PS-liposomes as tolerance-promoting adjuvant
Tolerogenics ToleroLiposphere technology
Apoptosis and immune tolerance
Tolerogenics S.à.r.l. is adapting a natural mechanism for the induction of immune tolerance. When cells die, which is a common process in development and maintenance of the organism, they undergo a process of programmed cell death, called apoptosis.
During this process certain changes in the cellular structure occur. One is the presentation of phosphatidylserine (PS) on the outer surface of the cell membrane. In viable cells this lipid is actively transported to the inner membrane and not exposed on the surface.
PS-receptors
Antigen-presenting cells (APC) are able to recognize surface-exposed PS with several different receptors (see Armstrong and Ravichandran 2011, EMBO rep 12:287-8; Brown and Neher 2014, Nat Rev Neurosci 15:209-16). PS is the main “eat-me” signal for APC. Interaction of PS with these receptors initiates a signal cascade which drives the cell towards a tolerogenic type. This is important, because under healthy conditions the cell is displaying self-antigens and the immune system needs to act tolerant and not inflammatory.
Phagocytosis of apoptotic cells by APC
When apoptosis is proceeding, the cell gets fragmented into smaller particles which are removed by internalization (phagocytosis) by specialized scavenger cells (phagocytes) like macrophages or dendritic cells. Proteins of the phagocytosed cells are processed and displayed as peptides on MHC-receptors on the surface of these phagocytes, which are designated as antigen-presenting cells (APC). Interaction of T-cells with these loaded MHC-receptors provide the basis for tolerance towards self-proteins.
PS-liposomes mimic apoptotic cells
PS-liposomes mimic apoptotic cell fragments and several experimental studies have demonstrated that PS-liposones provide tolerance-promoting effects (Hoffman et al 2005).
As demonstrated in recent study using a rat model of acute myocardial infarction intravenoues injection of PS-liposomes induced in macrophages secretion of the anti-inflammatory cytokines TGF-β and IL-10, commitant with down-regulation of pro-inflammatory markers such as TNFα and the surface marker CD86, a protein expressed on antigen-presenting cells that provides co-stimulatory signals necessary for T cell activation and survival (Harel-Adar et al. 2011, Proc. Natl. Acad. Sci. USA 108:1827-32).
PS-liposome technology of Tolerogenics
Tolerogenics S.à.r.l. utilizes hydrogel-embedded PS-liposomes. This technology provides a sustained release of embedded PS-liposomes over a time period of at least 3 days, enabling high local concentration and efficient interaction with peripheral APCs, including dendritic cells and macrophages.
By combination of hydrogelembedded PS-liposomes with hydroge-embedded allergens or autoantigen, the sustained release of both components allows efficient tolorogenic priming of allergen/autoantigen-specific APCs and susequent enhancement of tolerance-promoting Tregs.
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