Co-transplantation of autologous Treg cells in a cell therapy for Parkinson’s disease

Tae-Yoon Park, Jeha Jeon, Nayeon Lee, Jisun Kim, Bin Song, Jung-Ho Kim, Sang-Kyou Lee, Dongxin Liu, Young Cha, Minseon Kim, Pierre Leblanc, Todd M. Herrington, Bob S. Carter, Jeffrey S. Schweitzer and Kwang-Soo Kim ()
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Tae-Yoon Park: Harvard Medical School
Jeha Jeon: Harvard Medical School
Nayeon Lee: Harvard Medical School
Jisun Kim: Harvard Medical School
Bin Song: Harvard Medical School
Jung-Ho Kim: Yonsei University
Sang-Kyou Lee: Yonsei University
Dongxin Liu: Harvard Medical School
Young Cha: Harvard Medical School
Minseon Kim: Harvard Medical School
Pierre Leblanc: Harvard Medical School
Todd M. Herrington: Harvard Medical School
Bob S. Carter: Harvard Medical School
Jeffrey S. Schweitzer: Harvard Medical School
Kwang-Soo Kim: Harvard Medical School

Nature, 2023, vol. 619, issue 7970, 606-615

Abstract: Abstract The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson’s disease, which makes cell replacement a promising therapeutic approach1–4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5–8. Here we show that the surgical procedure itself (referred to here as ‘needle trauma’) triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. 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. By contrast, TH− grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson’s disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH− grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson’s disease.

Date: 2023
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DOI: 10.1038/s41586-023-06300-4

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