Phosphatidylserine-mediated Oral Tolerance

Elsevier

Available online 24 December 2022, 104660

Cellular ImmunologyAuthor links open overlay panelAbstract

Phosphatidylserine (PS) is an anionic phospholipid exposed on the surface of apoptotic cells. The exposure of PS typically recruits and signals phagocytes to engulf and silently clear these dying cells to maintain tolerance via immunological ignorance. However, recent and emerging evidence has demonstrated that PS converts an “immunogen” into a “tolerogen”, and PS exposure on the surface of cells or vesicles actively promotes a tolerogenic environment. This tolerogenic property depends on the biophysical characteristics of PS-containing vesicles, including PS density on the particle surface to effectively engage tolerogenic receptors, such as TIM-4, which is exclusively expressed on the surface of antigen-presenting cells. We harnessed the cellular and molecular mechanistic insight of PS-mediated immune regulation to design an effective oral tolerance approach. This immunotherapy has been shown to prevent/reduce immune response against life-saving protein-based therapies, food allergens, autoantigens, and the antigenic viral capsid peptide commonly used in gene therapy, suggesting a broad spectrum of potential clinical applications. Given the good safety profile of PS together with the ease of administration, oral tolerance achieved with PS-based nanoparticles has a very promising therapeutic impact.

Section snippetsIntroduction - Phosphatidylserine

Phosphatidylserine (PS) is an anionic phospholipid expressed abundantly on the eukaryotic plasma cell membrane and plays multiple important roles in biological processes, including thrombin generation, apoptosis, complement system activation, and virus entry.[1] PS is most commonly known for its role in apoptosis, which is a programmed biological process to eliminate unwanted, aged, or damaged cells in a non-inflammatory manner to maintain tissue homeostasis. The role of PS in apoptosis was

PS Is Not a Clean-up Crew but a Well-meaning Teacher

Although apoptosis is traditionally regarded as a silent event to clear apoptotic cells without the initiation of immune responses to maintain tissue homeostasis, recent evidence from our group demonstrated that PS-mediated cellular uptake is an active teaching process to induce peripheral tolerance towards self and foreign antigens.[8], [9], [10], [11], [12] The use of nanoparticles made of PS (containing a serine head group connected to two fatty acyl chains, referred to as double-chain PS)

PS Receptors in Immune Regulation

Several PS receptors on the surface of phagocytic cells responsible for PS recognition, binding, and subsequent cellular signaling have been identified. Among these receptors, transmembrane immunoglobulin and mucin domain (TIM) receptor and trio receptors Tyro3, Axl, and Mer (TAM) are shown to participate in PS-mediated immune regulation. TAM receptors are primarily expressed on the surface of antigen-presenting cells (APCs) such as macrophages, DCs, and natural killer cells.[13] The roles of

PS-mediated Oral Tolerance

The use of nanoparticles containing double-chain PS have been successful in reducing immune responses when given via parenteral route of administration. However, to further optimize the tolerogenic potential of this nanoparticle platform and to expand its clinical utilities to provide ease of administration to a broader range of patients, including pediatrics, several approaches were investigated, including switching to the oral route of administration and modifying the structural properties of

Structural and Biophysical Characteristics of PS-based Nanoparticles

While the common structure of PS primarily consists of a serine headgroup connected to two fatty acid acyl chains by a glycerol molecule (double-chain PS), several derivatives of PS can exist, which differ in the acyl chain length, number of acyl chains, and degree of unsaturation. These structural modifications can influence the biological functions of PS, as not all PS exposure leads to the same biological outcome.[1] Although TIM-4 receptor is essential for PS-mediated tolerance induction,[8]

Oral tolerance

The oral route of administration has been extensively studied for its ability to induce antigen-specific tolerance. Under the high antigen pressure that our guts encounter daily, the intestinal immune system has naturally evolved as a tightly regulated tolerance-induction site and anti-inflammatory environment, which helps tolerate harmless food antigens and commensal bacteria while still protecting the gut from pathogens.[19], [20] By delivering Lyso-PS nanoparticles via the oral route, we aim

Oral Tolerance Induced by Lyso-PS Nanoparticles

Differential Uptake of PS-based Nanoparticles following Oral Administration

Because Lyso-PS nanoparticles are stable in the harsh environment of the GI tract, they can be administered orally to target GALT for tolerance induction.[18] Although nanoparticles containing double-chain PS display similar stability in the GI tract following oral administration, single-chain Lyso-PS nanoparticles are transported more efficiently by M cells across the mucosal barrier than double-chain PS nanoparticles.

Oral Tolerance towards FVIII in HA Mouse Model

The oral tolerance induction potential of Lyso-PS nanoparticles was first observed with recombinant FVIII used in the treatment of HA, which is an inherited bleeding disorder caused by the lack of functional FVIII production. About 30% of the patients with severe HA develop inhibitory anti-FVIII antibodies, referred to as inhibitors, against the first-line treatment with recombinant FVIII.[39], [40], [41], [42] In patients with high responding inhibitory titers, effective clinical options often

Proposed Mechanism of Lyso-PS-mediated Oral Tolerance

The proposed mechanism of oral tolerance induced by Lyso-PS nanoparticles is still under extensive investigation and our speculations are portrayed in Figure 3. Following oral administration, Lyso-PS nanoparticles distribute throughout the GI tract and gain entry into the LP (1) through intact enterocytes and (2) by M cells. Due to their small size, Lyso-PS nanoparticles carrying antigens can travel across the enterocytes via passive phagocytosis.[61] M cells on Peyer’s patches also act as a

Conclusions

With unique biophysical characteristics, Lyso-PS nanoparticles display distinctive tolerogenic properties to induce effective oral tolerance via the generation of antigen-specific Tregs. Based on the rationale that pre-exposing a protein in the context of PS-based nanoparticles induces tolerance and blocks the patients’ immune response towards that protein prior to the initiation of the therapy, this approach stands as an encouraging supplement replacement therapy during the initial exposures

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

This work was funded by the National Institutes of Health R01 grant HL-70227 (SVB) and AI-169296 (SVB - MPI). We are grateful for the use of shared instruments provided by the Pharmaceutical Sciences Instrumentation Facility, University at Buffalo, State University of New York. Flow cytometry services were provided by the Optical Imaging and Analysis Facility in the School of Dental Medicine, University at Buffalo, The State University of New York. Figure 3 was created using BioRender.com.

Declaration of Competing Interest

The authors declare no known conflicts of interest.

Author Contributions

NHN, VC, and SVB wrote and edited the manuscript. All authors read and approved the manuscript.

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