A Non Leaky Artemis-Deficient Mouse that Accurately Models the Human SCID Phenotype Including Resistance to Hematopoietic Stem Cell Transplantation

摘要

Two Artemis-deficient (mArt^-/-) mouse models, independently generated on 129/SvJ backgrounds have the expected T^-B^-NK⁺SCID phenotype. However, they fail to mimic the human disease due to CD4⁺ T-cell leakiness. Moreover, immune reconstitution in these leaky mouse models following hematopoietic stem cell transplantation (HSCT) is more easily achieved than that seen in Artemis-deficient humans. To develop a more clinically relevant animal model we backcrossed the mArt^-/- mutation onto the C57Bl/6 (B6) background (99.9%) resulting in virtually no CD4⁺ T-cell leakiness compared to 129/SvJ mArt^-/- mice (0.3±0.25% vs 19.5±15.1%, p<0.001). The non-leaky mouse was also uniquely resistant to engraftment using allogeneic mismatched HSC, comparable to what is seen with human Artemis deficiency. The genetic background also influenced Artemis-associated radiation sensitivity with differing degrees of x-ray hypersensitivity evident in 129/SvJ and B6 backgrounds with both the mArt^-/- and mArt^-/+ genotypes. Our results indicate that immunogenic and DNA repair phenotypes associated with Artemis deficiency are significantly altered by genetic background, which has important implications for SCID diagnosis and treatment. Moreover, the B6 mArt^-/- mouse is a more accurate model for the human disease, and a more appropriate system for studying human Artemis-deficiency and for developing improved transplant and gene therapy regimens for the treatment of SCID children.