In vitro maintenance and proliferation of human hematopoietic stem cells is crucial for many clinical applications. Early hematopoietic cells express low levels of FLT-3 and c-kit receptors, as well ...as the interleukin-6 (IL-6) receptor signal transducing element, gp130, but do not express IL-6 receptor itself. Therefore, we have attempted to maintain human cord blood or bone marrow CD34(+) cells ex vivo in serum-free cultures containing stem cell factor (SCF) and FLT-3 ligand (FL) alone or together with a new recombinant molecule of soluble IL-6 receptor fused to IL-6 (IL6RIL6 chimera). The effect of IL6RIL6 chimera on the proliferation and differentiation of CD34(+) cells was compared with that of each chimera component added separately. The engraftment potential of in vitro-cultured cells was determined using our recently established functional in vivo assay for primitive human severe combined immunodeficiency (SCID)-repopulating cells (SRC). We report here that IL6RIL6 chimera induced significantly higher levels of progenitors and SRC compared with SCF + FL alone or together with IL-6 and soluble IL-6 receptor. IL6RIL6 chimera prolonged in vitro maintenance of SRC for up to 14 days. Stimulation of CD34(+)CD38(-/low) enriched cells with IL6RIL6 chimera maintained the early CD34(+)CD38(-/low) cell subpopulation, which could be detected in vitro for up to 14 days. Moreover, IL6RIL6 chimera preferentially stimulated the growth of early CD34(+)38(-/low) cells, resulting in significantly higher levels of progenitors compared with more mature CD34(+)38(+) cells. Taken together, these findings demonstrate the importance of IL6RIL6 chimera in stimulating the proliferation of early CD34(+). CD38(-)gp130(+)IL-6R(-) cells in vitro and extended maintenance of progenitors and SRC.
In recent years, umbilical cord blood has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack an human ...leukocyte antigen-matched marrow donor. Since 1998, about 2,500 patients have received UCB transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg, however more than 500 UCB transplantations have already been performed in adults. The "naive" nature of UCB lymphocytes may explain the lower incidence and severity of graft versus host disease encountered in UCBT compared to the allogeneic transplant setting. Furthermore, UCB is rich in primitive CD16-CD56++ natural killer cells, which possess significant proliferative and cytotoxic capacities and can be expanded using interleukin-12 or 15, so as to mount a substantial graft versus leukemia effect. The major disadvantage of UCB is the low yield of stem cells, resulting in higher graft failure rates and slower time to engraftment compared to bone marrow transplantation. A rational approach thus involves ex vivo expansion of UCB-derived hematopoietic precursors.
Objective: Esophageal strictures caused by caustic injury continue to be a plaguing problem. Halofuginone (HF) has been proven to inhibit the formation of fibrosis in various animal models and human ...diseases. Its mechanism appears to be through the suppression of the production of collagen α1(I) and transforming growth factor‐β signaling pathway. We tried to assess whether HF would have an effect on the formation of strictures after inducing caustic esophageal.
Materials and Methods: Esophageal injury was caused by injecting 25% NaOH to an isolated esophageal segment. Study group rats were treated with HF orally for 3 consecutive days before the injury and afterward. Control group rats received regular chow. The results were evaluated by upper gastrointestinal series (UGI) and through pathologic studies.
Results: HF treatment resulted in marked improvement in the esophageal strictures. The UGI series showed esophageal patency of 73% (45%–100%) in the treated animals (n = 7) as compared with almost no patency, 11% (5–16%), in the controls (n = 4) (P = .018). The histologic examination showed significantly less stricture and scarring in the treated group. Whereas the ratio between the esophageal wall thickness to mucosal thickness was 2.34 ± 0.23 in the study group, the control group had a ratio of 9.56 ± 0.69 (P = .0044). Finally, whereas 86% of the study group survived, all the rats in the control group died by day 20.
Conclusions: HF modulated the wound healing reaction caused by caustic injury of the esophagus in a rat model, resulting in increased esophageal patency, reduction in esophageal wall thickness, and increased survival.
The pathogenesis and clinical features of chronic graft-versus-host disease (cGVHD) resemble those of several autoimmune diseases, as evidenced by frequent dermal, hepatic, occular, oral, pulmonary, ...gastrointestinal and neuromuscular involvement. Serosal involvement, however, has only rarely been reported and most of the existing accounts are historical. We describe a boy transplanted in third CR of CALLA-positive ALL from his HLA-identical sister who developed cGVHD, which was complicated by a huge pericardial effusion as a part of severe polyserositis including pleural effusion, ascites, and polyarthritis. The patient shared the HLA antigens HLA-A2, B51, and DQW6 which are associated with autoimmune diseases.
Palladium-103 (103Pd) is one of the commonly used radioisotopes for prostate cancer treatment. The current irradiation technique used to produce this radioisotope suffers from several serious ...inherent drawbacks, of which one is the low beam current due to cooling limitation and the other is the electroplating process used to prepare the target. A liquid-metal jet impingement target cooling system developed at Soreq NRC demonstrated recently a cooling capacity of 8.4kW/cm2 while the pressure of the cooling liquid on the target back was less than 1bar. The latter value implies that the target can be made very thin and that the copper back-plate might be removed. Hence, we propose a new target design based on the use of a thin rhodium foil directly cooled by a liquid-metal such as gallium.
Recent investigations in animal models of human lymphoid and myeloid leukemia suggest that induction of immune-mediated antitumor effects is feasible at the stage of minimal residual disease (MRD) ...using allogeneic immunocompetent lymphocytes following initial reconstitution with T cell depletion and/or activation of reconstituting syngeneic or allogeneic immune cells by recombinant interleukin-2 (rIL2). Pilot clinical trials in patients with leukemias and lymphomas at high risk to relapse following autologous bone marrow transplantation (BMT) suggest that beneficial antitumor effects may be achieved at the stage of MRD by home immunotherapy as soon as hematopoietic reconstitution occurs using rIL2 (Cetus) and alpha interferon (Roferon A) (Hoffmann LaRoche). Although results obtained from our open trial seem encouraging, prospective randomized trials and longer observation periods are needed in order to confirm immune-mediated antitumor effects in conjunction with autologous BMT in patients with malignant hematological disorders at high risk to relapse. Likewise, it seems that amplification of anti-leukemia effects following allogeneic BMT is feasible by post-transplant infusion of donor's peripheral blood lymphocytes for prevention and/or treatment of relapse.
We analyzed the effect of in vivo ciprofloxacin and ceftazidime treatment on the development of myeloid progenitors and on the survival of lethally irradiated mice rescued with syngeneic bone marrow ...transplantation (BMT). Ciprofloxacin treatment (15 mg/kg per dose three times daily for 5 days) enhanced myeloid progenitor (colony-forming cell CFU-C) number in the bone marrow and the survival of mice transplanted with suboptimal doses (1 x 10(5) of sNgeneic bone marrow cells (BMC). Twenty days postirradiation, 50% (38 of 76) of saline-treated mice transplanted with 1 x 10(5) cells died compared with 25% (19 of 76) of ciprofloxacin-treated mice (p < 0.05). Similarly, ciprofloxacin treatment enhanced survival of mice transplanted with 1 x 10(6) syngeneic bone marrow cells: 50% (38 of 76) of saline-treated mice died within 20 days vs. 15% (12 of 80) of ciprofloxacin-treated mice. In contrast, treatment with ceftazidime did not affect progenitor cell number or survival. On day 8 postirradiation, although lethally irradiated mice transplanted with 1 x 10(5) BMC treated with ciprofloxacin demonstrated similar white blood cell (WBC) and red blood cell (RBC) counts as saline-treated mice, a (1.9 +/- 0.2)-fold increase in the percentage of polymorphonuclear cells (PMN) was observed in the peripheral blood of ciprofloxacin-treated mice. On day 5 postirradiation, ciprofloxacin-treated mice showed a (1.6 +/- 0.2)-fold increase in the number of peritoneal PMN and a 6.5-fold increase in their antibacterial activity towards Salmonella typhimurium in comparison with saline-treated mice.
PI-14 Hassoun, E.; Shimoni, A.; Nagler, A. ...
Clinical pharmacology and therapeutics,
02/2006, Letnik:
79, Številka:
2
Journal Article
Recenzirano
BACKGROUND
High dose busulfan (BU) is used in preparative chemotherapy regimens for patients undergoing stem cell transplantation (SCT). Myelo‐ and submyeloablative protocols for IV BU, have been ...developed to achieve stable PK while minimizing toxicity and relapse. We sought to examine the PK of BU in different protocols with vs. without fludarabine and to measure oxidative stress in these protocols.
PATIENTS & METHODS
46 SCT patients were studied. Blood samples for PK curves were drawn at the first and mid dosing period. For each protocol PK parameters were estimated using a 1‐compartment open model.
RESULTS
BU PK parameters, were: t 1/2= 2.83±0.75 hr, Cl=0.17±0.04 (1/hr)/Kg and Vd=0.69±0.19 1/Kg. AUC and Cmax increased lineary with increasing cumulative dose up to 12.8 mg/Kg (r2=0.997 and 0.994, respectively). BU PK were not changed by fludarabine. Initial plasma oxidative stress (OS) was highglutathione oxidative potential (Eh) = (‐285) ± (‐20) mV compared to normal values(‐315) ‐ (‐320) mV. BU aggravated OS: increased Eh by +40 mv and reduced uric acid levels (5.1 ± 2.0 to 2.6 ± 1.1 mg%).
CONCLUSIONS
IV BU PK are stable, linear, predictable and not affected by fludarabine. The optimization of the therapeutic range of BU AUC and plasma OS for the individual patient requires further research.
Clinical Pharmacology & Therapeutics (2005) 79, P10–P10; doi: 10.1016/j.clpt.2005.12.035
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