title: Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity.
abstract: High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2-3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.
authors.affiliation: Department of Neurosurgery, University Hospital Rotterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Driesse
authors.forename: M C
authors.initials: MC
authors.lastname: Esandi
authors.forename: J M
authors.initials: JM
authors.lastname: Kros
authors.forename: C J
authors.initials: CJ
authors.lastname: Avezaat
authors.forename: C
authors.initials: C
authors.lastname: Vecht
authors.forename: C
authors.initials: C
authors.lastname: Zurcher
authors.forename: I
authors.initials: I
authors.lastname: van der Velde
authors.forename: D
authors.initials: D
authors.lastname: Valerio
authors.forename: A
authors.initials: A
authors.lastname: Bout
authors.forename: P A
authors.initials: PA
authors.lastname: Sillevis Smitt
mesh_terms: D000256:Adenoviridae / Q000302:isolation & purification; D000257:Adenoviridae Infections / Q000175:diagnosis; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D016080:Arachnoid Cysts / Q000276:immunology / Q000628:therapy*; D001921:Brain / Q000821:virology; D002555:Cerebrospinal Fluid / Q000821:virology; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000134:cerebrospinal fluid; D016209:Interleukin-8 / Q000134:cerebrospinal fluid; D008253:Macaca mulatta; D008297:Male; D008587:Meningitis, Viral / Q000175:diagnosis; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000201:enzymology* / Q000276:immunology; D013116:Spinal Cord / Q000821:virology; D013937:Thymidine Kinase / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D015850:Interleukin-6; D016209:Interleukin-8; D013937:Thymidine Kinase; D015774:Ganciclovir