. Earlier in studies of murine hematopoiesis, we have shown stage-specific changes in Kit expression by the progenitors. The studies of human cells reported here are in agreement with observations in mice, and indicate that human hematopoietic stem cells are enriched in the Kit(low) population.


1998 ◽  
Vol 331 (3) ◽  
pp. 733-742 ◽  
Author(s):  
Masafumi YOSHIMURA ◽  
Yoshito IHARA ◽  
Tetsuo NISHIURA ◽  
Yu OKAJIMA ◽  
Megumu OGAWA ◽  
...  

Several sugar structures have been reported to be necessary for haemopoiesis. We analysed the haematological phenotypes of transgenic mice expressing β-1,4 N-acetylglucosaminyltransferase III (GnT-III), which forms bisecting N-acetylglucosamine on asparagine-linked oligosaccharides. In the transgenic mice, the GnT-III activity was elevated in bone marrow, spleen and peripheral blood and in isolated mononuclear cells from these tissues, whereas no activity was found in these tissues of wild-type mice. Stromal cells after long-term cultures of transgenic-derived bone marrow and spleen cells also showed elevated GnT-III activity, compared with an undetectable activity in wild-type stromal cells. As judged by HPLC analysis, lectin blotting and lectin cytotoxicity assay, bisecting GlcNAc residues were increased on both blood cells and stromal cells from bone marrow and spleen in transgenic mice. The transgenic mice displayed spleen atrophy, hypocellular bone marrow and pancytopenia. Bone marrow cells and spleen cells from transgenic mice produced fewer haemopoietic colonies. After lethal irradiation followed by bone marrow transplantation, transgenic recipient mice showed pancytopenia compared with wild-type recipient mice. Bone marrow cells from transgenic donors gave haematological reconstitution at the same level as wild-type donor cells. In addition, non-adherent cell production was decreased in long-term bone marrow cell cultures of transgenic mice. Collectively these results indicate that the stroma-supported haemopoiesis is compromised in transgenic mice expressing GnT-III, providing the first demonstration that the N-glycans have some significant roles in stroma-dependent haemopoiesis.


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1736.2-1736
Author(s):  
O. Burianov ◽  
L. Khimion ◽  
T. Omelchenko ◽  
E. Levitskyi ◽  
V. Lyanskorynsky

Background:traumatic ankle joint osteochondral lesions and defects (OHLD) is frequent cause of OA, chronic pain and loss of joint function; results of traditional treatment strategy are often unsatisfyingObjectives:to develop treatment algorithm for OHLD based on evaluation of previously determined main prognostic factors.Methods:the analysis of long-term (36 ± 4.5 months) treatment results of 239 patients after traumatic ankle joint OHLD revealed the following factors with the greatest predictive value (defined by PC – prognostic coefficient) for good result of treatment (defined as AOFAS function score 75-100 points): age < 40 years (PC = 8.5); size of OHLD ≤ 1.0 cm2; volume ≤ 1.5 cm3(PC = 8.0); osteoarthritis stage ≤ II (PC = 7.2). Based on these factors, a step-by-step, discrete and alternative algorithm for the choice of treatment tactics was created. The algorithm includes use of arthroscopic or open debridement, abrasive chondroplasty, bone marrow regeneration stimulation (microfracturing or tunneling), mosaic osteochondroplasty, arthroplasty or arthrodesis, the use of cellular regenerative technologies (bone marrow cells, platelet riched plasma), and others. Patients of older age with advanced OA need complex, step up approach, surgical treatment combined with regenerative cell technologies. The effectiveness of the differentiated approach to treatment was studied in 72 patients with OHLD (main group) in comparing to 72 patients in whom traditional treatment approaches were used, based on the stage of injury according to the Berndt & Hardy classification (comparison group).Results:compared to the traditional approach, the developed algorithm and treatment system allowed to half terms of hospitalization, to reduce the intensity of pain syndrome (by NRS) and increase the functional activity (by AOFAS) by 25%. In 3 years after trauma good/excellent results of treatment demonstrated 86% patients of main group and 32,2% of patients from comparing group (p<0,05).Conclusion:implementation of the developed treatment algorithm increases the number of good and excellent long-term results by 2.6 times and reduces the number of complications and unsatisfactory results by 4.9 times.Disclosure of Interests:None declared


2011 ◽  
Vol 57 (5) ◽  
pp. 535-543
Author(s):  
M.S. Dolgikh ◽  
D.N. Livak ◽  
M.E. Krasheninnikov ◽  
N.A. Onishchenko

The cultivation of multipotent mesenchymal stromal bone marrow cells and cells of A-431, MDCK, Vero, 3T3 and Hep-G2 was performed on polymeric films (PVA) with different hydrophobic fatty acid residues. The cells of different types grew on these films with different intensity, but in the most cases comparable with the cultivation control on usual plastic. The examined films were nontoxic to cells and sufficiently adhesive. They did not changed pH of cultural media, were optically transparent under microscope and comfortable in the experimental work. These films can be used as a model for the artificial organ construction. The covalent binding of different fatty acids to PVA shows possibility of the adaptable changes of films properties (hydrophobity and adhesiveness), and therefore possibility of the creation of optimal conditions for different cell types attachement and growth.


Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1460-1462 ◽  
Author(s):  
ME Pietrzyk ◽  
GV Priestley ◽  
NS Wolf

It was found in a long-term bromodeoxyuridine (BrdU) infusion study that two or more different subpopulations of bone marrow stem cells exist in mice. One of these subpopulations appears to be noncycling and forms approximately 10% of eight-day CFU-S. Another one, a subpopulation of slowly cycling bone marrow cells, is represented as 14- day CFU-S. The 14-day CFU-S have a regular increment in the percentage of the subpopulation entering the cycle over time, with a cell generation half-time of 21 days. The cycling status in these experiments was ascertained by in vivo continuous long-term BrdU infusion. An improved method is presented for long-term BrdU infusion with UV killing of cycled cells.


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