- Targeting macrophage dynamics to regulate the cardiovascular immune response
- Award date
- 16 January 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
This thesis is aimed at developing and applying macrophage-targeted therapies to modulate inflammatory responses in cardiovascular diseases. To that end, we took advantage of a myeloid cell-specific nanoparticle carrier platform based on high-density lipoprotein (HDL), for the purpose of selectively delivering therapeutic compounds to macrophages. The HDL nanoparticle platform simultaneously allows decreasing systemic exposure to the (immunomodulatory) drug, while directly engaging to the target cell population.
We focus on (imaging-guided) HDL nanoimmunotherapies in two different disease models, namely atherosclerosis and heart transplantation. Atherosclerosis is a chronic low-grade inflammatory disease in which macrophage inflammation drives disease progression. In solid organ transplantation, organ rejection is the cause of an acute inflammatory response.
We first describe the development of a novel CD40-TRAF6 signaling inhibitor and its nanotherapeutic implementation in a mouse model of atherosclerosis. Next we focussed on the inhibition of mTOR, a central regulator of cell metabolism, by use of a rapamycin based nanotherapeutic. These therapies led to a decrease in the number macrophages within the atherosclerotic plaque, reducing plaque inflammation.
Finally, we focus on the concept of macrophage-related ‘trained immunity’ in a mouse model of heart transplantation. Trained immunity is a recently discovered de facto innate immune memory, which is epigenetically regulated. While the current therapies for immune regulation in the field of transplantation are based on T cell tolerance, our nanoimmunotherapy relies on a yet unexplored macrophage-mediated mechanism. Here, we aim to increase the graft acceptance rate, by combining the inhibition of mTOR signaling with the inhibition of CD40-TRAF6 signaling.
Thesis (complete) (Embargo up to and including 16 January 2020)
Chapter 3: High density lipoprotein nanobiologics for precision medicine (Embargo up to and including 16 January 2019)
Chapter 4: TRAF-STOPping atherosclerosis: targeting of CD40-induced TRAF6 signaling in macrophages reduces (established) atherosclerosis (Embargo up to and including 16 January 2019)
Chapter 5: Multiparametric assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates (Embargo up to and including 16 January 2020)
Chapter 6: Targeting mTOR - S6K1 signaling inhibits macrophage activity and self-renewal in atherosclerosis (Embargo up to and including 16 January 2019)
Chapter 7: Targeting trained immunity promotes heart transplant acceptance (Embargo up to and including 16 January 2019)
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