Dataset Information

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

ABSTRACT: The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.

SUBMITTER: Matsuda M

PROVIDER: S-EPMC6445396 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

Matsuda Masashi M Ono Rintaro R Iyoda Tomonori T Endo Takaho T Iwasaki Makoto M Tomizawa-Murasawa Mariko M Saito Yoriko Y Kaneko Akiko A Shimizu Kanako K Yamada Daisuke D Ogonuki Narumi N Watanabe Takashi T Nakayama Manabu M Koseki Yoko Y Kezuka-Shiotani Fuyuko F Hasegawa Takanori T Yabe Hiromasa H Kato Shunichi S Ogura Atsuo A Shultz Leonard D LD Ohara Osamu O Taniguchi Masaru M Koseki Haruhiko H Fujii Shin-Ichiro SI Ishikawa Fumihiko F

Life science alliance 20190401 2

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acqu ...[more]

PMID: 30936185

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Project description:The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL-NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL-2r?null (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated.

Dataset Information

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

Publications

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

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