In a development that promises to advance stem cell therapies, scientists have demonstrated an effective strategy for inducing immunological tolerance of tissues derived from human embryonic stem cells (hESCs). The scientists, based at UC-San Diego, showed that expression of a pair of immune-suppressing molecules can allow allogenic hESCs to survive in “humanized” mice without triggering immune rejection.
The molecules are CTLA4-lg, an FDA-approved drug for treating rheumatoid arthritis that suppresses T-cells responsible for immune rejection, and a protein called PD-L1, which is known to be important for inducing immune tolerance in tumors. Just one or the other molecule fails to protect transplanted cells from rejection. The combination of both molecules, however, appears to be effective. The reasons why remain unclear, say the scientists.
The scientists reported their findings in Cell Stem Cell, in an article published January 2. In this article, the scientists emphasized that they demonstrated immunological tolerance in an in vivo context, in laboratory mice that contained a functional human immune system. To create their model of the human immune system, the scientists took immune-deficient laboratory mice and grafted into their bodies human fetal thymus tissues and hematopoietic stem cells derived from fetal liver of the same human donor. Ultimately, the mice contained a functional human immune system capable of mounting a vigorous immune rejection of foreign cells derived from hESCs.
With their mouse model, the scientists tested a variety of immune-suppressing molecules alone or in combination. It was then that the scientists hit upon the combination of CTLA4-lg and PD-L1. “If we express both molecules in cells derived from human embryonic cells, we can protect these cells from the allogenic immune rejection,” said Yang Xu, a professor of biology at UC San Diego who led the study. “If you have only one such molecule expressed, there is absolutely no impact. We still don’t know exactly how these pathways work together to suppress immune rejection, but now we’ve got an ideal system to study this.”
Reflecting on the study, Xu noted that it suggested a way of avoiding the shortcomings of systemic immunosuppressant drugs, which include cytotoxicity and increased risk of infection and cancer. “[With] organ transplantation to save patients with terminal diseases, [immunosuppressants have] been quite successful. But for stem cell therapies, the long-term use of toxic immunosuppressant drugs for patients who are being treated for chronic diseases like Parkinson’s disease or diabetes poses serious health problems.”
Besides pointing to new ways of overcoming the problem of allogenic immune rejection of hESC-derived cells by recipients, the study may offer tools needed to develop ways to activate the immune response to tumors. “You’re dealing with the same exact pathways that protect tumors from our immune system,” said Xu. “If we can develop strategies to disrupt or silence these pathways in tumors, we might be able to activate immunity to tumors. The humanized mouse system is really a powerful model with which to study human tumor immunity.”