In vivo administration of interferon γ does not cause marrow aplasia in mice with a targeted disruption of FANCC

Peter Kurre, Ponni Anandakumar, Markus Grompe, Hans Peter Kiem

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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 γ (IFN-γ) in vitro. The aim of this study was to explore these apoptosis-inducing effects of IFN-γ on the bone marrow of FANCC-/- mice as a potential strategy to select gene-corrected cells in vivo. Materials and Methods. Following pharmacokinetic studies to determine if serum concentrations effective in vitro can be achieved in vivo, we injected FANCC-/- mice with recombinant murine IFN-γ. 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-γ 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-γ did not impair progenitor cell clonogenicity in vitro. Pharmacokinetic data confirmed that the failure of IFN-γ 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-γ 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.

Original languageEnglish (US)
Pages (from-to)1257-1262
Number of pages6
JournalExperimental hematology
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2002

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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