Killer Control: Engineered Stem Cells Dodge Transplant Rejection

WRITTEN BY: Tara Fernandes

The first organ transplant—performed over 60 years ago—was a success because the donor and recipient were identical twins. It’s much riskier for patients receiving tissues from an unrelated donor due to mismatched gene variants that encode for molecules that decorate the surface of cells known as the major histocompatibility complex (MHC).

Foreign MHCs are perceived as a threat by the immune system, which immediately sets to work, destroying the transplanted tissue. To sidestep this response, patients who have received organ transplants have to take a lifelong course of immunosuppressant drugs. Pharmaceutically dampening immunity is far from ideal for these patients; the immune system is there to shield us from a constant barrage of pathogenic threats.

"As a cardiac surgeon, I would love to put myself out of business by being able to implant healthy cardiac cells to repair heart disease," explained Tobias Deuse, lead author in a recent study published in the Journal of Experimental Medicine, which explores novel solutions for these ongoing challenges in regenerative medicine.

"And there are tremendous hopes to one day have the ability to implant insulin-producing cells in patients with diabetes or to inject cancer patients with immune cells engineered to seek and destroy tumors,” added Deuse.

According to Deuse, evading immediate rejection of transplanted tissues by the immune system is the holy grail.

Deuse and colleagues at UC San Francisco have identified a way to achieve this by leveraging the immunobiology of stem cells. Specifically, they have developed a method for disarming the immune system's natural killer (NK) cells. These NK cells strongly influence the rejection or tolerance of transplanted tissues—if activated after implantation of the donor tissue, they flood the body with a cocktail of chemokines and cytokines that orchestrate the immune response. Reigning in these NK responses is, therefore, a key part of keeping transplanted organs safe.

Their stem cell-based approach was inspired by work in growing so-called “hypoimmune” cells in the lab. These genetically-engineered cells have in-built elements to turn off immune checkpoints—the activation switches of the immune system. Hypoimmune cells are designed to express high levels of a protein called CD47, which disarms specific innate immune cells via the SIRPα immune checkpoint, lulling them into a sense of security.

Interestingly, the team found that this mechanism was particularly effective for evading NK cells. A deeper dive revealed that NK cells start to express SIRPα after activation by cytokines as inflammation begins to ramp up.

The clinical significance of this discovery can not be understated, say regenerative medicine scientists. "NK cells have been a major barrier to the field's growing interest in developing universal cell therapy products that can be transplanted "off the shelf" without rejection, so these results are extremely promising," said Lewis Lanier, a world-renowned expert in NK cell biology.