Cell therapy holds promise as a treatment for Parkinson’s disease, but trials have found that the transplanted dopamine cells typically fail to survive. A study by researchers at McLean and Mass General Hospital has now identified a potential cause, demonstrating that the transplant surgical procedure itself, which they refer to as “needle trauma,” triggers a profound immune response and causes the death of most grafted dopamine neurons.

The team’s study also found that using regulatory T cells to supplement the neuronal cell therapy decreased the adverse effects of the surgical procedure in rodent models and improved therapeutic outcomes, survival, and graft recovery. They suggest that the findings point to a potential path for the “realistic” use of cell therapy to treat neurodegenerative disorders.

“We have been investigating personalized, stem-cell based therapies that reprogram a patient’s own cells to treat their Parkinson’s,” said Kwang-Soo Kim, PhD, at the Molecular Neurobiology Laboratory at McLean Hospital. “We have now made a major breakthrough using immune cells to improve delivery, survival, and recovery for neuronal cell therapies. Our findings show the power and flexibility of cell therapy to be modified and enhanced to become a realistic modality to treat conditions like Parkinson’s.” Kim is corresponding author of the team’s published paper in Nature, titled, “Co-transplantation of autologous Treg cells in a cell therapy for Parkinson’s disease.”

In the United States, only Alzheimer’s disease is a more common neurodegenerative disorder than Parkinson’s disease (PD), which is characterized by loss of midbrain dopaminergic neurons. The cardinal motor symptoms of PD, including tremor, rigidity, bradykinesia, and postural instability, correlate with the progressive degeneration of midbrain dopamine neurons (mDANs) in an area of the brain called the substantia nigra. The current standard of care is dopamine replacement therapy, which addresses only symptoms like tremors or stiffness with substantial side effects. And while cell replacement therapy represents “a promising therapeutic approach,” to PD treatment, the authors noted, “… poor survival of grafted mDANs remains an obstacle to successful clinical outcomes.”

Poor graft survival has represented a significant barrier since the 1980s. Researchers have proposed diverse mechanisms to explain cell death, and added various modifications to improve cell survival. Three years ago, Kim’s team demonstrated for the first time that personalized cell therapy could be used to replace dopamine neurons in a patient with sporadic PD. However, the results were restricted to a single patient and limited graft survival remained a key challenge.

For their newly reported study, Kim and colleagues hypothesized that regulatory T cells— which maintain immune homeostasis, contain inflammation, and prevent immune rejection—could be co-transplanted with the neurons to mitigate needle trauma and improve cell survival and disease recovery. “Treg cells are indispensable to the maintenance of normal immunological tolerance and homeostasis, and are so named owing to their modulation of other immune cells to contain inflammatory and immune rejection responses,” they pointed out. To test their hypothesis the researchers first transplanted midbrain dopaminergic neurons in previously validated mouse and rat models of PD. They observed how the surgical procedure resulted in acute inflammation and an adverse immune response in the brain tissue, which they termed needle trauma.

“When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation,” they wrote. “ … we show that the penetrating trauma of surgical implantation induces a host inflammatory response, including a robust innate immune response similar to that described in other models of TBI [traumatic brain injury] and that this immediate inflammatory response is specifically harmful to the desired therapeutic TH+ cell component of the graft.”

Next, the team co-transplanted regulatory T cells with the dopaminergic neurons. “We hypothesized that intra-striatal co-transplantation of host-autologous Treg cells would protect transplanted mDANs from needle-trauma-induced cell death during cell therapy (both allogeneic and autologous),” they commented. The investigators measured the survival of grafted neurons over two weeks. After five months, they reassessed this finding and observed how the grafted area was recovering.

“Initially, just one or two weeks after transplantation, the majority of the dopamine neurons died, rendering the cell therapy unsuccessful,” said Kim. “But when we added regulatory T cells to the transplant, survival of the grafted dopamine neurons increased. Also, behavior recovery was faster and more robust.”

Regulatory T cells not only improved the survival of grafted dopaminergic neurons but also significantly suppressed the outgrowth of non-dopaminergic cells, including reactive inflammatory cells, in host brains.

“This finding is very significant because a potential hazard associated with cell transplantation is often the outgrowth of undesirable, potentially harmful cells,” Kim said. “The most important criterion for cell therapy is safety.” The authors stated, “An unanticipated finding in this study was that co-transplantation of Treg cells substantially reduced the expansion of the grafts related to TH cells, resulting in a significantly smaller graft volume with a higher proportionate TH+ cell content and improved outgrowth from the grafts.”

So, while needle trauma induced significant brain cell death, the regulatory T cells were able to suppress this cell death, along with the adverse neuroinflammation and unwanted peripheral immune cells entering the injury site. “Needle trauma is a universal issue in cell therapies in the nervous system, not just for dopaminergic neurons or Parkinson’s disease,” said Bob Carter, MD, PhD, the chief of neurosurgery at Mass General Hospital and a co-author of the paper in Nature.  “Our principles can be applied widely to any cell therapy for other (neuro)degenerative disorders such as Alzheimer’s, ALS, or Huntington’s.”

The authors concluded, “Co-transplantation of mDAPs with Treg cells modulates the host immune response triggered by needle trauma and significantly protects mDANs while suppressing the proliferation of TH cells, which would benefit both the efficacy and safety of cell replacement therapy for PD and other neurodegenerative disorders.

Limitations of the study include its constraint to rodent models. Kim says the next steps are to understand the safety of these transplants, exactly how regulatory T cells improve the survival of dopaminergic neurons, and how to optimize their function.

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