In vivo administration of interferon gamma does not cause marrow aplasia in mice with a targeted disruption of FANCC.
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 gamma (IFN-gamma) in vitro. The aim of this study was to explore these apoptosis-inducing effects of IFN-gamma on the bone marrow of FANCC(-/-) mice as a potential strategy to select gene-corrected cells in vivo. Following pharmacokinetic studies to determine if serum concentrations effective in vitro can be achieved in vivo, we injected FANCC(-/-) mice with recombinant murine IFN-gamma. 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-gamma 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-gamma did not impair progenitor cell clonogenicity in vitro. Pharmacokinetic data confirmed that the failure of IFN-gamma to induce marrow aplasia occurred in spite of peak serum levels greater than 100-fold in excess of those effective in vitro.


CONCLUSIONS
We conclude that in spite of the well-documented in vitro apoptotic tendency of FA-phenotype hematopoietic cells, the in vivo administration of IFN-gamma 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.
Kurre
Peter
P
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Anandakumar
Ponni
P
Grompe
Markus
M
Kiem
Hans Peter
HP
D000741:Anemia, Aplastic / Q000209:etiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D018797:Cell Cycle Proteins; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000473:pathology / Q000628:therapy; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D015316:Genetic Therapy; D006207:Half-Life; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma