APC targeting
Tolerogenics PhagoAttract technology
“Find-me” molecules
“Find-me” signals arereleased from apoptotic cells to attract phagocytes including antigen-presenting cells (APCs) to the site of apoptotic cell death.
Several “find-me” signals have been identified such as fractalkine (chemokine CXC3CL1), lysophosphatidylcholine (LPC), sphingosine-1-phosphate (S1P) and the nucleotides ATP and UTP. These “find-me” signalsare regognized by corresponding receptors on the surface of phagocytes.
Concentration effect of ATP and UTP
Using a transwell migration assay, ATP and UTP have been demonstrated to effect maximal migration of phagocytes at a concentration of about 100 nM (Elliott et al. 2009, Nature 461:282-286). Both nucleotides act as non-redundent “find-me” signals.
In contrast, at concentrations of more than 1 µM ATP exerts pro-inflammatory effects since concentrations in this range are generated by necrotic cells (Kono and Rock 2008, Nature Rev. Immunol. 8:279-289).
Chemotactic gradients of “find-me” molecules
Phagocytes are extremely efficient in sensing and detecting apoptotic cells due to the sustained release of “find-me” molecules which generate a chemotactic gradient (for a review, see Ravichandran 2011, Immunity 35:445-455).
Nucleotide release from hydrogels
The hydrogel technology of Tolerogenics allows a sustained release of embedded nucleotides over a period of at least 2 days (Tolerogenics PhagoAttract technology). After a diffusion-based initial burst during the first hours, the sustained release of embedded nucleotides generates a chemotactic gradient that mimics the release of nucleotides from apoptotic cells. As a result, APCs are attracted to the hydrogel-embedded components including allergens or autoantigens and tolerance-promoting adjuvants are most efficiently phagocytosed by the attracted APCs.
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