IPS Cell Immunogenicity, Clinical Insights, & Possible Solutions

Can cells produced from autologous induced pluripotent stem cell (IPSC or IPS cell) cultures sometimes be immunogenic in patients?

This key question has remained somewhat unsettled due to varied findings over the years (e.g. see here), but many of us had generally felt in the last couple years that IPS cell derivative immunogenicity in an autologous context wouldn’t be a major problem.

This is a big deal because if human IPS cell cultures and in particular their derivatives are immunogenic (sparking a major immune response once transplanted that destroys them) even in an autologous setting that could necessitate the use of immunosuppression with their clinical use. In turn this would substantially reduce their potential advantage over human embryonic stem cells (hESC) for various clinical applications. Immunosuppressive therapy can be expensive and has its own potential side effects too for patients.

A new, very important Cell Stem Cell paper from a team led by Professor Yang Xu sheds significant new light on this key issue, but interestingly leaves the question answered so far at least as both “yes” and “no”. In short, autologous hIPSC derivative immunogenicity is present in some instances and not in others. The researchers used an innovative humanized mouse (Hu-mice) immunological model system. You can see a summary in image form from the paper above. They found that hIPSC derivative immunogenicity depends on the type of differentiated cell that is produced and the specific, associated antigens.

For instance, while IPS cell-derived retinal pigmented epithelial cells (RPE) were not significantly immunogenic in this system, smooth muscle cells (SMC) make from hIPSC did spark a substantial immune response. The rejection of the hIPSC-derived SMC was thought to be due to misexpression of immunogenic peptides that sparked a T cell response. The immunogenic factors are not normally expressed in SMC suggesting that tweaking hIPSC production protocols could be helpful here as the authors indicate:

“While SMCs differentiated from hiPSCs exhibit functionalities and global gene expression profiles highly similar to those of normal human counterparts, the finding that the immunogenic antigens expressed in hiPSC-derived SMCs are not expressed by normal human SMCs suggests that further improvement of the robustness of the differentiation process of hiPSCs could help to reduce the immunogenicity of hiPSC-derived cells.”

Therefore, how IPSC are made will impact their immunogenicity.

The data in this paper on RPE is encouraging, but the observations with SMC raise broader awareness that hIPSC derivatives cannot simply be assumed to be non-immunogenic in an autologous setting. What about liver, kidney or neural derivatives of hIPSC? Lung, heart?

It is also possible, since everybody’s immune system is different, that immunogenicity of any given hIPSC-derivative will vary depending on the patient.  If the immunogenicity of every patient’s hIPSC-derived cells ideally would be tested prior to transplantation, how would we do that? We’d need some kind of robust, high-throughput system like the teratoma and gene expression assays that are now used to screen human pluripotent stem cells for potency. Could the Hu-mice be used for this? The Hu-mice used here are indeed an elegant system, but how things play out in actual human patients with their own immune system could be different. Still they or some adaptation of that technology could prove very effective as an initial screening system.

Overall the findings of this new paper along with the recent news of the halt on the hIPSC trial for macular degeneration, together are signs of a more complicated road ahead to the beside for IPSC. They are not insurmountable hurdles, but rather indications of the IPSC field maturing to have a clearer understanding of the challenges facing it. This is a good thing, even if a bit bitter sweet, because it means we can find solutions and move forward.