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. 2015 Dec:72:1-10.
doi: 10.1016/j.biomaterials.2015.08.040. Epub 2015 Aug 20.

Towards programming immune tolerance through geometric manipulation of phosphatidylserine

Reid A Roberts #  1   2 , Timothy K Eitas #  1 , James D Byrne #  3   2 , Brandon M Johnson  1 , Patrick J Short  4 , Karen P McKinnon  1 , Shannon Reisdorf  1 , J Christopher Luft  3 , Joseph M DeSimone  3   4   5   6   7 , Jenny P Ting  1   8   9   10
Affiliations

Towards programming immune tolerance through geometric manipulation of phosphatidylserine

Reid A Roberts et al. Biomaterials. 2015 Dec.

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.

Keywords: Autoimmunity; Immunoengineering; Immunomodulation; Nanoparticles; PLGA; PRINT; Phosphatidylserine; Tolerance; Transplantation.

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Figures

Fig. 1
Fig. 1
SEM images of PRINT particles. A. Blank and PS-loaded 80 × 320 nm nanorods. B. Blank and PS-loaded 1 micron cylinders.
Fig. 2
Fig. 2
PS nanorods downregulate inflammatory responses in dendritic cells. A. ELISA analysis of IL-6 (left) and IL-12(p40) (right) in DC cultures stimulated with LPS(10 ng/ml) and IFNγ(10 ng/ml) for 18 h. PS was dosed at 25 μM in either liposomal (PS LIPO) or 80 × 20 nm nanorod formulation (PS Nanorod). Blank 80 × 320 nm PLGA particles (BLK PRINT) were used as a negative control. B. Flow cytometry-based histogram analysis of surface expression of CD86. Cells were initially gated as CD11c+. MFI represents Mean Fluorescent Intensity. Results are representative of three independent experiments. Error bars represent ± s.e.m. * = P < .0001.
Fig. 3
Fig. 3
Geometric manipulation of PS downregulates myelin-specific T cell activation and cytokine responses. A. ELISA analysis of 2D2 Tg CD4+ T cells activated with MOG35–55-pulsed DCs. Supernatants were collected 48 hpi. PS doses ranged from 12.5 to 50 μM in either liposomal (PS LIPO) or 80 × 20 nm nanorod formulation (PS Nanorod). B. Left, contour plot depicting intracellular flow cytometry-based of IL-10+, FoxP3+ population. Right, quantification of IL-10+, FoxP3+ cell population. Cells were initially gated as CD3+. C. ELISA analysis of 2D2 Tg CD4+ T cells activated with MOG35–55-pulsed DCs. Supernatants were collected 48 hpi. PS doses ranged from 12.5 to 50 μM in liposomal, 80 × 320 nm PLGA nanorod or 1 μm PLGA cylinder formulations. Results are representative of three independent experiments. Error bars represent ± s.e.m. * = P < .05; ** = P < .01; *** = P < .001; *** = P <.0001.
Fig. 4
Fig. 4
PS Nanorods suppress autoimmune responses in vivo. A. Clinical scores of mice treated as indicated. Scores represent the combination of two independent experiments of 5–6 mice per group. Mice were intravenously treated with 50 μg of liposomal PS (PS LIPO), 50 μg of PS on 80 × 320 nm PLGA nanorods (PS Nanorod), or an equivalent dose of Blank PLGA particles (BLK PRINT) at times indicated by arrows. B. Table depicting disease incidence, day on onset, and maximum score of mice depicted in panel A.
Fig. 5
Fig. 5
PS Nanorods are efficacious in reducing the activation of human immune cells. A. CFSE dilution analysis of allogenic human CD4+ T cell activation 7 days post activation. B. ELISA analysis of allogenic CD4+ T cell activation. Supernatants were collected 7 days post activation. Results are representative of two independent experiments with four CD4+ T cell donors and two DC donors. Cells were initially gated as CD3+. Error bars represent ± s.e.m. * = P < .05.
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