title: Creation of an immunodeficient HLA-transgenic mouse (HUMAMICE) and functional validation of human immunity after transfer of HLA-matched human cells.
abstract: Research on human immunology has been hindered by the lack of optimal small animal models, given that the protective immune responses of human and non-human species show significant differences. However, due to ethical constraints[1] and the high cost of clinical trials, it is urgent to improve the current animal models that can mimic faithfully human physiology, particularly the human immune system (HIS). HIS mice had been generated recently by engrafting human hematopoietic stem cells (hHSCs) or human peripheral mononuclear cells (hPBMCs) into highly immuno-deficient mice such as NSG, NOG or NRG mice. However, a major experimental drawback for studies using these models is the rapid onset of Graft-versus-Host Disease (GvHD). In the present study, we overcome this limitation by generating new immuno-deficient mice named "HUMAMICE" (HLA-A2+/+/DR1+/+/H-2-β2m-/-/IAβ-/-/Rag2-/-/IL2rγ-/-/Perf-/- mice), which expressed human HLA molecules instead of mouse MHC molecules (H-2), and whose immuno-deficient status was reversed by transferring functional HLA-matched PBMCs thus producing mice with an immuno-competent status with a functional human immune system. We showed that in this HLA-matched context, the hPBMC-transfer led to high lymphocytes engraftment rates without GvHD over three months in this novel mouse model. Furthermore, to evaluate the utility of the hPBMC-HUMAMICE, we immunized them with commercial vaccine of Hepatitis B virus (HBsAg, Hepvac@) which resulted in robust and reproducible production of high levels of HBsAg-specific antibodies, implying that both transferred T and B lymphocytes were functional in HUMAMICE. These responses are comparable to those observed in human clinical trials with this identical vaccine. In conclusion, these findings indicated that the HLA-matched-hPBMC-HUMAMICE represents a promising model for dissecting human immune responses in various human diseases, including infectious diseases, cancers and tumors, and to facilitate the development of novel vaccines and cellular therapies.
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Bingrun
authors.initials: B
authors.lastname: Liu
authors.affiliation: Service d'Hématologie de médecine interne, Hôpital Brabois, CHRU Nancy, Vandoeuvre les Nancy, France. And CNRS UMR 7365, IMoPa, Biopole de l'Université de Lorraine, Vandoeuvre les Nancy, France.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Rubio
authors.affiliation: INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Xinyue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.affiliation: Tumorothèque du service d'Hématologie de l'Hôpital Saint-Antoine. Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Ruoping
authors.initials: R
authors.lastname: Tang
authors.affiliation: INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.|IFRNT, Nephrology department, Le Kremlin Bicetre, Universite Paris-Sud, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Durrbach
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.|INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Ru
authors.affiliation: State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
authors.forename: Yusen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: INSERM U1197 (ex U1014), Hospital Paul Brousse, University of Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lone
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006086:Graft vs Host Disease; D015789:HLA-A2 Antigen / Q000235:genetics; D006510:Hepatitis B Antibodies / Q000096:biosynthesis*; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007963:Leukocytes, Mononuclear / Q000637:transplantation; D008214:Lymphocytes / Q000276:immunology; D008285:Major Histocompatibility Complex; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009368:Neoplasm Transplantation; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014611:Vaccination
chemical_list: D015789:HLA-A2 Antigen; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines