As if human embryonic stem cells didn’t have enough trouble already making it through governmental legislation, they also face rejection from another source: the immune system. In their latest study, Herman Waldmann and his team of talented immunologists from the University of Oxford report a simple strategy to induce long-lasting immune tolerance to stem cell transplants and their differentiated progeny.
Our immune system is excellent at recognizing foreign antigens. Evidently, this poses significant problems for transplantation and regenerative medicine. Induced pluripotent stem cells offer the possibility of ‘autologous’ transplants, but even these cells can face attack from the immune system.
Stem cells themselves also have specific problems not confronted by let’s say a transplanted kidney. During tolerance, the immune system is exposed to undifferentiated cells, but when cells start to differentiate, new antigens are revealed, which may lead to rejection. In addition, conventional immunosuppressants like cyclosporine can inhibit the differentiation of particular stem cells.
Waldmann’s approach for avoiding rejection is simple: stop the T cells! His team used non-depleting antibodies against the T cell antigens CD4, CD8 and CD40L to shut down T cell responses in immunocompetent mice. They injected neural precursor cells (NPCs) derived from human embryonic stem cells (hESCs) under the kidney capsule of mice, and treated them with these antibodies three times in the week following transplantation.
- Short-term immunosuppression led to long-term tolerance and all grafts survived after 90 days.
- NPCs differentiated and expressed neuronal, astrocyte and glial cell markers.
- Mice appeared to ‘remember’ this lesson in immune tolerance as a second graft of NPCs 90 days post-transplantation was accepted without any additional treatment.
- Mice transplanted with NPCs also readily accepted progenitor skin cells, which the team attributed to the expression of common antigens between the two tissues.
The accumulation of Foxp3+ regulatory T cells (Tregs), which limit responses from effector T cells, in the transplanted tissue may account for these results. Waldmann likens them to the ‘peacekeepers’ maintaining immune tolerance in the accepted tissue. It’s hoped that other protocols that harness the power of Tregs should enable the maturation of human stem cell grafts following their initial establishment.
Overcome your fear of rejection at Nature Communications, December 2014.