Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg immunodeficient mice

Christin M. Lepus; Thomas F. Gibson; Scott A. Gerber; Ivana Kawikova; Marian Szczepanik; Jaber Hossain; Vitaly Ablamunits; Nancy Kirkiles-Smith; Kevan C. Herold; Ruben O. Donis; Alfred L. Bothwell; Jordan S. Pober; Martha J. Harding

doi:10.1016/j.humimm.2009.06.005

Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc^-/-, Balb/c-Rag1^-/-γc^-/-, and C.B-17-scid/bg immunodeficient mice

Christin M. Lepus, Thomas F. Gibson, Scott A. Gerber, Ivana Kawikova, Marian Szczepanik, Jaber Hossain, Vitaly Ablamunits, Nancy Kirkiles-Smith, Kevan C. Herold, Ruben O. Donis, Alfred L. Bothwell, Jordan S. Pober, Martha J. Harding

Research output: Contribution to journal › Article › peer-review

103 Scopus citations

Abstract

Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34⁺ hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/γc^-/-, Balb/c-Rag1^-/-γc^-/-, and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/γc^-/- and Balb/c-Rag1^-/-γc^-/- harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/γc^-/- mice harbored higher levels of human T cells. NOD-scid/γc^-/- mice engrafted with HFL CD34⁺ HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/γc^-/- mice that is well suited for future studies toward the development of a fully competent humanized mouse model.

Original language	English (US)
Pages (from-to)	790-802
Number of pages	13
Journal	Human Immunology
Volume	70
Issue number	10
DOIs	https://doi.org/10.1016/j.humimm.2009.06.005
State	Published - Oct 2009
Externally published	Yes

Keywords

Delayed-type hypersensitivity
Hematopoietic stem cell
Human immune system development
Isotype switching
Mouse model

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1016/j.humimm.2009.06.005

Cite this

Lepus, C. M., Gibson, T. F., Gerber, S. A., Kawikova, I., Szczepanik, M., Hossain, J., Ablamunits, V., Kirkiles-Smith, N., Herold, K. C., Donis, R. O., Bothwell, A. L., Pober, J. S., & Harding, M. J. (2009). Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc^-/-, Balb/c-Rag1^-/-γc^-/-, and C.B-17-scid/bg immunodeficient mice. Human Immunology, 70(10), 790-802. https://doi.org/10.1016/j.humimm.2009.06.005

Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc^-/-, Balb/c-Rag1^-/-γc^-/-, and C.B-17-scid/bg immunodeficient mice. / Lepus, Christin M.; Gibson, Thomas F.; Gerber, Scott A. et al.
In: Human Immunology, Vol. 70, No. 10, 10.2009, p. 790-802.

Research output: Contribution to journal › Article › peer-review

Lepus, CM, Gibson, TF, Gerber, SA, Kawikova, I, Szczepanik, M, Hossain, J, Ablamunits, V, Kirkiles-Smith, N, Herold, KC, Donis, RO, Bothwell, AL, Pober, JS & Harding, MJ 2009, 'Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc^-/-, Balb/c-Rag1^-/-γc^-/-, and C.B-17-scid/bg immunodeficient mice', Human Immunology, vol. 70, no. 10, pp. 790-802. https://doi.org/10.1016/j.humimm.2009.06.005

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title = "Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg immunodeficient mice",

abstract = "Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34+ hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/γc-/- and Balb/c-Rag1-/-γc-/- harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/γc-/- mice harbored higher levels of human T cells. NOD-scid/γc-/- mice engrafted with HFL CD34+ HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/γc-/- mice that is well suited for future studies toward the development of a fully competent humanized mouse model.",

keywords = "Delayed-type hypersensitivity, Hematopoietic stem cell, Human immune system development, Isotype switching, Mouse model",

author = "Lepus, {Christin M.} and Gibson, {Thomas F.} and Gerber, {Scott A.} and Ivana Kawikova and Marian Szczepanik and Jaber Hossain and Vitaly Ablamunits and Nancy Kirkiles-Smith and Herold, {Kevan C.} and Donis, {Ruben O.} and Bothwell, {Alfred L.} and Pober, {Jordan S.} and Harding, {Martha J.}",

note = "Funding Information: We thank Dr. Leonard Shultz, Jackson Laboratories, and Dr. Drew Pardoll, Johns Hopkins University for the donations of breeding pairs of NOD- scid /γ −/− and Balb/c- Rag1 γ −/− mice, respectively; Drs. Li Wen and Sara Rockwell for the donations of control NOD and Balb/c mice, respectively; Dr. Bradford Poulos of the Human Fetal Tissue Repository, Albert Einstein College of Medicine, for human fetal liver tissue; Dr. Diane Krause and Wendy Haskell at the Yale Center of Excellence in Molecular Hematology (NIH No. DK0724429) for G-CSF-AB-isolex cells; Labor and Birth Yale–New Haven Hospital staff and Ann Marie Franco for UCB cells; Paul Bonjiorni for assistance with irradiation; and Lisa Gras, Louise Benson and Michelle Benevento for assistance with mice. Helpful discussions with Drs. Elizabeth Eynon, Anthony Rongvaux, Tim Willinger, and Diane Krause are also gratefully acknowledged. This study was supported by the Section of Comparative Medicine and NIH Grant P01-HL070295. MJH is the recipient of a Research Scholar Award from the American Gastroenterology Association.",

year = "2009",

month = oct,

doi = "10.1016/j.humimm.2009.06.005",

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pages = "790--802",

journal = "Human Immunology",

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T1 - Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg immunodeficient mice

AU - Lepus, Christin M.

AU - Gibson, Thomas F.

AU - Gerber, Scott A.

AU - Kawikova, Ivana

AU - Szczepanik, Marian

AU - Hossain, Jaber

AU - Ablamunits, Vitaly

AU - Kirkiles-Smith, Nancy

AU - Herold, Kevan C.

AU - Donis, Ruben O.

AU - Bothwell, Alfred L.

AU - Pober, Jordan S.

AU - Harding, Martha J.

N1 - Funding Information: We thank Dr. Leonard Shultz, Jackson Laboratories, and Dr. Drew Pardoll, Johns Hopkins University for the donations of breeding pairs of NOD- scid /γ −/− and Balb/c- Rag1 γ −/− mice, respectively; Drs. Li Wen and Sara Rockwell for the donations of control NOD and Balb/c mice, respectively; Dr. Bradford Poulos of the Human Fetal Tissue Repository, Albert Einstein College of Medicine, for human fetal liver tissue; Dr. Diane Krause and Wendy Haskell at the Yale Center of Excellence in Molecular Hematology (NIH No. DK0724429) for G-CSF-AB-isolex cells; Labor and Birth Yale–New Haven Hospital staff and Ann Marie Franco for UCB cells; Paul Bonjiorni for assistance with irradiation; and Lisa Gras, Louise Benson and Michelle Benevento for assistance with mice. Helpful discussions with Drs. Elizabeth Eynon, Anthony Rongvaux, Tim Willinger, and Diane Krause are also gratefully acknowledged. This study was supported by the Section of Comparative Medicine and NIH Grant P01-HL070295. MJH is the recipient of a Research Scholar Award from the American Gastroenterology Association.

PY - 2009/10

Y1 - 2009/10

N2 - Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34+ hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/γc-/- and Balb/c-Rag1-/-γc-/- harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/γc-/- mice harbored higher levels of human T cells. NOD-scid/γc-/- mice engrafted with HFL CD34+ HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/γc-/- mice that is well suited for future studies toward the development of a fully competent humanized mouse model.

AB - Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34+ hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/γc-/-, Balb/c-Rag1-/-γc-/-, and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/γc-/- and Balb/c-Rag1-/-γc-/- harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/γc-/- mice harbored higher levels of human T cells. NOD-scid/γc-/- mice engrafted with HFL CD34+ HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/γc-/- mice that is well suited for future studies toward the development of a fully competent humanized mouse model.

KW - Delayed-type hypersensitivity

KW - Hematopoietic stem cell

KW - Human immune system development

KW - Isotype switching

KW - Mouse model

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