Co-transplantation of Regulatory T Cells Improves Cell Replacement Therapy for Parkinson's Disease
Key findings
- Transplantation of autologously derived dopamine neurons has shown promise in both pre-clinical and clinical studies for the treatment of Parkinson's disease, but survival of the cells has been poor
- This study examined how the immediate reaction of host brain tissue to the surgical injury of transplantation affects the survival of the therapeutic tyrosine hydroxylase (TH)+ dopamine neurons within the graft
- In rodent models of autologous dopamine neuron transplantation, the penetrating trauma of surgical implantation induced an immediate host inflammatory response, termed needle trauma, that substantially harmed the TH+ cells that are key to the success of the therapy, but not TH- cells
- Regulatory T (Treg) cells derived from the host mitigated the needle trauma–induced harm to the dopaminergic cells in both autologous and xenogeneic grafts, leading to better improvement of motor deficits in this rat model of Parkinson's disease
- Co-transplantation of a patient's Treg cells could improve clinical outcomes of cell therapy after both autologous and allogeneic cell transplantation
The motor symptoms of Parkinson's disease (PD) correlate with selective, progressive degeneration of midbrain dopamine neurons. Transplantation of autologously derived dopamine neurons, that is, created from the patient's own cells, has shown promise in a recent clinical study, but survival of the cells has been poor.
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Researchers at Massachusetts General Hospital previously reported in NEJM the successful transplantation of midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem (iPS) cells, into a patient with PD without using immunosuppressants. However, functional recovery was only modest, suggesting cell survival was still limited.
Now, the group has determined an important reason why most grafted therapeutic neurons die and identified a method to substantially improve their survival. Todd M. Herrington, MD, PhD, director of Mass General's Deep Brain Stimulation Program, Bob S. Carter, MD, PhD, chief of the Department of Neurosurgery, Jeffrey S. Schweitzer, MD, PhD, neurosurgeon, Kwang-Soo Kim, PhD, director of the Molecular Neurobiology Laboratory at McLean Hospital, and colleagues detail their findings in Nature.
Rapid Loss of Therapeutic Cells After Transplantation
The researchers first transplanted iPS cell–derived midbrain dopamine progenitor cells from a patient with PD into mice humanized with immune cells autologous to the patient. They discovered the penetrating trauma of surgical implantation, which they term needle trauma, induced a host inflammatory response that harmed the therapeutic tyrosine hydroxylase (TH)+ cell portion of the graft. More than 90% of TH+ cells died within two weeks.
In contrast, TH− cells mostly survived whether they were transplanted into immunodeficient or immunocompetent host animals, including humanized mice. These findings were validated independently in human cell lines.
Effects of Treg Cells
In vitro, TH+ neurons were significantly rescued by co-incubation with autologous regulatory T cells. The team, therefore, decided to try co-transplanting autologous regulatory T (Treg) cells during surgical implantation of neurons, hoping to suppress the host inflammatory response to needle trauma.
In autologous and xenogeneic grafts in rodent models of PD, that strategy significantly protected both host neurons and grafted midbrain dopamine neurons from needle trauma–induced death and improved behavioral recovery.
This suggests that while using an autologous cell source can avoid the need for immunosuppression to blunt the host's adaptive immune response, i.e., tissue rejection, there is still a significant attack on the graft related to the innate immune response triggered by the needle trauma.
Unexpectedly, 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.
The Treg cells themselves did not persist in long-term grafts (assessed at six months), suggesting the benefits are related to modulation of the acute innate immune response and subsequent administration of the cells would not be required. The strategy should thus reduce a patient's time at risk of adverse effects and the extent of that risk.
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