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The goal of this clinical trail is to compare the differences in carotid plaque Treg cells' gene signature for activation, proliferation, and suppressive function using scRNA-seq in patients treated with IL-2 compared to control.
Up till now our Lab has looked at Tregs and immune cells in the blood. The question remains whether low dose IL-2 can have the desired effect on Tregs in atherosclerotic plaques where they could alter the pathophysiology and potentially clinical outcomes for patients.
Up until recently, the cellular composition and cell-specific expression patterns of human atherosclerotic plaques remained elusive. However, recent breakthroughs studies using scRNA-seq, CITE-seq, and single-cell ATAC-seq on human carotid plaques have offered important insight into plaque composition, cell heterogeneity, and cell-cell interactions giving new perspectives on mechanisms of disease. The next logical stage is to use this new insight and powerful biological tool to assist in drug development for patients.
Therefore, the aims of the study are:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low dose interleukin-2 | Experimental | Commercially available aldesleukin with a UK marketing authorisation will be used and will be initially prepared as per SmPC. |
|
| Control | Active Comparator | Standard of care treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Interleukin-2 [IL-2] | Drug | 5 sequential days of treatment (1.5MIU/day subcutaneously) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Difference in gene expression in Tregs | Comparing differential gene expression using scRNA-seq technologies, from isolated Tregs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score) | Time of surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in gene expression in Teff cells. | Comparing differential gene expression using scRNA-seq technologies, from isolated Teffs from carotid plaques from the two patient groups (IL-2 treatment and control). Differential gene expression will be assessed using standard techniques (Z-Score) | Time of surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Other immune cell and vascular smooth muscle cell gene expression | As per primary outcome measure but in immune cells and vascular smooth muscle cells (excluding Treg & Teff cells). Differential gene expression will be assessed using standard techniques (Z-Score) | Time of surgery |
| Ligand-receptor interactions. |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Addenbrookes Hospital | Cambridge | Cambridgeshire | CB2 0QQ | United Kingdom |
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Analysis blinded
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| Standard care - Carotid Endarterectomy | Procedure | Standard care for patients with carotid stenosis undergoing carotid endarterectomy |
|
| Immune cell gene signature, in plaque and blood. |
Difference in immune cell gene signature will be compared using scRNA-seq in both plaque and blood samples, and further compared between IL-2 and control groups. Comparative analysis will be completed using gene set enrichment analysis (Enrichment Score). |
| Time of surgery |
| Difference in gene expression patterns in Treg & Teff cells. | Comparison between Treg and Teff cells collected at baseline and day of surgery will be compared between IL-2 and control groups. Differential gene expression will be assessed using standard techniques (Z-Score) | Baseline and at time of surgery |
Differential regulation of ligand-receptor interactions between control and IL-2 treated cells will be identified by comparing single-cell/single-cell ligand-receptor interaction scores for the two groups. This measure is descriptive in nature. |
| Time of surgery |
| T-Cell receptor profile | Difference in TCR clonality in plaques between the two groups will be assessed from clonotypes based on identical V-J gene usage and identical CDR3 junctions. | Time of surgery |
| Inflammatory pathway activation. | Activation of inflammatory pathways both at plaque and systemic level. Assess for enrichment of genes involved in inflammatory pathways - enrichment score. | Time of surgery |
| ID | Term |
|---|---|
| D016893 | Carotid Stenosis |
| D002340 | Carotid Artery Diseases |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D007376 | Interleukin-2 |
| ID | Term |
|---|---|
| D007378 | Interleukins |
| D016207 | Cytokines |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008222 | Lymphokines |
| D011506 | Proteins |
| D001685 | Biological Factors |
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