AI Article Synopsis
- C57BL/6 Rag2(-/-)γc(-/-) mice are challenging for transplanting human immune systems due to their inability to recognize human CD47, which is crucial for preventing macrophages from attacking human stem cells.
- Genetic modification to inactivate CD47 allows these mice to tolerate the transplanted human hematopoietic stem cells without triggering CD47-SIRPα signaling.
- The resulting TKO-BLT mice can develop complex immune structures and exhibit signs of HIV infection, making them promising for studying human diseases and immune responses without the complications of graft-versus-host disease.
Article Abstract
The use of C57BL/6 Rag2(-/-)γc(-/-) mice as recipients for xenotransplantation with human immune systems (humanization) has been problematic because C57BL/6 SIRPα does not recognize human CD47, and such recognition is required to suppress macrophage-mediated phagocytosis of transplanted human hematopoietic stem cells (HSCs). We show that genetic inactivation of CD47 on the C57BL/6 Rag2(-/-)γc(-/-) background negates the requirement for CD47-signal recognition protein α (SIRPα) signaling and induces tolerance to transplanted human HSCs. These triple-knockout, bone marrow, liver, thymus (TKO-BLT) humanized mice develop organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissue that demonstrate high levels of multilineage hematopoiesis. Importantly, these mice have an intact complement system and showed no signs of graft-versus-host disease (GVHD) out to 29 weeks after transplantation. Sustained, high-level HIV-1 infection was observed via either intrarectal or intraperitoneal inoculation. TKO-BLT mice exhibited hallmarks of human HIV infection including CD4(+) T-cell depletion, immune activation, and development of HIV-specific B- and T-cell responses. The lack of GVHD makes the TKO-BLT mouse a significantly improved model for long-term studies of pathogenesis, immune responses, therapeutics, and vaccines to human pathogens.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862274 | PMC |
| http://dx.doi.org/10.1182/blood-2013-06-506949 | DOI Listing |
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