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(2022) Bello, IdrisThesisThe inflammatory artery diseases atherosclerosis and abdominal aortic aneurysm (AAA) are major causes of morbidity and mortality and there is significant attention towards identifying and targeting prominent inflammatory mediators underpinning these cardiovascular diseases. In the first chapter, the role of the pro-inflammatory and pro-oxidant enzyme myeloperoxidase (MPO) in inflammatory artery disease was studied. A clinical study showed that while circulating plasma MPO levels were not different in AAA patients versus healthy controls, immunohistochemistry showed that the MPO protein was prevalent in human AAA tissue. In the angiotensin II (AngII)-infusion model of AAA and atherosclerosis in apolipoprotein-E gene-deficient (ApoE–/–) mice, administration of 2-thioxanthines (2-TX), a clinically-trialled MPO inhibitor, significantly inhibited AAA but not atherosclerosis. Paradoxically, MPO gene-deficiency did not affect AngII-induced AAA but attenuated atherosclerosis. Notably, 2-TX significantly inhibited AAA in ApoE–/–MPO–/– mice, indicating 2-TX protects against aortic disease in the absence of MPO. The role of MPO in the diabetes-accelerated atherosclerosis in ApoE–/– mice was also examined. While MPO gene-deficiency did not impact on the degree of diabetes it significantly reduced diabetes-accelerated atherosclerosis at the brachiocephalic artery and aortic sinus, but not aortic arch, indicating that MPO exhibits site-specific effect on atherosclerosis. A second chapter focused on semicarbizide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a pro-inflammatory enzyme that facilitates the vascular recruitment of activated leukocytes. Treatment of AngII-infused ApoE–/– mice with a clinically-viable SSAO/VAP-1 inhibitor significantly protected against AAA and atherosclerosis, independent of alterations to plasma lipid levels. A third chapter tested the therapeutic efficacy of apolipoprotein A-I (ApoA-I), the major cardioprotective protein in high-density lipoproteins, and a class of immunomodulatory nanoparticles (INPs), which selectively target and disable a pro-inflammatory monocyte subset. Although ApoA-I treatment did not impact on the development of arterial disease in AngII-infused, aged ApoE–/– mice, INPs provided significant protection against AAA and atherosclerosis in these mice. This novel research provides new insights on the roles of MPO and SSAO in AAA and atherosclerosis and identified clinically-viable inhibitors of MPO and SSAO and a class of biodegradable immunomodulatory nanoparticles as potential new therapeutics for treating inflammatory artery disease.
Copper chelation overcomes the immunosuppressive neuroblastoma tumour microenvironment to enhance anti-GD2 immunotherapy(2024) Rouaen, JourdinThesisAnti-GD2 immunotherapy has significantly enhanced survival of high-risk neuroblastoma patients however efficacy is strongly hampered by the immunosuppressive tumour microenvironment. Given the emerging link between copper and immune evasion, we assessed the impact of copper chelation therapy on neuroblastoma using the agents tetraethylenepentamine (TEPA) and the clinically approved analogue triethylenetetramine (TETA; marketed as Cuprior®). Using the preclinical TH-MYCN model, we performed single-cell RNA sequencing supported by OPAL multiplex immunohistochemistry and cytokine profiling to assess cellular and molecular changes occurring with TEPA treatment in the neuroblastoma tumour microenvironment. Copper chelation was observed to successfully deplete intratumoural copper to reinvigorate anti-tumour immunity as signalled by increased infiltration and activity of pro-inflammatory immune cells, specifically N1 neutrophils. Mechanistic in vitro assays reveal sequestration of copper by neuroblastoma cells causing dysregulated neutrophil function, with successful reversal upon TEPA treatment. Findings propose a novel mechanism of immune evasion, highlighting copper chelation as a therapeutic strategy to counteract immunosuppression. Copper chelation is further shown to increase GD2 expression, while also enhancing neutrophil antibody-dependent cellular cytotoxicity in vitro. Using the TH-MYCN model, TEPA was found to potentiate anti-GD2 therapy to achieve durable tumour control. This was associated with increased Fc-receptor-bearing natural killer and CD11B+ myeloid cells capable of performing antibody-dependent cellular cytotoxicity. Finally, we evaluated TETA for repurposing as a novel immunomodulatory agent. Comparative in vitro studies with TEPA confirm the ability of TETA to deplete intratumoural copper and downregulate immune checkpoint proteins Programmed Death-Ligand 1 (PD-L1) and indoleamine-pyrrole 2,3-dioxygenase (IDO). Using the preclinical NXS2 model, TETA exhibited an exceptional safety profile without altering copper levels or GD2 expression in healthy nerve tissue. Combination with anti-GD2 therapy achieved durable tumour control with no relapses occurring after treatment cessation and was similarly associated with infiltration of pro-inflammatory immune cells. Collectively, study findings credential copper chelation as a non-toxic strategy to overcome the immunosuppressive tumour microenvironment and improve neuroblastoma patient outcomes.