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At the Bench-Parkinson's Disease
Immune-Modulating Drug Rescues Cell Death in Parkinson's Disease

ARTICLE IN BRIEF

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DR. BEATE WINNER: “Our findings indicate a critical role for IL-17 producing T cells in human PD-associated neuronal cell death.”

Researchers reported that increased T cells were detected in the brains and blood of Parkinson's disease patients, indicating the role of lymphocytes in PD pathogenesis.

A new study adds to the mounting evidence that the adaptive immune system plays a direct role in killing midbrain neurons in patients with Parkinson's disease (PD).

The paper by German scientists, published in the July 5 Cell Stem Cell, suggests that among the key immune players are interleukin-17 (IL-17) producing T cells that are increased in the brains and blood of PD patients and trigger a pro-inflammatory condition that kills these neurons.

They reported that an immune-modulating drug blocking IL-17 and approved to treat psoriasis did work to rescue neuronal cell death in the lab-based experiments.

Despite the long-lasting dogma, that the blood-brain barrier is intact in PD and hinders immune cells (such as T- and B-cells) to enter the brain, several groups of scientists have reported an increase in T cells in the postmortem midbrain of Parkinson's patients and alterations of T cell populations in the blood of living patients.

Beate Winner, MD, associate professor in the department of stem cell biology at the University of Erlangen-Nuremberg, and her colleagues wanted to determine whether the T cells directly affect midbrain neurons.

For the study, they collected fibroblasts from patients and used an induced pluripotent stem cell (iPSC) technique to generate midbrain neurons that are affected in PD. Then, they isolated T cells from the same patients and co-cultured the identical patients' neurons and the T cells and discovered that T cells were potent enough to kill the neurons. This effect was largely mediated by the cytokine IL-17, which is produced by the specific population of T cells, TH17 cells. This population was found increased in the blood of PD patients, Dr. Winner and her colleagues reported.

“We were really surprised about the difference between PD patients and controls whose T cells did not kill the neurons,” said Dr. Winner.

Many scientists have agreed that inflammation does occur in PD, but it has been attributed to innate immune triggers that were assumed to be a consequence of the underlying pathology.

In the last decade or so, several teams have discovered CD4+ and CD8+ T cells in postmortem brains of PD patients, and their alterations in blood from PD patients. T cells are activated during the body's adaptive immune response to infections, or they are activated during an autoimmune response that might trigger aberrant inflammation. Dr. Winner and her colleagues set out to figure out what T cells are doing in PD. Are they direct players in the pathological events?

STUDY METHODS, FINDINGS

The German scientists recruited six early stage PD patients and an equal number of controls. The first set of experiments began with three patients and controls; they confirmed the findings with the next set of study volunteers. They used iPSC methods to make midbrain neurons and then collected blood from each study subject and isolated T cells. They activated T cells ex vivo in an antigen-independent way and looked for the cytokines produced by the T cells, which is how they identified an increase in TH17 cells in patients and not in the controls.

They co-cultured T cells in a dish with the iPSC midbrain neurons (a ratio of one-to-one) and found that the patient's T cells were capable of directly killing the midbrain neurons. In the T cell-neuron co-cultures, they found increased levels of tumor necrosis factor, IL-1b, and IL-6, but IL-17 showed the most robust increase in PD patients.

Further work showed that the T cell-induced neuronal cell death was mediated by IL-17 and IL-17 receptor signaling and activation of NFkB, a transcription factor found activated in pro-inflammatory conditions. Even a ratio of one T cell to 10 midbrain neurons triggered a significant increase in neuronal cell death, the scientists said. Neurons did not die when T cells were not added to the culture.

Blocking IL-17 prevented the death of the midbrain neurons. Also, adding the IL-17 antibody secukinumab (the psoriasis drug) rescued the neuronal death, said Iryna Prots, PhD, an immunologist and co-author of the study.

“Our findings indicate a critical role for IL-17 producing T cells in human PD-associated neuronal cell death,” said Dr. Winner. The group also replicated earlier findings showing the presence of T cells in postmortem PD brains. In the blood from 10 sporadic PD patients and controls, they identified an increase in TH 17 cells. This increase was not correlated with the amount of dopaminergic medications the patients had been taking, the scientists said.

EXPERT COMMENTARY

“This is good work,” said neurobiologist David Sulzer, PhD, professor of psychiatry, neurology and pharmacology at Columbia University Medical Center. He and his colleagues published a paper in Nature last year showing that a population of T cells in the blood of patients with Parkinson's disease recognizes alpha-synuclein peptides.

It is still not clear whether this autoimmune response triggers the disease process or contributes to the neuronal degeneration. “The idea that TH17 cells are involved in Parkinson's is exciting. When you have a good study, it raises a lot of new questions. Why and how would TH17 be involved in cell death? Do iPSC midbrain neurons have the same complement of receptors that bind TH17 that midbrain neurons in the human brain do? What are the steps that lead to the killing of neurons, or are there events upstream that activate this chain of events? Then, how is it doing that? TH17 is not known to be a killer T cell. What is the mechanism? What about microglia? Are there other cells required for neuronal cell death to occur?”

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INCREASED NUMBERS OF T cells were detected in postmortem PD midbrains, and increased frequencies of IL-17 producing cells were found in the blood of PD patients. The T cells induced neuronal death in PD, which was mediated by IL-17-IL-17R signaling and activation of NFKB.

“There has been an appreciation that neuro-inflammation plays a role in Parkinson's,” said Ted M. Dawson, MD, PhD, director of the Institute for Cell Engineering and director of the Morris K. Udall Parkinson's Disease Research Center at Johns Hopkins University School of Medicine. “This study suggests that adaptive immunity plays a role in PD, and this finding creates an opportunity to test drugs used for classical immune disorders. I think there needs to be a lot more work to prove that the immune system is the initiator in PD. It is more likely that the immune system is being recruited in response to the disease process.”

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DR. DAVID SULZER said it is still not clear whether this autoimmune response triggers the disease process or contributes to the neuronal degeneration.

David G. Standaert, MD, PhD, the John N. Whitaker professor and chair of neurology at the University of Alabama at Birmingham, said that PD is a very complicated disease that has genetic and environmental triggers. “This study is building on other work showing that the immune system is involved in PD. I do think there is an immune component, and that it likely contributes to progression. If we could pinpoint a vulnerability in the immune system, it could be a good target for treatments.”

His group is about to launch a study on inflammation in early PD. They are also looking at the possibility that the LRRK2 gene, known to trigger PD, is involved with immune signaling. “If we could find the right way to modulate the immune system we may be able to slow the disease process.” •

THE SCIENCE EXPLAINED: INDUCED PLURIPOTENT STEM CELLS

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WHAT IT IS: In 2007, scientists discovered that they can create an unlimited number of induced pluripotent stem cells (iPSC) from human adult fibroblasts and coax them to become cells of different lineages or most types of cells of the body. These adult skin cells can be reprogrammed to turn back the clock and behave like an embryonic cell.

THE TECHNIQUE: Researchers isolate and culture fibroblasts and four reprogramming genes are overexpressed — Sox2, Oc4, c-Myc, and Klf4. In the current study, the researchers collected fibroblasts or skin cells from patients with Parkinson's disease (and normal volunteers) and used the induced pluripotent stem cells to create a population of mid-brain neurons to study.

HOW IT IS USED: iPSCs are an essential tool in understanding disease states and developing compound or cell-based treatments. Since the cells are self-renewing and pluripotent, they represent an unlimited source of patient-derived cells. Researchers are using this technique to create more accurate models of diseases and gain insight into the pathophysiology of different disorders.

LINK UP FOR MORE INFORMATION:

•. Sommer A, Maxreiter F, Krach F, et al. Th17 lymphocytes induced neuronal cell death in a human iPSC-based model of Parkinson's disease https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30297-2. Cell Stem Cell 2018; 23(1):121–131.
    •. Bolte AC, Lukens JR. Th17 cells in Parkinson's disease: The bane of the midbrain https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30298-4. Cell Stem Cell 2018: 23(1):5–6.
    •. Sulzer D, Alcalay RN, Garretti F, et al. T cells from patients with Parkinson's disease recognize α-synuclein peptides https://www.nature.com/articles/nature22815. Nature 2017; 5449(7671): 656–661.