Investigating immunosuppression as a disease modifying strategy in Parkinson's disease

Increasingly, the immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Epidemiological studies have shown that the risk of developing PD is linked to polymorphisms in immune-related genes, increased by the presence of inflammatory conditions and reduced by the use of immunosuppressant and anti-inflammatory drugs. The immune also system shows an abnormal profile in PD patients. Microglia, the immune cells of the brain, are activated in PD. Abnormalities are also present in the peripheral immune system, with T-lymphocytes primed to respond to alpha-synuclein and a higher proportion of pro-inflammatory subsets, impaired regulatory function and a lack of immunosenescence normally seen with aging. T lymphocytes infiltrate the brain in PD, where they are found in higher numbers than in controls. Inflammatory cytokine levels are also elevated in the cerebrospinal fluid in PD[1], and a pro-inflammatory cytokine profile in the blood has been linked to faster disease progression. There is currently no treatment to slow the progression of PD and given the substantial evidence supporting the role of the immune system, we are conducting a phase 2 double-blind randomised controlled trial of azathioprine (“AZA-PD”), an immunosuppressant medication, to investigate whether suppressing the peripheral immune system has a disease-modifying effect in PD. At the time of writing, I am still blinded to treatment allocation, therefore this thesis does not include any data on the clinical efficacy of azathioprine. Chapter 1 explores the background and rationale for this treatment strategy, including a review of published trials targeting the immune system in PD. Chapter 2 describes the design of the AZA-PD clinical trial, with a summary of the trial protocol and a justification of the eligibility criteria and selection of the outcome measures. This chapter also covers the progress of the trial, including recruitment, adverse events and treatment withdrawals. Chapter 3 discusses the optimisation of the immunophenotyping analysis using flow cytometry which is being used as an exploratory outcome measure in AZA-PD, and reports the baseline immune profile of the trial cohort compared to a matched control group, as well as the profile of a group of patients with REM sleep behaviour disorder (RBD). This analysis illustrates the potential utility of FBC-derived variables as biomarkers in PD, and positions innate immune cell populations, particularly classical monocytes and natural killer (NK) cells, as variables of interest in the final trial analysis. Chapter 4 reports the imaging data from the sub-group of AZA-PD trial participants who had [11C]- PK11195 PET prior to starting treatment, which assesses microglia activation. The [11C]- PK11195 binding potential in regions of interest is compared to that of a previously collected control cohort. This analysis suggests the pallidum, putamen and lateral orbital gyrus as areas to take forward to the investigation of the potential effect of peripheral immunosuppression with azathioprine on neuroinflammation. This chapter also shows a correlation between peripheral NK populations and whole brain [11C]- PK11195 signal. Chapter 5 uses multiple regression analysis to explore the contribution of these markers of peripheral and central immune to the clinical phenotype of the AZA-PD trial participants prior to starting treatment. Chapter 6 analyses the treatment effect of azathioprine on both the peripheral and central immune profiles, using flow cytometry immunophenotyping analysis and [11C]- PK11195 binding potentials. Chapter 7 presents the key conclusions from this thesis and plans for future work.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Greenland, Julia

Advisor dc:contributor.advisor

• Williams-Gray, Caroline

• Clinical trial
• Immune system
• Parkinson's disease

Licence

• https://www.repository.cam.ac.uk/bitstreams/9e472a52-baf2-4174-858c-2f320508835c/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.111379

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/372511