Humanized Mice for Immune System Investigation: Progress, Promise and Challenges

Overview

Journal Nat Rev Immunol

Specialty Allergy & Immunology

Date 2012 Oct 13

PMID 23059428

Citations 495

Authors

Leonard D Shultz

Michael A Brehm

J Victor Garcia-Martinez

Dale L Greiner

Affiliations

Soon will be listed here.

Abstract

Significant advances in our understanding of the in vivo functions of human cells and tissues and the human immune system have resulted from the development of 'humanized' mouse strains that are based on severely immunodeficient mice with mutations in the interleukin-2 receptor common γ-chain locus. These mouse strains support the engraftment of a functional human immune system and permit detailed analyses of human immune biology, development and functions. In this Review, we discuss recent advances in the development and utilization of humanized mice, the lessons learnt, the remaining challenges and the promise of using humanized mice for the in vivo study of human immunology.

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References

Balazs A, Chen J, Hong C, Rao D, Yang L, Baltimore D . Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. 2011; 481(7379):81-4. PMC: 3253190. DOI: 10.1038/nature10660. View

Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K . NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002; 100(9):3175-82. DOI: 10.1182/blood-2001-12-0207. View

Johnston S, Dustin M, Hibbs M, Springer T . On the species specificity of the interaction of LFA-1 with intercellular adhesion molecules. J Immunol. 1990; 145(4):1181-7. View

Dash P, Gorantla S, Gendelman H, Knibbe J, Casale G, Makarov E . Loss of neuronal integrity during progressive HIV-1 infection of humanized mice. J Neurosci. 2011; 31(9):3148-57. PMC: 3059783. DOI: 10.1523/JNEUROSCI.5473-10.2011. View

Yang W, Wei W, Shi C, Zhu J, Ying W, Shen Y . Pluripotin combined with leukemia inhibitory factor greatly promotes the derivation of embryonic stem cell lines from refractory strains. Stem Cells. 2008; 27(2):383-9. DOI: 10.1634/stemcells.2008-0974. View

Mota J, Rico-Hesse R . Humanized mice show clinical signs of dengue fever according to infecting virus genotype. J Virol. 2009; 83(17):8638-45. PMC: 2738212. DOI: 10.1128/JVI.00581-09. View

Gorantla S, Makarov E, Finke-Dwyer J, Castanedo A, Holguin A, Gebhart C . Links between progressive HIV-1 infection of humanized mice and viral neuropathogenesis. Am J Pathol. 2010; 177(6):2938-49. PMC: 2993281. DOI: 10.2353/ajpath.2010.100536. View

Denton P, Othieno F, Martinez-Torres F, Zou W, Krisko J, Fleming E . One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol. 2011; 85(15):7582-93. PMC: 3147928. DOI: 10.1128/JVI.00537-11. View

Nicolini F, Cashman J, Hogge D, Humphries R, Eaves C . NOD/SCID mice engineered to express human IL-3, GM-CSF and Steel factor constitutively mobilize engrafted human progenitors and compromise human stem cell regeneration. Leukemia. 2003; 18(2):341-7. DOI: 10.1038/sj.leu.2403222. View

10.

Greiner D, Brehm M, Hosur V, Harlan D, Powers A, Shultz L . Humanized mice for the study of type 1 and type 2 diabetes. Ann N Y Acad Sci. 2012; 1245:55-8. PMC: 3384500. DOI: 10.1111/j.1749-6632.2011.06318.x. View

11.

Issa F, Hester J, Goto R, Nadig S, Goodacre T, Wood K . Ex vivo-expanded human regulatory T cells prevent the rejection of skin allografts in a humanized mouse model. Transplantation. 2010; 90(12):1321-7. PMC: 3672995. DOI: 10.1097/TP.0b013e3181ff8772. View

12.

Long B, Stoddart C . Alpha interferon and HIV infection cause activation of human T cells in NSG-BLT mice. J Virol. 2012; 86(6):3327-36. PMC: 3302309. DOI: 10.1128/JVI.06676-11. View

13.

Nadig S, Wieckiewicz J, Wu D, Warnecke G, Zhang W, Luo S . In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010; 16(7):809-13. PMC: 2929438. DOI: 10.1038/nm.2154. View

14.

Mold J, Venkatasubrahmanyam S, Burt T, Michaelsson J, Rivera J, Galkina S . Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010; 330(6011):1695-9. PMC: 3276679. DOI: 10.1126/science.1196509. View

15.

Lockridge J, Chen X, Zhou Y, Rajesh D, Roenneburg D, Hegde S . Analysis of the CD1 antigen presenting system in humanized SCID mice. PLoS One. 2011; 6(6):e21701. PMC: 3128084. DOI: 10.1371/journal.pone.0021701. View

16.

Chappaz S, Finke D . The IL-7 signaling pathway regulates lymph node development independent of peripheral lymphocytes. J Immunol. 2010; 184(7):3562-9. DOI: 10.4049/jimmunol.0901647. View

17.

Racki W, Covassin L, Brehm M, Pino S, Ignotz R, Dunn R . NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection. Transplantation. 2010; 89(5):527-36. PMC: 2901915. DOI: 10.1097/TP.0b013e3181c90242. View

18.

Van Lent A, Dontje W, Nagasawa M, Siamari R, Bakker A, Pouw S . IL-7 enhances thymic human T cell development in "human immune system" Rag2-/-IL-2Rgammac-/- mice without affecting peripheral T cell homeostasis. J Immunol. 2009; 183(12):7645-55. DOI: 10.4049/jimmunol.0902019. View

19.

Denton P, Garcia J . Humanized mouse models of HIV infection. AIDS Rev. 2011; 13(3):135-48. PMC: 3741405. View

20.

Covassin L, Laning J, Abdi R, Langevin D, Phillips N, Shultz L . Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rγ(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol. 2011; 166(2):269-80. PMC: 3219902. DOI: 10.1111/j.1365-2249.2011.04462.x. View