Optimization of a myeloid cell transfusion strategy for infected neutropenic hosts

Spellberg, Brad; Collins, Mary; Avanesian, Valentina; Gomez, Mayela; Edwards, John E.; Cogle, Christopher R.; Applebaum, David; Fu, Yue; Ibrahim, Ashraf S.

doi:10.1189/jlb.0906549

Cited by 20 publications

(20 citation statements)

References 44 publications

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“…Two days after the treatment (on the day neu-tropenia began), mice were infected via the tail vein with R. oryzae and treated with placebo, anidulafungin (10 mg/kg/day), LAmB (3 mg/kg/day [based on preliminary data demonstrating limited survival benefit for infected mice treated with this dose]), or a combination for 6 days starting 24 h after infection, reflecting the duration of neutropenia in this model (10). Only mice treated with combination therapy demonstrated survival benefit compared to those treated with the placebo (Fig.…”

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confidence: 99%

Combination Echinocandin-Polyene Treatment of Murine Mucormycosis

Ibrahim

Gebremariam

et al. 2008

Antimicrob Agents Chemother

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106

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confidence: 99%

Combination Echinocandin-Polyene Treatment of Murine Mucormycosis

Ibrahim

Gebremariam

et al. 2008

Antimicrob Agents Chemother

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166

106

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“…Glycosuria and ketonuria were confirmed in all mice prior to infection. For the neutropenic model, mice were made neutropenic by a single intraperitoneal dose of 200 mg of cyclophosphamide/kg of body weight on day Ϫ2 relative to infection, resulting in approximately 7 days of neutropenia (6,7,12,13). Mice were infected via the tail vein with Rhizopus oryzae 99-880, a clinical brain isolate known to be virulent in the murine model (4, 5, 11).…”

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confidence: 99%

Posaconazole Mono- or Combination Therapy for Treatment of Murine Zygomycosis

Ibrahim

Gebremariam

Schwartz

et al. 2009

Antimicrob Agents Chemother

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We compared the efficacy of combination posaconazole-liposomal amphotericin B (LAmB) therapy to monotherapy with either drug in diabetic ketoacidotic or neutropenic mice with disseminated zygomycosis caused by Rhizopus oryzae. Combination therapy was no better than LAmB alone, and posaconazole monotherapy did not improve survival or reduce fungal burden versus placebo.Posaconazole has in vitro activity against the agents of zygomycosis and has been used as salvage therapy for patients refractory to or intolerant of polyenes (2, 15). To determine if up-front posaconazole-polyene combination therapy would improve the outcome of zygomycosis, we tested the efficacy of liposomal amphotericin B (LAmB), posaconazole, or the combination LAmB plus posaconazole therapy in our standard diabetic ketoacidotic (DKA) and neutropenic mouse models of disseminated zygomycosis.For the DKA model, BALB/c male mice were rendered diabetic with a single intraperitoneal injection of 210 mg/kg streptozotocin 10 days prior to fungal challenge, as we have previously described (3-5). Glycosuria and ketonuria were confirmed in all mice prior to infection. For the neutropenic model, mice were made neutropenic by a single intraperitoneal dose of 200 mg of cyclophosphamide/kg of body weight on day Ϫ2 relative to infection, resulting in approximately 7 days of neutropenia (6,7,12,13). Mice were infected via the tail vein with Rhizopus oryzae 99-880, a clinical brain isolate known to be virulent in the murine model (4, 5, 11). LAmB (Gilead Sciences), posaconazole oral suspension (Western Medical Supplies), a combination of both, or placebo (5% dextrose solution) was administered once daily for 4 days starting at 24 h postinfection.For the initial experiment in the DKA model, a dose-ranging study was conducted to determine the optimal dose of posaconazole. DKA mice were infected via the tail vein with R. oryzae 99-880 and treated with posaconazole at 10, 30, or 60 mg/kg/day administered via oral gavage. No dose of posaconazole improved survival versus placebo (Fig. 1A). Both lower doses of posaconazole resulted in a trend to worse survival (P ϭ 0.1 for 10 and 30 mg/kg/day versus placebo).For the subsequent combination study, DKA mice were infected with R. oryzae 99-880 and treated with 15 mg/kg/day LAmB intravenously (i.v.), 60 mg/kg/day posaconazole by oral gavage, a combination of both, or placebo. LAmB monotherapy and the combination of LAmB plus posaconazole significantly improved time to death compared to placebo (P Ͻ 0.05 for both comparisons by log rank test) (Fig. 1B). In contrast, posaconazole monotherapy mediated a nonsignificant trend to improve time to death compared to placebo (P ϭ 0.2). There was no significant difference in time to death between mice treated with combination therapy and LAmB monotherapy (P ϭ 0.3).To define the impact of antifungal therapy on tissue fungal burden in the DKA model, mice were infected as described above and treated with LAmB, posaconazole, combination therapy, or placebo. Treatment was initiated 8 h af...

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“…HL-60 cells (American Type Culture Collection) were cultured and activated as described elsewhere [20, 21]. In brief, cells were activated for 3 days by incubation in the presence of 1.3% (vol/vol) DMSO and 2.5 μ mol/L RA.…”

Section: Methodsmentioning

confidence: 99%

“…Mice were made neutropenic by a single intraperitoneal injection of cyclophosphamide (230 mg/kg), resulting in 7 days of neutropenia, as described elsewhere [20, 21, 23]. For the aspergillosis model, a second dose of cyclophosphamide was administered on day 3 after infection.…”

Section: Methodsmentioning

confidence: 99%

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Safety and Efficacy of Activated Transfected Killer Cells for Neutropenic Fungal Infections

Lin¹,

Ibrahim²,

Baquir³

et al. 2010

J INFECT DIS

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Background Invasive fungal infections cause considerable morbidity and mortality in neutropenic patients. White blood cell transfusions are a promising treatment for such infections, but technical barriers have prevented their widespread use. Methods To recapitulate white blood cell transfusions, we are developing a cell-based immunotherapy using a phagocytic cell line, HL-60. We sought to stably transfect HL-60 cells with a suicide trap (herpes simplex virus thymidine kinase), to enable purging of the cells when desired, and a bioluminescence marker, to track the cells in vivo in mice. Results Transfection was stable despite 20 months of continuous culture or storage in liquid nitrogen. Activation of these transfected cells with retinoic acid and dimethyl sulfamethoxazole enhanced their microbicidal effects. Activated transfected killer (ATAK) cells were completely eliminated after exposure to ganciclovir, confirming function of the suicide trap. ATAK cells improved the survival of neutropenic mice with lethal disseminated candidiasis and inhalational aspergillosis. Bioluminescence and histopathologic analysis confirmed that the cells were purged from surviving mice after ganciclovir treatment. Comprehensive necropsy, histopathology, and metabolomic analysis revealed no toxicity of the cells. Conclusions These results lay the groundwork for continued translational development of this promising, novel technology for the treatment of refractory infections in neutropenic hosts.

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Optimization of a myeloid cell transfusion strategy for infected neutropenic hosts

Cited by 20 publications

References 44 publications

Combination Echinocandin-Polyene Treatment of Murine Mucormycosis

Combination Echinocandin-Polyene Treatment of Murine Mucormycosis

Posaconazole Mono- or Combination Therapy for Treatment of Murine Zygomycosis

Safety and Efficacy of Activated Transfected Killer Cells for Neutropenic Fungal Infections

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