Transplantation was a significant medical breakthrough in the mid-20th century which has since saved tens of thousands of lives, yet even the very first successful organ transplant revealed a key challenge: immune rejection. While being transplanted into the host, the cells from foreign sources do not carry the antigens representing ‘self’ on their cell membrane, which usually act as the license to keep them safe from the surveillance of the host immune system. As a result, the transplanted patient might undergo immune rejection, where the immune cells attack the transplanted cells, eliciting a series of inflammatory responses which can be lethal. Therefore, the discovery of immunosuppressive drugs, such as corticosteroids, became critical in protecting the recipients from auto-immune responses in the long term; as a compromise which renders them more susceptible to future infections.

“The cell line has potential for treating Parkinson’s disease”

However, the central nervous system was once considered ‘immunoprivileged’: lacking professional cells for antigen recognition or lymphatic vessels for the transport of large groups of immune cells, and therefore not at risk of these auto-immune responses if exposed to new antigens through transplantation. This belief led waves of passionate investigation into cell-replacement therapies in neurodegenerative disorders, and more recent studies aim to use human pluripotent stem cells (hPSCs) to generate new functional neurons (since neurons do not regenerate after birth) and then to replace damaged neurons by transplanting them into patients.

This research provides a potential cure for many neurodegenerative disorders, such as Parkinson’s disease (PD), where the loss of dopaminergic neurons leads to debilitating motor symptoms like tremors and muscle rigidity together with other cognitive decline and disorders. However, some recent studies have shown that such immune privilege is not absolute as the grafted neurons could still indirectly trigger local inflammatory responses, raising the risk of rejection (like in other organ transplants) to such replacement therapies.

Chiara Pavan’s team recently announced a potential solution to this dilemma, by opening up a brand new way to evade the immune system. They genetically engineered the hPSC cell line to overexpress eight immunomodulatory transgenes, and named the cell line H1-FS-8IM. One might wonder: how were these eight genes picked? Not surprisingly, nature has always been a loyal source of inspiration: all eight genes modified in H1-FS-8IM were shown to assist in naturally-occurring immune surveillance evasion mechanisms in placenta and cancer cells.

“It’s a one-cell-fits-all proposal”

The team then injected neurons derived from the H1-FS-8IM cell line into mice whose immune cells were replaced with human immune cells, and found that no significant rejection was observed. They also reported that the cloaked H1-FS-8IM-derived dopaminergic neurons were capable of reversing the motor deficits found in Parkinson’s, and structurally integrating into the Parkinsonian mice brain.

A significant advantage of such ‘cloaked’ cells compared to traditional immunosuppressive drugs is that they avoid systemic immunosuppression. As a result, there is less probability that the patients would suffer from future infections as they would with compromised immune systems. Furthermore, the H1-FS-8IM cells are pluripotent – they have the capacity to become almost any cell type in adult humans – making the cell line a universal donor source which brings encouraging potential for treating neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and spinal cord injury. “It’s a one-cell-fits-all proposal,” says Clare Parish, a co-author of the study.

In addition, the research group considered the risk of cancerization once the engineered cells are implanted. They added a ‘suicide gene’ which codes for two enzymes being fused together. When the drug ganciclovir is added, the enzymes become activated and arrest further cell division.

There are still limitations to the study: long-term survival of the grafted H1-FS-8IM derived cells requires further investigation, and further study might require using new Parkinsonian mice models. However, the significance of such advances is immense. As discussed in the original research publication, such single universal immune-evasive PSCs, “will ultimately expand the candidate pool of patients for neural grafting, not only in the treatment of PD but for a plethora of other neurological conditions.”