BLT-humanized C57BL/6 Rag2−/−γc−/−CD47−/− mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection

KJ Lavender, WW Pang, RJ Messer… - Blood, The Journal …, 2013 - ashpublications.org
KJ Lavender, WW Pang, RJ Messer, AK Duley, B Race, K Phillips, D Scott, KE Peterson…
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
The use of C57BL/6 Rag2−/− γ c−/− 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−/− γ c−/− background negates the
requirement for CD47-signal recognition protein α (SIRPα) signaling and induces tolerance …
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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