title: BLT-humanized C57BL/6 Rag2-/-γc-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection.
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.
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT;
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Lavender
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Pang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Messer
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Duley
authors.forename: Brent
authors.initials: B
authors.lastname: Race
authors.forename: Katie
authors.initials: K
authors.lastname: Phillips
authors.forename: Dana
authors.initials: D
authors.lastname: Scott
authors.forename: Karin E
authors.initials: KE
authors.lastname: Peterson
authors.forename: Charles K
authors.initials: CK
authors.lastname: Chan
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Timothy
authors.initials: T
authors.lastname: Dudek
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Hasenkrug
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D064593:Heterografts; D006801:Humans; D007111:Immunity, Cellular; D008221:Lymphoid Tissue / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout
references.citation: J Interferon Cytokine Res. 1999 May;19(5):533-41
references.pmid: 10386866
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13218-23
references.pmid: 21788509
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13224-9
references.pmid: 21788504
references.citation: Br J Haematol. 1998 Nov;103(2):335-42
references.pmid: 9827902
references.citation: J Virol. 2007 Dec;81(23):13259-64
references.pmid: 17881441
references.citation: J Virol. 2010 Nov;84(21):11076-88
references.pmid: 20702619
references.citation: J Virol. 2009 Jul;83(14):7305-21
references.pmid: 19420076
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13744-9
references.pmid: 17699632
references.citation: Diabetes. 1993 Nov;42(11):1574-8
references.pmid: 8405697
references.citation: J Immunol. 1992 Oct 15;149(8):2816-22
references.pmid: 1383328
references.citation: J Exp Med. 2001 Aug 20;194(4):541-9
references.pmid: 11514609
references.citation: AIDS. 1989 Mar;3(3):155-63
references.pmid: 2540772
references.citation: J Radiat Res. 2010;51(2):145-56
references.pmid: 19959877
references.citation: Science. 2000 Jun 16;288(5473):2051-4
references.pmid: 10856220
references.citation: Nat Immunol. 2007 Dec;8(12):1313-23
references.pmid: 17982459
references.citation: Annu Rev Immunol. 1996;14:179-205
references.pmid: 8717512
references.citation: Science. 2004 Apr 2;304(5667):104-7
references.pmid: 15064419
references.citation: J Immunol. 2005 May 15;174(10):6477-89
references.pmid: 15879151
references.citation: Blood. 2005 Sep 1;106(5):1565-73
references.pmid: 15920010
references.citation: Mucosal Immunol. 2008 Nov;1(6):475-88
references.pmid: 19079215
references.citation: Blood. 2002 Nov 1;100(9):3175-82
references.pmid: 12384415
references.citation: Immunity. 1999 Aug;11(2):163-71
references.pmid: 10485651
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2804-8
references.pmid: 1372992
references.citation: Science. 1988 Sep 23;241(4873):1632-9
references.pmid: 2971269
references.citation: Blood. 2013 Feb 21;121(8):1316-25
references.pmid: 23293079
references.citation: Blood. 2008 Apr 15;111(8):4293-6
references.pmid: 18270327
references.citation: PLoS Med. 2007 Dec;4(12):e348
references.pmid: 18052607
references.citation: PLoS One. 2009 Dec 21;4(12):e8379
references.pmid: 20027308
references.citation: PLoS One. 2012;7(9):e44664
references.pmid: 22957096
references.citation: Nat Med. 2006 Nov;12(11):1316-22
references.pmid: 17057712
references.citation: Science. 1988 Dec 23;242(4886):1684-6
references.pmid: 3201256
references.citation: Blood. 2006 Jul 15;108(2):487-92
references.pmid: 16410443
references.citation: J Virol. 2007 Mar;81(6):2700-12
references.pmid: 17182671
references.citation: Cell Mol Immunol. 2010 Sep;7(5):334-40
references.pmid: 20228834
references.citation: J Exp Med. 1990 Oct 1;172(4):1055-63
references.pmid: 2212942
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3290-4
references.pmid: 1373493
references.citation: Nat Protoc. 2008;3(12):1932-40
references.pmid: 19180077