An interesting paper was published this week from the labs of Brian Cummings and Aileen Anderson
at the University of California, Irvine. Anderson is a member of the Reeve International Research Consortium on Spinal Cord Injury and married to Cummings. Their work with stem cells forms the basis of the ongoing clinical trial in Switzerland, sponsored by StemCells, Inc., transplanting fetal stem cells in people injured from a month to a year at time of surgery.
As we have noted previously in this blog, Anderson and Cummings have a very strong interest in the immune system, and this paper reflects that, asking the question, what does the suppression of the immune system do to the behavior and efficacy of the stem cells themselves? The research team suggests that dampening the immune system may indeed modify the characteristics of the stem cells.
The paper, titled “Immunosuppressants Affect Human Neural Stem Cells In Vitro but Not in an In Vivo Model of Spinal Cord Injury
,” appeared in the journal Stem Cells Translational Medicine.
If the immune system is doing its job, any cell transplant that is recognized by the immune system as “non self” will be attacked and devoured. Thus, in all stem cell transplants, including the StemCells, Inc. trial patients are immune suppressed. There are three main drugs used for this: calcineurin inhibitors, such as cyclosporine; tacrolimus; or an mTOR (mammalian target of rapamycin) inhibitor such rapamycin.
From the paper:
These compounds alter immunophilin ligand signaling pathways, which are known to interact downstream with mediators for human neural stem cell (hNSC) differentiation and proliferation, suggesting that immunosuppressants may directly alter hNSC properties.
What they did: they investigated the effects of immune suppression on cells, first in culture (in vitro).
All immunosuppressants tested increased neuronal differentiation, and [cyclosporine] and rapamycin inhibited proliferation in vitro. No immunosuppressant-mediated effects on [neural stem cell] survival or migration in vitro were detected.
This suggested to the scientists that immunosuppression might, however, alter [stem cell] properties in living animals (in vivo). They found no immune suppressant effect in living animals.
We tested this hypothesis by administering immunosuppressants to constitutively immunodeficient spinal cord injured mice and assessed survival, proliferation, differentiation, and migration of [hCNS-SCns or human central nervous system-derived stem cells propagated as neurospheres] after 14 weeks. In parallel, we administered immunosuppressants to immunocompetent spinal cord injury (SCI) mice and also evaluated [stem cell] engraftment and fate. We identified no effect of immunosuppressants on the overall [stem cell] fate profile in either xenotransplantation [from another species] model. Despite a lower level of human cell engraftment in immunocompetent SCI mice, functional locomotor recovery was observed in animals receiving hCNS-SCns transplantation with no evidence of allodynia [pain].
These data suggest that local cues in the microenvironment could exert a stronger influence on [stem cells] than circulating levels of immunosuppressants.
The authors note, however, that humans and rodents have different systems of metabolism and that drugs don’t necessarily function the same across species. The immune suppression case is far from being resolved but toning down the immune system does not appear to be disadvantageous.
: this is the fourth consecutive blog on immune response and trauma recovery. I didn’t plan it that way – that’s just how the papers rolled out. Clearly, thoguh, the immune system is critical to the field of regenerative medicine. And because immune response can be both good and bad for recovery, therapies cannot proceed to clinic without fully understanding how the body’s defense system works in relation to the intervention.
The transplantation immunology field is quite robust. For example the California stem cell agency (California Institute for Regenerative Medicine) recently awarded a whole cycle of grants, totaling 19 projects
funded at over $25 million, to study stem cells interacting with the immune system; several of these studies are looking at the thymus and the engineering of more tolerant T-cells that have been tricked into thinking cell transplants are self and not foreign invaders.