Towards programming immune tolerance through geometric manipulation of phosphatidylserine

Abstract

The possibility of engineering the immune system in a targeted fashion using biomaterials such as nanoparticles has made considerable headway in recent years. However, little is known as to how modulating the spatial presentation of a ligand augments downstream immune responses. In this report we show that geometric manipulation of phosphatidylserine (PS) through fabrication on rod-shaped PLGA nanoparticles robustly dampens inflammatory responses from innate immune cells while promoting T regulatory cell abundance by impeding effector T cell expansion. This response depends on the geometry of PS presentation as both PS liposomes and 1 micron cylindrical PS-PLGA particles are less potent signal inducers than 80 × 320 nm rod-shaped PS-PLGA particles for an equivalent dose of PS. We show that this immune tolerizing effect can be co-opted for therapeutic benefit in a mouse model of multiple sclerosis and an assay of organ rejection using a mixed lymphocyte reaction with primary human immune cells. These data provide evidence that geometric manipulation of a ligand via biomaterials may enable more efficient and tunable programming of cellular signaling networks for therapeutic benefit in a variety of disease states, including autoimmunity and organ rejection, and thus should be an active area of further research.

In vivo reprogramming of immune cells: Technologies for induction of antigen-specific tolerance

“…Lastly, the surface properties of particles such as charge can be modulated to mimic naturally occurring apoptotic bodies (i.e. highly negative) by coating the particle surface with synthetic (poly(ethylenealt-maleic anhydride)) or natural materials (phosphatidylserine) to mediate uptake by cell debris-clearance pathways [74, 75]. …”

Engineering Biomaterials to Direct Innate Immunity

“…[84][85][86] Being able to harness apoptotic cell clearance pathways without the need to use live cells could provide great benefit toward understanding of how tolerance is generated. [80,88] For example, studies by Hess et al revealed that the dose and density at which self-antigen is delivered on QDs correlates with therapeutic efficacy. Studies using antigen coupled particles have already demonstrated efficacy in mouse models using a variety of administration strategies, including subcutaneous injection to target draining LNs, [80] oral administration to target DCs found in the gut, [85] and intravenous injection to target APCs in the liver [84] as well as the spleen.…”

Modulating the immune system through nanotechnology

“…Interestingly, not only the presence of PS, but also its geometrical surface disposition was found to play a role in tolerance induction. For example, Roberts et al observed that PLGA NPs displaying a nanorod-presentation were more efficient at inducing tolerogenic responses than the spherical ones [153]. …”