{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/379761"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/379761","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Targeting Inflammation in Atherosclerosis: The Role of Low-dose Interleukin 2 in Acute Coronary Syndromes","abstract":"The primary aetiology of acute coronary syndromes (ACS) is atherosclerosis. Historically, atherosclerosis was thought to be driven by traditional risk factors, such as hyperlipidaemia. However, we now know that inflammation plays a central role in its pathophysiology. In ACS there is an acute flare of this inflammatory process, and in some individuals, this is followed by a chronic residual inflammatory state. The acute flare causes irreversible damage to the myocardium by leading to larger infarcts and adverse remodelling, and the chronic residual inflammatory state can lead to recurrent cardiovascular (CV) events. Despite advances in the treatment of ACS, recurrent major adverse cardiovascular events (MACE) occur in up to 40-50% of individuals.1-3 Anti-inflammatory agents such as canakinumab and colchicine have improved CV outcomes in patients with ischaemic heart disease (IHD).4 5 However, these have come at a cost due to serious, and at times, fatal, side-effects as a result of immunosuppression. Furthermore, there was no difference in all-cause mortality between treatment agents and placebo. A clinical need exists for a targeted anti-inflammatory therapy in ACS that can immunomodulate without immunosuppression. Regulatory T (Tregs) cells play an important immunomodulatory role in ACS, promoting healing and repair.6 Interleukin 2 (IL-2) is central to Treg cell development and expansion.7 Whilst low-dose IL-2 therapy has been successfully used in autoimmune and inflammatory conditions, its use is currently contraindicated in severe IHD.8 In the LILACS (low-dose interleukin 2 in participants with stable ischaemic heart disease and acute coronary syndromes) trial - part A, patients with IHD received varying doses of low-dose IL-2.9 It was well tolerated and led to an increase in the Treg cell population.10 The work of this thesis involves two trials: The LILACS - part B trial and the IVORY (low-dose interleukin-2 for the reduction of vascular inflammation in acute coronary syndromes) trial.11 Both trials were undertaken in patients presenting with ACS. LILACS was a Phase I/IIa trial, in which low-dose IL-2 was demonstrated to be safe and well tolerated in ACS. It also increased the number of circulating Treg cells in a dose-dependent manner. IVORY was a double-blind, randomised, placebo-controlled, Phase IIb trial. Patients presenting with ACS and high-sensitivity C-reactive protein (hsCRP) levels ≧ 2mg/L were randomised to receive either low-dose IL-2 or placebo. The primary outcome was the difference in arterial inflammation in the index vessel on the follow-up scans between the groups as measured by 2-Deoxy-2-[fluorine-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). We demonstrated that low-dose IL-2 reduced arterial inflammation in patients presenting with ACS. There was a strong correlation between the additive treatment effect of low-dose IL-2 and baseline inflammation. Low-dose IL-2 also increased Tregs and led to the reduction in proinflammatory T effector cells. The treatment was again well tolerated with no severe adverse reactions noted. Graphical summary: IVORY demonstrated a reduction in arterial inflammation in those with residual inflammation post MI despite optimal medical therapy (OMT). Phase III trials are needed to explore if this reduction in arterial inflammation leads to a reduction in MACE. In summary, this thesis brings together concepts of contemporary elements of translational medicine such as drug re-purposing, personalised medicine, and use of surrogate clinical endpoints through the application of imaging biomarkers. This work presents promising data for the safety and anti-inflammatory effect of low-dose IL-2 in ACS. Larger trials are now needed to evaluate its impact on clinical cardiovascular outcomes.","abstract_html":"The primary aetiology of acute coronary syndromes (ACS) is atherosclerosis. Historically, atherosclerosis was thought to be driven by traditional risk factors, such as hyperlipidaemia. However, we now know that inflammation plays a central role in its pathophysiology. In ACS there is an acute flare of this inflammatory process, and in some individuals, this is followed by a chronic residual inflammatory state. The acute flare causes irreversible damage to the myocardium by leading to larger infarcts and adverse remodelling, and the chronic residual inflammatory state can lead to recurrent cardiovascular (CV) events. Despite advances in the treatment of ACS, recurrent major adverse cardiovascular events (MACE) occur in up to 40-50% of individuals.1-3 Anti-inflammatory agents such as canakinumab and colchicine have improved CV outcomes in patients with ischaemic heart disease (IHD).4 5 However, these have come at a cost due to serious, and at times, fatal, side-effects as a result of immunosuppression. Furthermore, there was no difference in all-cause mortality between treatment agents and placebo. A clinical need exists for a targeted anti-inflammatory therapy in ACS that can immunomodulate without immunosuppression. Regulatory T (Tregs) cells play an important immunomodulatory role in ACS, promoting healing and repair.6 Interleukin 2 (IL-2) is central to Treg cell development and expansion.7 Whilst low-dose IL-2 therapy has been successfully used in autoimmune and inflammatory conditions, its use is currently contraindicated in severe IHD.8 In the LILACS (low-dose interleukin 2 in participants with stable ischaemic heart disease and acute coronary syndromes) trial - part A, patients with IHD received varying doses of low-dose IL-2.9 It was well tolerated and led to an increase in the Treg cell population.10 The work of this thesis involves two trials: The LILACS - part B trial and the IVORY (low-dose interleukin-2 for the reduction of vascular inflammation in acute coronary syndromes) trial.11 Both trials were undertaken in patients presenting with ACS. LILACS was a Phase I/IIa trial, in which low-dose IL-2 was demonstrated to be safe and well tolerated in ACS. It also increased the number of circulating Treg cells in a dose-dependent manner. IVORY was a double-blind, randomised, placebo-controlled, Phase IIb trial. Patients presenting with ACS and high-sensitivity C-reactive protein (hsCRP) levels ≧ 2mg/L were randomised to receive either low-dose IL-2 or placebo. The primary outcome was the difference in arterial inflammation in the index vessel on the follow-up scans between the groups as measured by 2-Deoxy-2-[fluorine-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). We demonstrated that low-dose IL-2 reduced arterial inflammation in patients presenting with ACS. There was a strong correlation between the additive treatment effect of low-dose IL-2 and baseline inflammation. Low-dose IL-2 also increased Tregs and led to the reduction in proinflammatory T effector cells. The treatment was again well tolerated with no severe adverse reactions noted. Graphical summary: IVORY demonstrated a reduction in arterial inflammation in those with residual inflammation post MI despite optimal medical therapy (OMT). Phase III trials are needed to explore if this reduction in arterial inflammation leads to a reduction in MACE. In summary, this thesis brings together concepts of contemporary elements of translational medicine such as drug re-purposing, personalised medicine, and use of surrogate clinical endpoints through the application of imaging biomarkers. This work presents promising data for the safety and anti-inflammatory effect of low-dose IL-2 in ACS. Larger trials are now needed to evaluate its impact on clinical cardiovascular outcomes.","abstract_has_math":false,"creators":["Sriranjan, Rouchelle"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Rudd, James"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-03-31","date_published":"2024-03-31","updated_at":"2026-07-22T22:24:20Z","subjects":["ATHEROSCLEROSIS","CLINICAL TRIALS","INFLAMMATION","RCT","T CELL BIOLOGY"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e5cd9f91-a4b1-42f7-a295-70a397be3fbb/download","http://purl.org/NET/rdflicense/allrightsreserved"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000295151201","0000000322433117"],"render_values":[{"text":"0000-0002-9515-1201","href":"https://orcid.org/0000-0002-9515-1201","code":true},{"text":"0000-0003-2243-3117","href":"https://orcid.org/0000-0003-2243-3117","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.115731","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Rudd, James"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["MEDICAL RESEARCH COUNCIL UK BRITISH HEART FOUNDATION NATIONAL INSTITUTE OF HEALTHCARE RESEARCH"]},{"key":"dc:creator","label":"Author","values":["Sriranjan, Rouchelle"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000295151201","0000000322433117"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2024-03-31"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/379761"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ATHEROSCLEROSIS","CLINICAL TRIALS","INFLAMMATION","RCT","T CELL BIOLOGY"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e5cd9f91-a4b1-42f7-a295-70a397be3fbb/download","http://purl.org/NET/rdflicense/allrightsreserved"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2026-02-11"]},{"key":"dc:rights.embargotype","label":"Dc Rights Embargotype","values":["embargo"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["https://doi.org/10.17863/CAM.115731"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/85b9bfc4-8fb4-43ac-b654-006838268d3f/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The primary aetiology of acute coronary syndromes (ACS) is atherosclerosis. Historically, atherosclerosis was thought to be driven by traditional risk factors, such as hyperlipidaemia. However, we now know that inflammation plays a central role in its pathophysiology. In ACS there is an acute flare of this inflammatory process, and in some individuals, this is followed by a chronic residual inflammatory state. The acute flare causes irreversible damage to the myocardium by leading to larger infarcts and adverse remodelling, and the chronic residual inflammatory state can lead to recurrent cardiovascular (CV) events. Despite advances in the treatment of ACS, recurrent major adverse cardiovascular events (MACE) occur in up to 40-50% of individuals.1-3 Anti-inflammatory agents such as canakinumab and colchicine have improved CV outcomes in patients with ischaemic heart disease (IHD).4 5 However, these have come at a cost due to serious, and at times, fatal, side-effects as a result of immunosuppression. Furthermore, there was no difference in all-cause mortality between treatment agents and placebo. A clinical need exists for a targeted anti-inflammatory therapy in ACS that can immunomodulate without immunosuppression. Regulatory T (Tregs) cells play an important immunomodulatory role in ACS, promoting healing and repair.6 Interleukin 2 (IL-2) is central to Treg cell development and expansion.7 Whilst low-dose IL-2 therapy has been successfully used in autoimmune and inflammatory conditions, its use is currently contraindicated in severe IHD.8 In the LILACS (low-dose interleukin 2 in participants with stable ischaemic heart disease and acute coronary syndromes) trial - part A, patients with IHD received varying doses of low-dose IL-2.9 It was well tolerated and led to an increase in the Treg cell population.10 The work of this thesis involves two trials: The LILACS - part B trial and the IVORY (low-dose interleukin-2 for the reduction of vascular inflammation in acute coronary syndromes) trial.11 Both trials were undertaken in patients presenting with ACS. LILACS was a Phase I/IIa trial, in which low-dose IL-2 was demonstrated to be safe and well tolerated in ACS. It also increased the number of circulating Treg cells in a dose-dependent manner. IVORY was a double-blind, randomised, placebo-controlled, Phase IIb trial. Patients presenting with ACS and high-sensitivity C-reactive protein (hsCRP) levels ≧ 2mg/L were randomised to receive either low-dose IL-2 or placebo. The primary outcome was the difference in arterial inflammation in the index vessel on the follow-up scans between the groups as measured by 2-Deoxy-2-[fluorine-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). We demonstrated that low-dose IL-2 reduced arterial inflammation in patients presenting with ACS. There was a strong correlation between the additive treatment effect of low-dose IL-2 and baseline inflammation. Low-dose IL-2 also increased Tregs and led to the reduction in proinflammatory T effector cells. The treatment was again well tolerated with no severe adverse reactions noted. Graphical summary: IVORY demonstrated a reduction in arterial inflammation in those with residual inflammation post MI despite optimal medical therapy (OMT). Phase III trials are needed to explore if this reduction in arterial inflammation leads to a reduction in MACE. In summary, this thesis brings together concepts of contemporary elements of translational medicine such as drug re-purposing, personalised medicine, and use of surrogate clinical endpoints through the application of imaging biomarkers. This work presents promising data for the safety and anti-inflammatory effect of low-dose IL-2 in ACS. Larger trials are now needed to evaluate its impact on clinical cardiovascular outcomes."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["f39ff482990d67d23072932bfa10e0e9","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Targeting Inflammation in Atherosclerosis: The Role of Low-dose Interleukin 2 in Acute Coronary Syndromes"]}]}],"canonical_facts":{"dc:contributor.advisor":["Rudd, James"],"dc:contributor.sponsor":["MEDICAL RESEARCH COUNCIL UK BRITISH HEART FOUNDATION NATIONAL INSTITUTE OF HEALTHCARE RESEARCH"],"dc:creator":["Sriranjan, Rouchelle"],"dc:creator.authoridentifier":["0000000295151201","0000000322433117"],"dc:date.issued":["2024-03-31"],"dc:description.abstract":["The primary aetiology of acute coronary syndromes (ACS) is atherosclerosis. Historically, atherosclerosis was thought to be driven by traditional risk factors, such as hyperlipidaemia. However, we now know that inflammation plays a central role in its pathophysiology. In ACS there is an acute flare of this inflammatory process, and in some individuals, this is followed by a chronic residual inflammatory state. The acute flare causes irreversible damage to the myocardium by leading to larger infarcts and adverse remodelling, and the chronic residual inflammatory state can lead to recurrent cardiovascular (CV) events. Despite advances in the treatment of ACS, recurrent major adverse cardiovascular events (MACE) occur in up to 40-50% of individuals.1-3 Anti-inflammatory agents such as canakinumab and colchicine have improved CV outcomes in patients with ischaemic heart disease (IHD).4 5 However, these have come at a cost due to serious, and at times, fatal, side-effects as a result of immunosuppression. Furthermore, there was no difference in all-cause mortality between treatment agents and placebo. A clinical need exists for a targeted anti-inflammatory therapy in ACS that can immunomodulate without immunosuppression. Regulatory T (Tregs) cells play an important immunomodulatory role in ACS, promoting healing and repair.6 Interleukin 2 (IL-2) is central to Treg cell development and expansion.7 Whilst low-dose IL-2 therapy has been successfully used in autoimmune and inflammatory conditions, its use is currently contraindicated in severe IHD.8 In the LILACS (low-dose interleukin 2 in participants with stable ischaemic heart disease and acute coronary syndromes) trial - part A, patients with IHD received varying doses of low-dose IL-2.9 It was well tolerated and led to an increase in the Treg cell population.10 The work of this thesis involves two trials: The LILACS - part B trial and the IVORY (low-dose interleukin-2 for the reduction of vascular inflammation in acute coronary syndromes) trial.11 Both trials were undertaken in patients presenting with ACS. LILACS was a Phase I/IIa trial, in which low-dose IL-2 was demonstrated to be safe and well tolerated in ACS. It also increased the number of circulating Treg cells in a dose-dependent manner. IVORY was a double-blind, randomised, placebo-controlled, Phase IIb trial. Patients presenting with ACS and high-sensitivity C-reactive protein (hsCRP) levels ≧ 2mg/L were randomised to receive either low-dose IL-2 or placebo. The primary outcome was the difference in arterial inflammation in the index vessel on the follow-up scans between the groups as measured by 2-Deoxy-2-[fluorine-18] fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). We demonstrated that low-dose IL-2 reduced arterial inflammation in patients presenting with ACS. There was a strong correlation between the additive treatment effect of low-dose IL-2 and baseline inflammation. Low-dose IL-2 also increased Tregs and led to the reduction in proinflammatory T effector cells. The treatment was again well tolerated with no severe adverse reactions noted. Graphical summary: IVORY demonstrated a reduction in arterial inflammation in those with residual inflammation post MI despite optimal medical therapy (OMT). Phase III trials are needed to explore if this reduction in arterial inflammation leads to a reduction in MACE. In summary, this thesis brings together concepts of contemporary elements of translational medicine such as drug re-purposing, personalised medicine, and use of surrogate clinical endpoints through the application of imaging biomarkers. This work presents promising data for the safety and anti-inflammatory effect of low-dose IL-2 in ACS. Larger trials are now needed to evaluate its impact on clinical cardiovascular outcomes."],"dc:format.checksum.md5":["f39ff482990d67d23072932bfa10e0e9","87eda9de84448d1f82354d60eee3eb5f"],"dc:identifier.doi":["https://doi.org/10.17863/CAM.115731"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/85b9bfc4-8fb4-43ac-b654-006838268d3f/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/379761"],"dc:rights":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/e5cd9f91-a4b1-42f7-a295-70a397be3fbb/download","http://purl.org/NET/rdflicense/allrightsreserved"],"dc:rights.embargodate":["2026-02-11"],"dc:rights.embargotype":["embargo"],"dc:subject":["ATHEROSCLEROSIS","CLINICAL TRIALS","INFLAMMATION","RCT","T CELL BIOLOGY"],"dc:title":["Targeting Inflammation in Atherosclerosis: The Role of Low-dose Interleukin 2 in Acute Coronary Syndromes"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:20Z"}