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81.
J A Zaucha C Yu C D Lothrop R A Nash G Sale G Georges H P Kiem G P Niemeyer M Dufresne Q Cao R Storb 《Biology of blood and marrow transplantation》2001,7(1):14-24
Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase (PK) deficiency can be corrected by marrow allografts from healthy littermates after a conventional high-dose myeloablative conditioning regimen. The nonmyeloablative conditioning regimen used here, which consisted of a sublethal dose of 200 cGy total body irradiation before and immunosuppression with mycophenolate mofetil and cyclosporine after a dog leukocyte antigen (DLA)-identical littermate allograft, has been found to be effective in establishing stable mixed donor/host hematopoietic chimerism in normal dogs. We explored the feasibility of nonmyeloablative marrow allografts for the treatment of canine PK deficiency and studied the effect of stable allogeneic mixed hematopoietic chimerism on the natural course of the disease. Five affected dogs received transplants, of which 3 dogs had advanced liver cirrhosis and myelofibrosis. Both complications were presumed to be due to iron overload. All 5 dogs showed initial engraftment. Two rejected their grafts after 6 weeks but survived with completeautologous marrow recovery and return of the disease. One died from liver failure on day 27 with 60% donor engraftment. Two dogs have shown sustained mixed donor/host chimerism for more than a year with 85% and 12% donor hematopoietic cells, respectively. Overall clinical response correlated with the degree of donor chimerism. The dog with the low degree of chimerism achieved partial resolution of hemolysis, but the disease symptoms persisted as manifested by increasing iron overload resulting in progression of marrow and liver fibrosis. The dog with the high degree of donor chimerism achieved almost complete resolution of hemolysis with a decrease of marrow iron content and resolution of marrow fibrosis. These observations suggest that mixed hematopoietic chimerism can be relatively safely established in dogs with PK deficiency even in the presence of advanced liver cirrhosis. However, although effective in correcting or delaying the development of myelofibrosis, a low degree of mixed chimerism was not sufficient to prevent continued hemolysis of red blood cells of host origin. Complete donor chimerism appears necessary to achieve a long-term cure. 相似文献
82.
OBJECTIVE: Hematopoietic cells from patients with Fanconi anemia (FA) and mice carrying a targeted disruption of the gene encoding complementation group C protein (FANCC(-/-)) demonstrate an apoptotic phenotype in response to alkylating agents and cytokines including interferon gamma (IFN-gamma) in vitro. The aim of this study was to explore these apoptosis-inducing effects of IFN-gamma on the bone marrow of FANCC(-/-) mice as a potential strategy to select gene-corrected cells in vivo. Following pharmacokinetic studies to determine if serum concentrations effective in vitro can be achieved in vivo, we injected FANCC(-/-) mice with recombinant murine IFN-gamma. Hematopoietic effects were investigated by serial determinations of blood counts, progenitor colony formation, and marrow cellularity. RESULTS: Serial weekly intraperitoneal administrations of escalating doses of rmIFN-gamma did not affect peripheral blood counts in FANCC(-/-) mice, even after subsequent antibody-mediated fas ligation. Additionally, prolonged exposure after sequential daily administration of recombinant IFN-gamma did not impair progenitor cell clonogenicity in vitro. Pharmacokinetic data confirmed that the failure of IFN-gamma to induce marrow aplasia occurred in spite of peak serum levels greater than 100-fold in excess of those effective in vitro. CONCLUSION: We conclude that in spite of the well-documented in vitro apoptotic tendency of FA-phenotype hematopoietic cells, the in vivo administration of IFN-gamma with and without subsequent fas ligation does not induce bone marrow failure in FANCC(-/-) (129SvJ strain) mice. Additional selective pressure may be necessary to achieve targeted ablation of uncorrected, FA-phenotype, marrow cells. 相似文献
83.
Watts KL Nelson V Wood BL Trobridge GD Beard BC Humphries RK Kiem HP 《Experimental hematology》2012,40(3):187-196
The use of umbilical cord blood for allogeneic transplantation has increased dramatically over the past years. However, the limited number of cells available in a single cord blood unit remains a serious obstacle. Here, we wished to establish a nonhuman primate cord blood transplantation model that would allow us to test various hematopoietic stem cell expansion and gene therapy strategies. We implemented HOXB4-mediated expansion based on our previous experience with HOXB4 in autologous cells. Cord blood units were divided into two equal parts; half of the cells were transduced with a yellow fluorescent protein control vector and cryopreserved, and half were transduced with a HOXB4GFP vector, expanded, and cryopreserved. Both fractions of cells were transplanted into Macaca nemestrina subjects. We found that neutrophil recovery occurred within 19 days in all animals, and both neutrophil and platelet recovery were substantially accelerated compared to human single unit cord blood transplants. In addition, HOXB4-transduced and expanded cells resulted in superior engraftment of all hematopoietic lineages in all animals over nonexpanded controls. In conclusion, we have successfully established a nonhuman primate cord blood transplantation model and demonstrated that HOXB4 stimulates expansion and engraftment of repopulating cells. The availability of such a model has significant implications for developing and testing strategies to improve clinical cord blood transplantation, as it will allow comparison of different stem cell expansion methodologies within a single animal. Furthermore, it can be used in long-term follow-up studies to determine how specific expansion techniques affect engraftment of various hematopoietic lineages. 相似文献
84.
Leblanc CM Lang B Bencivenga A Chetaille AL Dancey P Dent P Miettunen P Oen K Rosenberg A Roth J Scuccimarri R Tse SM Benseler S Cabral DA Campillo S Chédeville G Duffy CM Duffy KW Haddad E Huber AM Laxer R Levy D Johnson N Ramsey S Shiff N Schmeling H Schneider R Stringer E Yeung RS Tucker LB 《The Journal of rheumatology》2012,39(9):1875-1879
85.
Diurnal variations of the effectivity of beta-endorphin (beta-End), dynorphin (DYN), Met-enkephalin (Met-Enk), D-Met2-Pro5-enkephalinamide (D-Met-Pro-Enk) and morphine to induce prolactin (PRL) and adrenocorticotropin (ACTH)/corticosterone (CS) release in intact and adrenalectomized rats have been examined. The response to morphine (10 mg/kg s.c.), Met-Enk (200 micrograms/rat i.c.v.) and D-Met-Pro-Enk (0.5 microgram/rat i.c.v.) did not change with different times of the day, while that to beta-End (0.5 microgram/rat i.c.v.), DYN (1 microgram/rat i.c.v.) and U50-488H, a selective kappa agonist (10 mg/kg s.c.), showed a circadian rhythm in stimulating PRL release, with a higher increase in the afternoon (16.00-17.00 h) than in the morning (08.00-09.00 h). In adrenalectomized rats the loss of this circadian rhythm was shown. The CS release evoked by morphine, D-Met-Pro-Enk, Met-Enk and DYN was demonstrable only in the morning when the basal CS level was significantly lower than in the afternoon. The afternoon release of ACTH by morphine was higher than in the morning in adrenalectomized rats. beta-End and U50-488H were equally active in the morning and in the afternoon in increasing CS secretion. The present results suggest that the diurnal rhythm in the response of CS and PRL release to opioids is in relation with the glucocorticoid secretion. 相似文献
86.
Gerald Johnson Kiem N. Nguyen Zhonglin Liu Ping Gao Roberto Pasqualini Robert D. Okada 《Journal of nuclear cardiology》1997,4(3):217-225
Background
99mTc-labeled (bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(V)) (99mTcN-NOET) is a new lipophilic, neutral-charge cardiac perfusion imaging agent that demonstrates apparent redistribution in
animal models and humans. The purpose of this study was to determine whether the kinetics of 99mTcN-NOET are suitable for the detection of resting ischemia.
Methods and Results Microspheres were injected at baseline and simultaneously with 99mTcN-NOET after a 90% reduction in resting flow in the left circumflex coronary artery in six open-chest canine experiments.
The relationship of flow and activity early after injection was determined in one experiment by termination at 10 minutes.
The flow ratio (left circumflex/left anterior descending coronary artery) after stenosis fell significantly (0.87±0.04 vs
0.46±0.04; p<0.05). The end-tissue 99mTc ratio (0.78±0.05) was significantly higher than the flow ratio at injection (0.46±0.04; p<0.05), indicating substantial redistribution. In vivo imaging was conducted during 2 hours in five experiments, followed
by ex vivo imaging. Myocardial clearance from 10 minutes onward was biphasic in left anterior descending and monophasic in
left circumflex coronary arteries. Myocardial clearance from 10 to 60 minutes was delayed in left circumflex (35.5%±8.1%)
versus left anterior descending coronary arteries (49.2%±8.6%; p<0.05). No significant difference was observed from 60- to 120-minute clearance. Five of five experiments demonstrated initial
defects and complete fill-in at 90 to 120 minutes by qualitative assessment. Quantitation of ex vivo images confirmed significant
redistribution.
Conclusions Resting ischemia caused by moderate to severe stenosis can be detected on scans with 99mTcN-NOET. Redistribution was near complete in this model by 90 to 120 minutes. 99mTcN-NOET is a promising new agent for the detection of coronary artery disease in viable myocardium and warrants further investigation. 相似文献
87.
88.
The introduction of recombinant genetic material into human cells for therapeutic purposes offers tremendous potential. However, almost from the beginning, the application of gene therapy has been characterized by the striking discrepancy between its promise and realization. Over the past 15 years, much has been learned about the various gene transfer systems and the requirements for efficient hematopoietic stem cell gene transfer. In the current review, we will summarize recent improvements in hematopoietic stem cell gene transfer, describe some of the promising results from recent clinical applications and the impediments that remain. 相似文献
89.
Effects of HOXB4 overexpression on ex vivo expansion and immortalization of hematopoietic cells from different species 总被引:1,自引:0,他引:1
Overexpression of the human HOXB4 has been shown to induce the expansion and self-renewal of murine hematopoietic stem cells. In preparation for clinical studies, we wished to investigate the effects of HOXB4 on cells from other species, in particular preclinical large animals such as dogs and nonhuman primates. Thus, we transduced CD34(+) cells from nonhuman primates, dogs, and humans with a HOXB4-expressing gammaretroviral vector and a yellow fluorescent protein-expressing control vector. Compared with the control vector, HOXB4 overexpression resulted in a much larger increase in colony-forming cells in dog cells (28-fold) compared with human peripheral blood, human cord blood, and baboon cells (two-, four-, and fivefold, respectively). Furthermore, we found that HOXB4 overexpression resulted in immortalization with sustained growth (>12 months) of primitive hematopoietic cells from mice and dogs but not from monkeys and humans. This difference correlated with increased levels of retrovirally overexpressed HOXB4 in dog and mouse cells compared with human and nonhuman primate cells. The immortalized cells did not show any evidence of insertional mutagenesis or chromosomal abnormalities. Competitive congenic transplantation experiments showed that HOXB4-expanded mouse cells engrafted well after 1 or 3 months of expansion, and no leukemia was observed in mice. Our findings suggest that the growth promoting effects of HOXB4 are critically dependent on HOXB4 expression levels and that this can result in important species-specific differences in potency. Disclosure of potential conflicts of interest is found at the end of this article. 相似文献
90.