title: A phagocytic cell line markedly improves survival of infected neutropenic mice.
abstract: Disseminated candidiasis is a frequent infection in neutropenic patients, in whom it causes 50% mortality, despite antifungal therapy. As the duration of neutropenia is the strongest predictor of survival in neutropenic patients with invasive fungal infections, neutrophil transfusions are a logical, therapeutic option. However, significant technical barriers have prevented the clinical use of neutrophil transfusions. To overcome these barriers, we identified a human phagocytic cell line that could be administered to candidemic hosts in lieu of freshly harvested neutrophils. HL-60 cells killed Candida albicans in vitro. Activation of HL-60 cells with dimethyl sulfoxide and retinoic acid abrogated the cells' proliferation and augmented their killing of C. albicans. Administration of activated HL-60 cells to candidemic, neutropenic mice significantly improved survival (53% vs. 0%). Live HL-60 cells chemotaxed to sites of infection, phagocytized C. albicans, and reduced the fungal burden in key target organs. Although unactivated HL-60 cells also reduced tissue fungal burden in vivo, they did not improve survival as a result of their toxicity in infected mice. In contrast, no toxicity as a result of activated HL-60 cells was observed at up to 2 months of follow-up. To our knowledge, this is the first description of a cell line-based immunotherapy for an infectious disease. With further refinements, activated HL-60 cells have the potential to overcome the technical barriers to neutrophil transfusions.
authors.affiliation: Los Angeles Biomedical Institute, Harbor-UCLA Medical Center, Torrance, CA 90502, USA. bspellberg@labiomed.org
authors.forename: Brad J
authors.initials: BJ
authors.lastname: Spellberg
authors.forename: Mary
authors.initials: M
authors.lastname: Collins
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
authors.forename: John E
authors.initials: JE
authors.lastname: Edwards
authors.forename: Yue
authors.initials: Y
authors.lastname: Fu
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Ibrahim
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D018922:HL-60 Cells / Q000276:immunology / Q000637:transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D009503:Neutropenia / Q000139:chemically induced / Q000382:microbiology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000637:transplantation*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D014212:Tretinoin; D004121:Dimethyl Sulfoxide