Transgenic mouse conditionally expressing MMP12 for studying myelopoiesis, immunity and tumorigenesis
US9279117B2 · kind B2 · utility
Assignee
Inventors
Key dates
| Filing date | Jan 18, 2012 |
| Grant date | Mar 8, 2016 |
| Priority date | — |
| Expiry date | Jul 17, 2032 |
Classification
- Technology area (CPC C)Chemistry; Metallurgy
- CPC primaryC12Y304/24065
- WIPO fieldBiotechnology
- WIPO sectorChemistry
Abstract
A myeloid-specific c-fms-rtTA/(TetO)7-CMV-MMP12 bitransgenic mouse model was created. Induction of MMP12 abnormally elevated frequencies and numbers of common myeloid progenitor (CMP) and granulocyte/macrophage progenitor (GMP) populations, and decreased the frequency and number of the megakaryocyte/erythrocyte progenitor (MEP) population in bone marrow. CD11b+/Gr-1+ immature cell population increased in multiple organs. An immunosuppressive function on T cell proliferation and function by CD11b+/Gr-1+ immature cells was seen in vitro and in vivo from MMP12 over-expression. MMP12 stimulated (Lin−) progenitor cells to differentiate into CD11b+/Gr-1+ immature cells showing immunosuppression on T cell proliferation and function in vitro. Regulatory T cells were increased. In the lung, concentration of interleukin (IL)-6 was increased, which activated oncogenic signal transducer and increased expression of Stat3 downstream genes in epithelial tumor progenitor cells. Spontaneous emphysema and lung adenocarcinoma sequentially developed after MMP12 over-expression. MMP12-induced myeloid cell autonomous defect led to abnormal myelopoiesis, immune suppression and lung adenocarcinoma.
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