Can We Treat Parkinson’s Disease by Suppressing the Immune System?
For the majority of people who are diagnosed with Parkinson’s, we recommend treatment with a dopamine-based medication. Similar recommendations have been made by doctors for over 50 years, and with good reason – drugs which replace or mimic dopamine represent a highly effective treatment for alleviating many of the core symptoms of Parkinson’s. However, a major limitation of dopamine therapies is that they do not prevent the degeneration of brain cells, and so progression to disabling complications such as balance problems, falls and dementia continues relentlessly in spite of treatment. The need for new therapies which can slow down the disease is long overdue.
A potential new strategy for slowing the disease process involves targeting immune cells. Our immune system plays a critical role in responding to infections and repairing damage in the body, but it can also play a detrimental role when it becomes over activated - leading to excessive inflammation in conditions such as rheumatoid arthritis and Crohn’s disease. It has been known for many years that inflammation occurs in the brain in Parkinson’s disease. More recently, we have also found that immune cells in the blood are activated in this condition, and raised inflammatory markers in the blood predict faster progression of the disease over time. When taken together with the fact that inherited variations in immune genes are linked to an altered risk of developing Parkinson’s, all this suggests that the immune system warrants serious consideration as a potential new treatment target.
But the relationship between immune changes in the blood, brain inflammation and nerve cell damage in Parkinson’s is still far from clear. To help us better understand this, my group has recently completed a study of post-mortem brains from patients with the disease, compared to brains from individuals who have died at a similar age without Parkinson’s (Kouli et al, Acta Neuropathol Commun, 2020). We found more inflammation in the brains of Parkinson’s patients who developed dementia when compared to Parkinson’s patients without dementia and to controls, particularly in brain regions which are relevant to memory and thinking. Another key finding was that immune cells from the peripheral blood (T cells) had infiltrated key brain regions, and the infiltration was greater in PD dementia patients, and linked to local inflammation and deposits of alpha synuclein (a protein which forms clumps in PD brain). The findings of our study suggest: (i) that inflammation in relevant brain regions is linked to the severity of symptoms; and (ii) that this inflammation is linked to the entry of activated immune cells from the blood into the brain.
But although these findings strengthen the link between immune changes, brain inflammation and Parkinson’s disease, we have by no means demonstrated a causal effect; in other words, we cannot be sure whether activated immune cells in the blood actually contribute to brain inflammation and drive faster disease progression, or whether they simply represent a bystander effect. The only way to definitively answer this question is with a clinical trial of a drug which suppresses immune cells in people with Parkinson’s disease…and we are excited to now be embarking on such a trial. The AZA-PD trial (Greenland JC et al, BMJ Open 2020, ISRCTN14616801) involves ‘repurposing’ an immunosuppressant medication (azathioprine) which is known to be a safe and effective treatment for other inflammatory conditions. This ‘proof of concept’ trial is running here in Cambridge in the UK, and will recruit 60 patients with early stage Parkinson’s. Participants will be allocated at random to receive either azathioprine tablets or placebo tablets for 12 months, and we will assess the impact of the treatment on clinical progression of the disease, as well as on immune markers in the blood and cerebrospinal fluid, and inflammation in the brain (measured using PET scanning). After a few months of delay due to the Covid-19 pandemic, we hope to begin recruiting participants in early 2021, and look forward to sharing results with you in 3 years’ time…. If the findings are positive, this will pave the way for larger trials of immunosuppressive therapies and potentially open up a brand new treatment strategy for slowing the progression of Parkinson’s.
The AZA-PD trial is funded by the Cure Parkinson’s Trust and the Cambridge Centre for Parkinson-Plus, and supported by the NIHR Cambridge Biomedical Research Centre. (The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care.)
References
Kouli, A., Camacho, M., Allinson, K. et al. Neuroinflammation and protein pathology in Parkinson’s disease dementia. Acta neuropathologica communications 2020;8(1):211. doi.org/10.1186/s40478-020-01083-5
Greenland JC, Cutting E, Kadyan S, Bond S, Chhabra A, Williams-Gray CH. Azathioprine immunosuppression and disease modification in Parkinson’s disease (AZA-PD): a randomised double-blind placebo-controlled phase II trial protocol. BMJ Open 2020;10:e040527. doi: 10.1136/bmjopen-2020-040527
Caroline Williams-Gray, MRCP PhD is a principal research associate at the Department of Clinical Neurosciences, University of Cambridge, UK and a honorary consultant neurologist at Cambridge University Hospitals NHS Trust, UK. She has been involved in many past World Parkinson Congresses and is currently a member of the Clinical Science Subcommittee for the 6th World Parkinson Congress to be held in Barcelona, Spain from 4-7 July 2023.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®