PHARMACOLOGICAL MODULATION OF THE ADAPTIVE IMMUNE SYSTEM IN ISCHAEMIC HEART DISEASE

Inflammation plays a key role in the disease processes of both atherosclerosis and myocardial infarction (MI). Regulatory T (Treg) cells are a subset of the adaptive immune system involved in immune tolerance. Animal models show that increasing Treg cell numbers in atherosclerosis can limit disease progression. Several small clinical studies have used low dose interleukin-2 (ld-IL-2) to increase Treg cells in patients with various autoimmune but not cardiovascular diseases. Therefore, a phase 1/2a, randomised, placebo-controlled, double-blind, dose-escalation, two-part clinical trial was performed to test ld-IL-2 (aldesleukin) given once daily subcutaneously, for five consecutive days. In Part A, 25 patients with stable ischaemic heart disease were treated in 5 dose groups (0.3, 0.6, 1.2, 2.4 and 3 x106 IU/day); whilst in Part B, 16 patients with acute coronary syndrome were treated in two dose groups (1.5 and 2.5 x106 IU/day). Results showed that ld-IL-2 was safe and well tolerated across the dose range. The 1.5 x106 IU/day dose increased Treg cell levels by the pre-specified 75% and did not increase effector T cells numbers. There were additional novel findings in other immune cells and cytokine markers. B cell subsets in animal models worsen post-MI inflammation and remodelling. Antibody mediated depletion of B cells in mice limited myocardial injury and improved cardiac function. Rituximab is a monoclonal antibody targeted against human B cells and has been used in the treatment of certain autoimmune diseases and cancers. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, a phase 1/2a, open-label, dose-escalation, single-arm, clinical trial was set up to test rituximab in patients with ST-elevation MI. In total, 24 patients were treated in 4 escalating dose groups (200, 500, 700 and 1000 mg). Rituximab was administrated intravenously as a single dose within 48hours of symptoms onset. Rituximab was well tolerated at all doses. Rituximab caused rapid and significant depletion of B cells within 30 minutes of starting the infusion which suggests its use in acute MI is biologically plausible. At 6 months B cell repopulation occurred in a dose-dependent manner. In addition, several new insights into the pharmacodynamics of rituximab were gained. These results have paved the way for future phase 2b trials, one of which is underway.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Zhao, Tian xiao

Advisor dc:contributor.advisor

• Mallat, Ziad

• Atherosclerosis
• Myocardial infarction
• Regulatory T cells
• B cells

Licence

• https://www.repository.cam.ac.uk/bitstreams/da17b4aa-54f5-43c3-9842-8b27353de7e9/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.55391

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/308300