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

Park, Tae Yoon; Jeon, Jeha; Lee, Nayeon; Kim, Jisun; Song, Bin; Kim, Jung Ho; Lee, Sang-Kyou; Liu, Dongxin; Cha, Young; Kim, Min‐Seon; Leblanc, Pierre; Herrington, Todd M.; Carter, Bob S.; Schweitzer, Jeffrey S.; Kim, Kwang-Soo

doi:10.1038/s41586-023-06300-4

Cited by 27 publications

(12 citation statements)

References 51 publications

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“…Aside from immunosuppression, several other approaches are being considered with regards to dampening down immune responses to neuronal and other cell therapies, including the development of "hypoimmunogenic" cell lines, lacking MHC-I and/or MHC-II and overexpressing immunomodulatory molecules such as CD47 64,65 . Co-transplantation of regulatory immune cells is also being explored in autologous transplantation to suppress surgery-induced immune activation 66 . Our data suggest that genetic engineering of RC17derived NPCs is not required.…”

Section: Discussionmentioning

confidence: 99%

“…All monocytes were utilised fresh due to the known issues of poor viability of cryopreserved monocytes. Full detailed protocol can be found on protocols.io 66 . Monocytes, MACS-enriched from fresh PBMC were seeded at 0.5x10 6 cells/cm 2 in RPMI plus 5% heat-inactivated human AB serum (Merck Life Sciences) and 100 U/ml penicillin-streptomycin and cultured with 50 ng/ml rhIL-4 (Biolegend) and 50 ng/ml rhGM-CSF (Biolegend) for 6 days with half media changes on day 3.…”

Section: Monocyte-derived Dendritic Cell (Modc) Differentiationmentioning

confidence: 99%

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The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

Curle,

Fazal,

Qarin

et al. 2024

Preprint

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Parkinsons Disease involves the progressive loss of dopaminergic neurons (DAn), prompting clinical trials replacing cell loss with neural grafts. This includes the transplantation of pluripotent stem cell-derived DAn progenitor cells (NPC) currently under investigation in the STEM-PD trial. To determine the likelihood of immune rejection post-grafting, we characterised the immunogenicity of the STEM-PD product (RC17-hESC-derived NPCs), comparing them to human foetal ventral mesencephalic tissue (hfVM) previously tested in trials, including our own TRANSEURO trial. Despite MHC-Class I expression, upregulated by proinflammatory cytokines, no immune response to NPCs was detected in vitro. Instead, they were immunosuppressive. Transcriptomic analysis revealed similarities between RC17-NPCs and hfVM, both strongly upregulating antigen processing and presentation pathways in response to IFNgamma. Furthermore, immunosuppressant mycophenolate mofetil detrimentally affected NPC survival and differentiation in vitro. Overall, our data suggest that aggressive immunosuppression is not required following hESC-NPC transplantation and that caution should be exercised when selecting the immunosuppressive regimen.

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Section: Discussionmentioning

confidence: 99%

Section: Monocyte-derived Dendritic Cell (Modc) Differentiationmentioning

confidence: 99%

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

Curle,

Fazal,

Qarin

et al. 2024

Preprint

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“…We hypothesize that Tregs are likely to amplify the overall immune dysregulation in H. pylori -infected Pink1 −/− mice by their impaired suppression of the autoreactive CD8 T cells, thus exacerbating disease development. The role of Tregs in PD has been under focus recently and several clinical trials targeting the Treg population have been initiated (Olson et al, 2023; Park et al, 2023). The mouse model described here provides a relevant preclinical system to assess the effects of Treg modulation in future studies.…”

Section: Discussionmentioning

confidence: 99%

Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1^−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction

Kazanova,

Sung,

Oliveira

et al. 2024

Preprint

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Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of motor function. Diagnosis occurs late: after motor symptom development downstream of the irreparable loss of a large proportion of the dopaminergic neurons in thesubstantia nigraof the brain. Understanding PD pathophysiology in its pre-motor prodromal phase is needed for earlier diagnosis and intervention. Genetic risk factors, environmental triggers, and dysregulated immunity have all been implicated in PD development. Here, we demonstrate in a mouse model deficient in the PD-associated genePink, that infection with the human PD-associated gastric bacteriumHelicobacter pylorileads to development of motor and cognitive signs resembling prodromal features of PD. This was also associated with proliferation and activation of primary mitochondria-reactive CD8 T cells and infiltration of CD8 T cells into the brain. Development of the motor and cognitive phenotypes in the infectedPink1−/−mice was abrogated when CD8 T cells were depleted prior to infection. We anticipate that this new model, which integrates genetic PD susceptibility, a PD-relevant environmental trigger, and specific immune changes that are required for symptom development, will be a valuable tool for increasing our understanding of this complex disease.

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“…However, prolonged usage of these medications frequently compromises the recipient's immune system, leading to infections and inadequate suppression of transplanted cells 94–96 . According to research findings, regulatory T cells have been found to exert a temporary inhibitory effect on the proliferation of CD8+ T cells, thereby providing a limited defense against rejection for a duration of approximately 2 months 97 . However, the unresolved matter of persistent immune rejection continues to be a matter of great concern.…”

Section: Limiting Factors In Heterogeneous Cell Transplantation For T...mentioning

confidence: 99%

Role and limitation of cell therapy in treating neurological diseases

Li,

Tao

et al. 2024

Ibrain

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The central role of the brain in governing systemic functions within human physiology underscores its paramount significance as the focal point of physiological regulation. The brain, a highly sophisticated organ, orchestrates a diverse array of physiological processes encompassing motor control, sensory perception, cognition, emotion, and the regulation of vital functions, such as heartbeat, respiration, and hormonal equilibrium. A notable attribute of neurological diseases manifests as the depletion of neurons and the occurrence of tissue necrosis subsequent to injury. The transplantation of neural stem cells (NSCs) into the brain exhibits the potential for the replacement of lost neurons and the reconstruction of neural circuits. Furthermore, the transplantation of other types of cells in alternative locations can secrete nutritional factors that indirectly contribute to the restoration of nervous system equilibrium and the mitigation of neural inflammation. This review summarized a comprehensive investigation into the role of NSCs, hematopoietic stem cells, mesenchymal stem cells, and support cells like astrocytes and microglia in alleviating neurological deficits after cell infusion. Moreover, a thorough assessment was undertaken to discuss extant constraints in cellular transplantation therapies, concurrently delineating indispensable model‐based methodologies, specifically on organoids, which were essential for guiding prospective research initiatives in this specialized field.

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

Cited by 27 publications

References 51 publications

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1^−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction

Role and limitation of cell therapy in treating neurological diseases

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

Cited by 27 publications

References 51 publications

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

The immunological profile of RC17 hESC-derived dopaminergic neural progenitor cellsin vitro: implications for the STEM-PD clinical trial

Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction

Role and limitation of cell therapy in treating neurological diseases

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Modeling gene-environment interactions in Parkinson’s Disease:Helicobacter pyloriinfection ofPink1^−/−mice induces CD8 T cell-dependent motor and cognitive dysfunction