Reconstitution of Immune Cell in Liver and Lymph Node of Adult- and Newborn-engrafted Humanized Mice

Overview

Journal BMC Immunol

Publisher Biomed Central

Specialty Allergy & Immunology

Date 2016 Jun 17

PMID 27307066

Citations 6

Authors

Crystal Dykstra

Amanda J Lee

Evan J Lusty

Mira M Shenouda

Mahsa Shafai

Fatemeh Vahedi

Marianne V Chew

Stephen Collins

Ali A Ashkar

Affiliations

Soon will be listed here.

Abstract

Background: Humanized mouse models are an increasingly popular preclinical model to study the human immune response in a biological system. There are a variety of protocols to generate these mice, each differing in the strain of the recipient, source of hematopoietic stem cells, and mode of transplantation. Though there is well-documented reconstitution information regarding the spleen, blood, and bone marrow, there is little information regarding reconstitution of the lymph node and liver. In this report, we sought to compare reconstitution levels in a variety of immunological tissues, including the lymph node and liver, between mice engrafted intravenously as adults and intrahepatically in newborns.

Results: CD34+ cells were enriched from cord blood and transplanted intravenously into irradiated adult NOD-Rag1(-/-)IL2rγ(-/-) (NRG) mice or intra-hepatically into irradiated newborn NRG mice. At 9-28 weeks post-engraftment, immunological tissues were processed and analyzed for human lymphoid and myeloid subsets. Adult and newborn engrafted humanized mice were comparable in long-term reconstitution of human CD45 cells and subsequent lymphoid and myeloid subsets in the spleen, bone marrow, thymus, lymph node, and liver. Mice engrafted as newborns had a higher level of T-cells and a lower level of B-cells compared to mice engrafted as adults. We observed significant levels of human immune cell engraftment in both the lymph node and the liver, with a predominant adaptive immune population in both compartments.

Conclusions: Human immune cells repopulate liver and mesenteric lymph nodes of NRG mice and can be used to study the human immune system in the gastrointestinal tract.

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References

Traggiai E, Chicha L, Mazzucchelli L, Bronz L, Piffaretti J, Lanzavecchia A . Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004; 304(5667):104-7. DOI: 10.1126/science.1093933. View

Bility M, Zhang L, Washburn M, Curtis T, Kovalev G, Su L . Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis. Nat Protoc. 2012; 7(9):1608-17. PMC: 3979325. DOI: 10.1038/nprot.2012.083. View

Wilson E, Bial J, Tarlow B, Bial G, Jensen B, Greiner D . Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Res. 2014; 13(3 Pt A):404-12. PMC: 7275629. DOI: 10.1016/j.scr.2014.08.006. View

Norris S, Doherty D, Collins C, McEntee G, Traynor O, Hegarty J . Natural T cells in the human liver: cytotoxic lymphocytes with dual T cell and natural killer cell phenotype and function are phenotypically heterogenous and include Valpha24-JalphaQ and gammadelta T cell receptor bearing cells. Hum Immunol. 1999; 60(1):20-31. DOI: 10.1016/s0198-8859(98)00098-6. View

Strowig T, Chijioke O, Carrega P, Arrey F, Meixlsperger S, Ramer P . Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence. Blood. 2010; 116(20):4158-67. PMC: 2993621. DOI: 10.1182/blood-2010-02-270678. View

Ishikawa F, Yasukawa M, Lyons B, Yoshida S, Miyamoto T, Yoshimoto G . Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice. Blood. 2005; 106(5):1565-73. PMC: 1895228. DOI: 10.1182/blood-2005-02-0516. View

Hata K, Van Thiel D, Herberman R, Whiteside T . Natural killer activity of human liver-derived lymphocytes in various liver diseases. Hepatology. 1991; 14(3):495-503. View

Kwant-Mitchell A, Ashkar A, Rosenthal K . Mucosal innate and adaptive immune responses against herpes simplex virus type 2 in a humanized mouse model. J Virol. 2009; 83(20):10664-76. PMC: 2753120. DOI: 10.1128/JVI.02584-08. View

Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty S, Teichmann L . Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014; 32(4):364-72. PMC: 4017589. DOI: 10.1038/nbt.2858. View

10.

Golden-Mason L, Kelly A, Doherty D, Traynor O, McEntee G, Kelly J . Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development. Clin Exp Immunol. 2004; 138(1):94-101. PMC: 1809196. DOI: 10.1111/j.1365-2249.2004.02586.x. View

11.

Brehm M, Shultz L, Greiner D . Humanized mouse models to study human diseases. Curr Opin Endocrinol Diabetes Obes. 2010; 17(2):120-5. PMC: 2892284. DOI: 10.1097/MED.0b013e328337282f. View

12.

Billerbeck E, Horwitz J, Labitt R, Donovan B, Vega K, Budell W . Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. J Immunol. 2013; 191(4):1753-64. PMC: 3735836. DOI: 10.4049/jimmunol.1201518. View

13.

Huntington N, Legrand N, Alves N, Jaron B, Weijer K, Plet A . IL-15 trans-presentation promotes human NK cell development and differentiation in vivo. J Exp Med. 2008; 206(1):25-34. PMC: 2626663. DOI: 10.1084/jem.20082013. View

14.

Brehm M, Racki W, Leif J, Burzenski L, Hosur V, Wetmore A . Engraftment of human HSCs in nonirradiated newborn NOD-scid IL2rγ null mice is enhanced by transgenic expression of membrane-bound human SCF. Blood. 2012; 119(12):2778-88. PMC: 3327456. DOI: 10.1182/blood-2011-05-353243. View

15.

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

16.

Shultz L, Ishikawa F, Greiner D . Humanized mice in translational biomedical research. Nat Rev Immunol. 2007; 7(2):118-30. DOI: 10.1038/nri2017. View

17.

Chen Q, Khoury M, Chen J . Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci U S A. 2009; 106(51):21783-8. PMC: 2789167. DOI: 10.1073/pnas.0912274106. View

18.

Manz M . Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007; 26(5):537-41. DOI: 10.1016/j.immuni.2007.05.001. View

19.

Washburn M, Bility M, Zhang L, Kovalev G, Buntzman A, Frelinger J . A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology. 2011; 140(4):1334-44. PMC: 3066273. DOI: 10.1053/j.gastro.2011.01.001. View

20.

Brehm M, Cuthbert A, Yang C, Miller D, DiIorio P, Laning J . Parameters for establishing humanized mouse models to study human immunity: analysis of human hematopoietic stem cell engraftment in three immunodeficient strains of mice bearing the IL2rgamma(null) mutation. Clin Immunol. 2010; 135(1):84-98. PMC: 2835837. DOI: 10.1016/j.clim.2009.12.008. View