TY - JOUR
T1 - In vivo administration of interferon γ does not cause marrow aplasia in mice with a targeted disruption of FANCC
AU - Kurre, Peter
AU - Anandakumar, Ponni
AU - Grompe, Markus
AU - Kiem, Hans Peter
N1 - Funding Information:
This work was presented in part at the 43 rd meeting of the American Society of Hematology in Orlando, FL, Dec 2001. This work was supported by NIH grant P30 DK47754. P.K. was supported by the Fanconi Anemia Research Fund. We are indebted to Hana R. Paik and Vladimir Lesnikov for expert technical assistance.
PY - 2002/11/1
Y1 - 2002/11/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0301-472X(02)00932-3
DO - 10.1016/S0301-472X(02)00932-3
M3 - Article
C2 - 12423678
AN - SCOPUS:0036840671
SN - 0301-472X
VL - 30
SP - 1257
EP - 1262
JO - Experimental hematology
JF - Experimental hematology
IS - 11
ER -