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J Immunol Methods. 2015 Dec;427:42-50. doi: 10.1016/j.jim.2015.09.005. Epub 2015 Sep 26.

Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.

Author information

1
Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA.
2
Department of Pathology, New York University School of Medicine, New York, NY, USA.
3
Division of Parasitology, Department of Microbiology, New York University School of Medicine, New York, NY, USA.
4
Leidos, San Diego, CA, USA.
5
Leidos, Frederick, MD, USA.
6
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
7
Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, NY, USA. Electronic address: mtsuji@adarc.org.

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.

KEYWORDS:

HLA class II molecule; Human IgG; Human immune system mice; P. falciparum circumsporozoite protein; Protective anti-malaria immunity

PMID:
26410104
DOI:
10.1016/j.jim.2015.09.005
[Indexed for MEDLINE]

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