title: Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice.
abstract: Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pietzner
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: B M
authors.initials: BM
authors.lastname: Merscher
authors.affiliation: Department of Internal Medicine, Division of Nephrology, Goethe University, Frankfurt, Germany.
authors.forename: P C
authors.initials: PC
authors.lastname: Baer
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: R P
authors.initials: RP
authors.lastname: Duecker
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Eickmeier
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Fußbroich
authors.affiliation: Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Bader
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Del Turco
authors.affiliation: Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross, Goethe University, Frankfurt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Henschler
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zielen
authors.affiliation: Division of Allergy, Pulmonology, and Cystic Fibrosis, Department for Children and Adolescents, Children's Hospital, Goethe University, Frankfurt, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schubert
mesh_terms: D064591:Allografts; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000378:metabolism; D016026:Bone Marrow Transplantation; D051379:Mice; D008817:Mice, Mutant Strains; D019172:Transplantation Conditioning; D014916:Whole-Body Irradiation
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse