Novel Engraftment and T Cell Differentiation of Human Hematopoietic Cells in ART-/- IL2RG-/Y SCID Pigs

被引：23

作者：

Boettcher, Adeline N. ^{[1
]}

Li, Yunsheng ^{[1
]}

Ahrens, Amanda P. ^{[2
]}

Kiupel, Matti ^{[3
]}

Byrne, Kristen A. ^{[4
]}

Loving, Crystal L. ^{[4
]}

Cino-Ozuna, A. Giselle ^{[5
]}

Wiarda, Jayne E. ^{[4
,6
,7
]}

Adur, Malavika ^{[1
]}

Schultz, Blythe ^{[1
]}

Swanson, Jack J. ^{[8
]}

Snella, Elizabeth M. ^{[1
]}

Ho, Chak-Sum ^{[9
]}

Charley, Sara E. ^{[1
]}

Kiefer, Zoe E. ^{[1
]}

Cunnick, Joan E. ^{[1
]}

Putz, Ellie J. ^{[1
]}

Dell'Anna, Giuseppe ^{[2
]}

Jens, Jackie ^{[1
]}

Sathe, Swanand ^{[10
]}

Goldman, Frederick ^{[11
]}

Westin, Erik R. ^{[11
]}

Dekkers, Jack C. M. ^{[1
]}

Ross, Jason W. ^{[1
]}

Tuggle, Christopher K. ^{[1
]}

机构：

[1] Iowa State Univ, Dept Anim Sci, Ames, IA 50011 USA

[2] Iowa State Univ, Lab Anim Resources, Ames, IA USA

[3] Michigan State Univ, Coll Vet Med, Dept Pathobiol & Diagnost Invest, E Lansing, MI 48824 USA

[4] ARS, USDA, Food Safety & Enter Pathogen Unit, Natl Anim Dis Ctr, Ames, IA USA

[5] Kansas State Univ, Vet Diagnost Lab, Manhattan, KS 66506 USA

[6] Iowa State Univ, Coll Vet Med, Immunobiol Grad Program, Ames, IA USA

[7] Oak Ridge Inst Sci & Educ, Agr Res Serv Participat Program, Oak Ridge, TN USA

[8] McFarland Clin, Ames, IA USA

[9] Gift Hope Organ & Tissue Donor Network, Itasca, IL USA

[10] Iowa State Univ, Vet Clin Sci, Ames, IA USA

[11] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA

来源：

FRONTIERS IN IMMUNOLOGY | 2020年 / 11卷

基金：

美国国家卫生研究院;

关键词：

severe combined immunodeficiency; SCID; swine; biomedical model; humanization; SEVERE COMBINED IMMUNODEFICIENCY; REGULATORY PROTEIN ALPHA; IMMUNE-SYSTEM; KNOCKOUT PIGS; ARTEMIS; MOUSE; MICE; MUTATIONS; SUPPORT; MODEL;

D O I：

10.3389/fimmu.2020.00100

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Pigs with severe combined immunodeficiency (SCID) are an emerging biomedical animal model. Swine are anatomically and physiologically more similar to humans than mice, making them an invaluable tool for preclinical regenerative medicine and cancer research. One essential step in further developing this model is the immunological humanization of SCID pigs. In this work we have generated T- B- NK- SCID pigs through site directed CRISPR/Cas9 mutagenesis of IL2RG within a naturally occurring DCLRE1C (ARTEMIS)(-/-) genetic background. We confirmed ART(-/-) IL2RG(-/Y) pigs lacked T, B, and NK cells in both peripheral blood and lymphoid tissues. Additionally, we successfully performed a bone marrow transplant on one ART(-/-) IL2RG(-/Y) male SCID pig with bone marrow from a complete swine leukocyte antigen (SLA) matched donor without conditioning to reconstitute porcine T and NK cells. Next, we performed in utero injections of cultured human CD34(+) selected cord blood cells into the fetal ART(-/-) IL2RG(-/Y) SCID pigs. At birth, human CD45(+) CD3 epsilon(+) cells were detected in cord and peripheral blood of in utero injected SCID piglets. Human leukocytes were also detected within the bone marrow, spleen, liver, thymus, and mesenteric lymph nodes of these animals. Taken together, we describe critical steps forwards the development of an immunologically humanized SCID pig model.

引用

页数：17

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