A type of mouse widely used to assess how the human immune system responds to transplanted stem cells does not reflect what is likely to occur in patients, according to researchers at the Stanford University School of Medicine. Their research is published in today's Cell Reports.
Known as "humanized" mice, the animals have been engineered to have a human, rather than a murine, immune system. However, the researchers found that the humanized mice are unable to robustly reject the transplantation of genetically mismatched human stem cells. As a result, they can't be used to study the immunosuppressive drugs that patients will likely require after transplant.
Former postdoctoral scholar, Nigel Kooreman, M..D, a lead author on the study, and his colleagues found that two varieties of humanized mice were unable to completely reject unrelated human embryonic stem cells or iPS cells, despite the fact that some human immune cells homed to and were active in the transplanted stem cell grafts. In some cases, the cells not only thrived, but grew rapidly to form cancers called teratomas. In contrast, mice with unaltered immune systems quickly dispatched both forms of human pluripotent stem cells.
"In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would," said Joseph Wu, M.D., Ph.D., director of Stanford's Cardiovascular Institute and professor of cardiovascular medicine and of radiology. "We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can't do that with these animals."
To understand more about what was happening, Kooreman and his colleagues created a new mouse model similar to the humanized mice. Instead of reconstituting the animals' nonexistent immune systems with human cells, they used immune and bone marrow cells from a different strain of mice. Unlike the humanized mice, these new mice robustly rejected human pluripotent stem cells as well as mouse stem cells from a genetically mismatched strain of mice. In other words, their newly acquired immune systems appeared to be in much better working order.
The researchers think the discrepancy between the two types of animals may have something to do with the complexity of the immune system and the need to further optimize the humanized mouse model to perhaps include other types of cells or signaling molecules. However, for now, they are warning other researchers of potential pitfalls in using this model to screen for immunosuppressive drugs that could be effective after human stem cell transplants.