title: Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.
abstract: In this study, we developed human immune system (HIS) mice that possess functional human CD4+ T cells and B cells, named HIS-CD4/B mice. HIS-CD4/B mice were generated by first introducing HLA class II genes, including DR1 and DR4, along with genes encoding various human cytokines and human B cell activation factor (BAFF) to NSG mice by adeno-associated virus serotype 9 (AAV9) vectors, followed by engrafting human hematopoietic stem cells (HSCs). HIS-CD4/B mice, in which the reconstitution of human CD4+ T and B cells resembles to that of humans, produced a significant level of human IgG against Plasmodium falciparum circumsporozoite (PfCS) protein upon immunization. CD4+ T cells in HIS-CD4/B mice, which possess central and effector memory phenotypes like those in humans, are functional, since PfCS protein-specific human CD4+ T cells secreting IFN-γ and IL-2 were detected in immunized HIS-CD4/B mice. Lastly, PfCS protein-immunized HIS-CD4/B mice were protected from in vivo challenge with transgenic P. berghei sporozoites expressing the PfCS protein. The immune sera collected from protected HIS-CD4/B mice reacted against transgenic P. berghei sporozoites expressing the PfCS protein and also inhibited the parasite invasion into hepatocytes in vitro. Taken together, these studies show that our HIS-CD4/B mice could mount protective human anti-malaria immunity, consisting of human IgG and human CD4+ T cell responses both specific for a human malaria antigen.
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Jordana G A
authors.initials: JG
authors.lastname: Coelho-dos-Reis
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Mitchell
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Raquel Tayar
authors.initials: RT
authors.lastname: Nogueira
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Tsao
authors.affiliation: Leidos, San Diego, CA, USA.
authors.forename: Amy R
authors.initials: AR
authors.lastname: Noe
authors.affiliation: Leidos, Frederick, MD, USA.
authors.forename: Ramses
authors.initials: R
authors.lastname: Ayala
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sahi
authors.affiliation: Leidos, Frederick, MD, USA.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Gutierrez
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nussenzweig
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Nardin
authors.affiliation: Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, NY, USA.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Nussenzweig
authors.affiliation: Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA. Electronic address: mtsuji@adarc.org.
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D064593:Heterografts; D000949:Histocompatibility Antigens Class II; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D017780:Malaria Vaccines; D016778:Malaria, Falciparum / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic / Q000276:immunology*; D015800:Protozoan Proteins / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan
keywords: HLA class II molecule; Human IgG; Human immune system mice; P. falciparum circumsporozoite protein; Protective anti-malaria immunity