Dataset Information

The Preconditioning of Busulfan Promotes Efficiency of Human CD133+ Cells Engraftment in NOD Shi-SCID IL2R?cnull (NOG) Mice via Intra-Bone Marrow Injection.

ABSTRACT: Human CD133+ stem cells were injected into the bone marrow cavity of NOG (NOD Shi-SCID IL2R?cnull) mice with or without preconditioning of busulfan in order to assess the efficiency of human CD133+ cells engraftment. Peripheral blood from CD133+-engrafted NOG mice was analyzed by flow cytometry. The results showed that human CD19+ B lymphocytes could be detected at 4 weeks post-transplantation, and human CD4+, CD8+ subsets of T lymphocytes, CD19- CD14- HLA-DR+ DCs and CD19- CD14+ monocytes could be detected at 16 weeks post-transplantation. The survival rate of mice in busulfan-untreated group (100%) was slightly higher than that in the busulfan-pretreated group (83%) (P > 0.05). However, the differentiation efficiency of CD133+ stem cells in busulfan-pretreated group was significantly higher than that in the untreated group (P < 0.05). This data imply that CD133+ cells could be a good resource for a humanized mouse model, and the preconditioning of busulfan could be more conducive to accelerating the differentiation of human CD133+ cells in NOG mice by intra-bone marrow injection.

SUBMITTER: Guo X

PROVIDER: S-EPMC6719503 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

The Preconditioning of Busulfan Promotes Efficiency of Human CD133+ Cells Engraftment in NOD Shi-SCID IL2Rγcnull (NOG) Mice via Intra-Bone Marrow Injection.

Guo Xiaofang X Yin Xiaoxiao X Zhu Wenjuan W Pan Ying Y Wang Hui H Liang Yinming Y Zhu Xiaofei X

Cell transplantation 20190415 7

Human CD133+ stem cells were injected into the bone marrow cavity of NOG (NOD Shi-SCID IL2Rγcnull) mice with or without preconditioning of busulfan in order to assess the efficiency of human CD133+ cells engraftment. Peripheral blood from CD133+-engrafted NOG mice was analyzed by flow cytometry. The results showed that human CD19+ B lymphocytes could be detected at 4 weeks post-transplantation, and human CD4+, CD8+ subs ...[more]

PMID: 30983406

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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

The Preconditioning of Busulfan Promotes Efficiency of Human CD133+ Cells Engraftment in NOD Shi-SCID IL2R?cnull (NOG) Mice via Intra-Bone Marrow Injection.

Publications

The Preconditioning of Busulfan Promotes Efficiency of Human CD133+ Cells Engraftment in NOD Shi-SCID IL2Rγcnull (NOG) Mice via Intra-Bone Marrow Injection.

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