“A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.”
If you missed part one, it’s here: https://nonvenipacem.com/2022/02/07/the-deadly-new-world-of-vaccines-and-monoclonal-antibodies-introduction-to-humanized-mice/
Yesterday we learned about BLT mice. Today we get the next step, BLT-L mice. This “advance” takes the fully human mouse model that employed live human bone marrow, liver, thymus and stem cells, and adds Lung to the mix. Human lung transplanted into a mouse with a fully human immune system, in order to study… coronaviridae, among other things. This study is from August, 2019. Interesting, no?
At this point I want to acknowledge the work of Julie Collorafi as being the first to uncover much of this. You may recall she appeared on the Barnhardt Podcast not long ago. Her twitter handle is @KindeandTrue and you really need to check out her website: https://www.fetalindustry.com/
Okay. BLT-L mice. Here is how it works. Read it in their own words:
The human innate and adaptive immune system of BLT-L mice
“We generated an in vivo model with human lung implants and an autologous human immune system by constructing BLT mice with autologous human lung implants (BLT-L humanized mice). BLT-L mice were constructed by surgically implanting (1) autologous human thymus and liver tissue under the kidney capsule and (2) human lung tissue subcutaneously into the back of the same preconditioned (irradiated) immunodeficient mouse followed by bone marrow transplantation with autologous human hematopoietic stem cells (Fig. (Fig.3a).3a). Over time, BLT-L mice developed human lung implants and robust levels of human hematopoietic cells (hCD45+) in peripheral blood (PB) that were sustained for at least 8 months (last time analyzed) (Fig. (Fig.3b).3b). The PB of BLT-L mice was reconstituted with human myeloid cells, B cells and T cells, including CD4+ and CD8+ T cells (Supplementary Fig. 5).”
Systemic reconstitution of BLT-L humanized mice with human innate and adaptive immune cells.
a, Construction of BLT-L humanized mice. b, Human hematopoietic cells (hCD45+) in PB of BLT-L mice (n = 26 mice, 5 cohorts). Colors indicate BLT-L mouse cohorts. c, Immunofluorescence staining for human epithelial, endothelial and mesenchymal cells in a human lung implant of a BLT-L mouse (n = 4 mice analyzed; positive cells, red; nuclei, blue). Images shown are at ×10 magnification (scale bars, 50 µm). d, Human hematopoietic (hCD45) cells including dendritic cells (hCD11c), macrophages (hCD68), B cells (hCD20), NK/NK T cells (hCD56) and T cells (hCD3, hCD4 and hCD8) in the human lung implant (n = 3 mice analyzed; positive cells, brown). Images shown are at ×40 magnification (scale bars, 50 µm). e, Levels of hCD45 cells including human myeloid cells (hCD33), B cells (hCD19) and T cells (hCD3) as well as the ratio of human CD4/CD8 T cells in the human lung implants (open circles) of BLT-L mice (hCD45, hCD33 and hCD3 analysis, n = 18 implants; and hCD19 and hCD4/CD8 analysis, n = 15 implants). f, Human CD45+ cells in tissues of BLT-L mice (n = 4 mice analyzed) by flow cytometry. GI, gastrointestinal. FRT, female reproductive tract. In b and e, horizontal lines represent mean ± s.e.m. SSC, side scatter.