June 14, 2024

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Harvard: Parkinson’s disease cell therapy improves survival of midbrain dopamine cell transplants

Harvard: Parkinson’s disease cell therapy improves survival of midbrain dopamine cell transplants



 

Harvard: Parkinson’s disease cell therapy improves survival of midbrain dopamine cell transplants. 

Parkinson’s disease arises from the selective and progressive degeneration of midbrain dopaminergic neurons (mDANs) in the substantia nigra of the brain, implying that cell transplantation is a novel therapy with the potential to cure Parkinson’s disease, for example by Human induced pluripotent stem cells (hiPSC) or embryonic stem cell-derived midbrain dopamine (mDA) cells, especially autologous mDA cells.

 

In 2020, the research team of Professor Kwang-Soo Kim of Harvard Medical School successfully used MRI-guided stereotaxic surgery to perform autologous hiPSC-derived mDA transplantation for a 69-year-old patient with a 10-year history of Parkinson’s disease, humanized The mouse model showed that the cells were not immunogenic, the patients did not receive immunosuppressive drugs after surgery, the transplanted cells survived the 24-month observation period, and the patient’s motor assessment and symptom scale scores remained stable or moderately improved, L The daily dose of dopa decreased by 6% [1].

 

This suggests that even with autologous transplantation, cell survival may be limited and symptom improvement not significant. In order to improve the survival rate of transplantation, some research teams have proposed to greatly increase the number of transplanted cells, or to use cells at an earlier stage of differentiation.

Professor Kim’s team believes that these methods may solve some problems, but the risk of adverse events will also increase, including graft overgrowth, destruction of recipient brain structures and/or tumor formation. They still want to find a safer way.

 

In “Nature” magazine, Professor Kim’s team published the latest research results [2], they found that the surgery itself during cell transplantation can cause acute neuroinflammation, leading to the death of most transplanted mDA cells, while mDA cells When co-transplanted with regulatory T cells, it can effectively inhibit the adverse effects of the operation itself, significantly improve the survival of transplanted cells, and improve the therapeutic effect in the Parkinson’s disease rat model .

 

Harvard: Parkinson's disease cell therapy improves survival of midbrain dopamine cell transplants

 

By transplanting Parkinson’s disease patient-derived midbrain dopamine progenitor cells (mDAP) into autologous immune cell humanized mice, the researchers found that less than 1% of mDAP (equivalent to less than 10% of mDAN) survived Not only that, they also observed that a large number of immune cells from the humanized host’s immune system, such as human macrophages and microglia, white blood cells, and T lymphocytes, accumulated near the transplanted cells.

 

However, the researchers feel that these mice are immune deficient, which may not be enough to explain the problem. They selected rats with normal immune function and performed sham transplantation operations on the rats that did not contain any cells. The results still observed Acute release of proinflammatory cytokines and immediate activation of astrocytes and microglia at the injection site , implying an immune response to penetrating brain injury (i.e., surgical needle-stick trauma) in the rat brain .

 

On day 4, the level of interferon-γ (IFN-γ) positive cells peaked, and many other inflammatory cells also peaked on day 7, and began to decline a month later. Correspondingly, brain cells near the injection site Mortality also peaked at day 7. Therefore, the researchers speculate that these transplanted cells with mDAP may also die in the same way.

 

Harvard: Parkinson's disease cell therapy improves survival of midbrain dopamine cell transplants

IFN-γ (c) peaked at day 4, other inflammatory cells (a, b) peaked at day 7

 

Through in vitro cell experiments, the researchers ruled out the possibility that the early death of mDAN was caused by the immunogenicity of transplanted autologous mDAP, and verified the cell death induced by pro-inflammatory cytokines . After 7 days of co-culture, about 15% of the total cells % died, of which more than 80% of mDAN died.

 

It seems that the problem is here.

 

In traumatic brain injury (TBI), initially, there is also an infiltration of inflammatory cells, followed by an infiltration of regulatory T cells into the damaged area, repairing the damage and helping to restore homeostasis [3,4]. Therefore, the researchers believe that simultaneous transplantation of regulatory T cells may be an effective way to reduce acute neuroinflammation induced by needle-stick trauma.

 

Autologous regulatory T cell transplantation in rats significantly suppressed the acute induction of pro-inflammatory cytokines at day 2 and the infiltration of inflammatory cells at day 7, and also protected neurons from death in rats. There is a dose-response relationship in the inhibition of autologous regulatory T cells on the infiltration of MHCII+ inflammatory cells, and the maximum effect is achieved when 20,000 cells are transplanted.

 

Harvard: Parkinson's disease cell therapy improves survival of midbrain dopamine cell transplants

Inflammatory cell infiltration was reduced (e, f), and neurons survived abundantly (g)

 

Finally, the researchers tested the possibility that co-transplantation of regulatory T cells protected mDAN from death.

 

They first transplanted patient-derived iPSC-derived mDAP and the rat’s own regulatory T cells into Parkinson’s disease rats, and the rats taking the immunosuppressive drug CsA had a significant improvement in rotational symptoms at 20 weeks after transplantation, while those who did not take CsA , symptoms did not improve, which was consistent with the researchers’ expectations.

 

At 2 weeks after transplantation, only mDAP-transplanted rats showed inflammatory cell infiltration and mDAP death, and CsA treatment and/or regulatory T cell co-transplantation rescued a large number of mDAPs, and the effect of regulatory T cells was better than that of CsA.

It should be noted that at 20 weeks, mDAPs still died even after Tregs were co-transplanted, suggesting that Tregs could only provide short-term protection under the condition of xenotransplantation, and only daily administration of CsA rescued mDAPs.

 

Harvard: Parkinson's disease cell therapy improves survival of midbrain dopamine cell transplants

Inhibition of inflammatory cell infiltration (c, d) and protection of mDAP (e, f) by regulatory T cells and CsA

 

Autologous transplantation of patient-derived iPSC-derived mDAPs and regulatory T cells co-transplanted in humanized mice with patient immune cells showed a significant increase in survival at 2 months with co-transplantation compared with mDAP alone increased the number of mDAPs.

The premature death of the mice may be due to graft-versus-host disease (GVHD), as previous studies have shown that humanized mice are often injected with human peripheral blood mononuclear cells (PMBC) into immunodeficient (NSG) mice. Mice died of GVHD within 30-90 days afterward.

 

In nonhumanized NSG mice, a significant improvement in Parkinson’s disease-associated rotational behavior and forelimb function similar to xenograft experiments was observed 20 weeks after co-transplantation.

Due to the immunodeficiency of NSG mice, the researchers did not observe immune rejection even without the use of immunosuppressive drugs.

 

Overall, this study presents a realistic approach to improve the survival of transplanted cells when using cell transplant therapy to treat Parkinson’s disease: co-transplantation of regulatory T cells.

Professor Kim said that this discovery is very important.

The most important criterion for cell therapy is safety. In the next step, they will continue to study how regulatory T cells can improve the survival of dopaminergic neurons and how to optimize their functions.

 

 

 

 

 

references:

[1] Schweitzer JS, Song B, Herrington TM, et al. Personalized iPSC-derived dopamine progenitor cells for Parkinson’s disease[J]. New England Journal of Medicine, 2020, 382(20): 1926-1932.

[2] Park, TY., Jeon, J., Lee, N. et al. Co-transplantation of autologous Treg cells in a cell therapy for Parkinson’s disease. Nature (2023). https://doi.org/10.1038/ s41586-023-06300-4

[3] Alam A, Thelin EP, Tajsic T, et al. Cellular infiltration in traumatic brain injury[J]. Journal of neuroinflammation, 2020, 17: 1-17.

[4] Karve IP, Taylor JM, Crack P J. The contribution of astrocytes and microglia to traumatic brain injury[J]. British journal of pharmacology, 2016, 173(4): 692-702.

Harvard: Parkinson’s disease cell therapy improves survival of midbrain dopamine cell transplants

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