Abstract
We have shown that PLG nanoparticles loaded with peptide antigen can reduce disease in animal models of autoimmunity and in a phase 1/2a clinical trial in celiac patients. Clarifying the mechanisms by which antigen-loaded nanoparticles establish tolerance is key to further adapting them to clinical use. The mechanisms underlying tolerance induction include the expansion of antigen-specific CD4+ regulatory T cells and sequestration of autoreactive cells in the spleen. In this study, we employed nanoparticles loaded with two model peptides, GP33–41 (a CD8 T cell epitope derived from lymphocytic choriomeningitis virus) and OVA323–339 (a CD4 T cell epitope derived from ovalbumin), to modulate the CD8+ and CD4+ T cells from two transgenic mouse strains, P14 and DO11.10, respectively. Firstly, it was found that the injection of P14 mice with particles bearing the MHC I-restricted GP33–41 peptide resulted in the expansion of CD8+ T cells with a regulatory cell phenotype. This correlated with reduced CD4+ T cell viability in ex vivo co-cultures. Secondly, both nanoparticle types were able to sequester transgenic T cells in secondary lymphoid tissue. Flow cytometric analyses showed a reduction in the surface expression of chemokine receptors. Such an effect was more prominently observed in the CD4+ cells rather than the CD8+ cells.
Highlights
Introduction published maps and institutional affilPolymer-based nanoparticles are being explored as platforms for immunotherapy.Examples include treatment for type 1 diabetes (T1D) [1], other forms of antigen-specific therapy [2], and as cancer vaccines [3,4]
We have reported that tolerance can be induced in non-obese diabetic (NOD).scid mice that receive transgenic diabetogenic CD8+ NY8.3 T cells by using particles encapsulating the IGRP mimotope peptide NRP-A7, suggesting that Ag-PLG nanoparticles are able to expand CD8+ Tregs [6]
Cells 2021, 10, 3445 reported in a recent phase two trial in patients at risk for development of T1D following treatment with teplizumab [27]. We demonstrate that both CD8+ P14 (GP33–41 -specific) and CD4+ DO11.10 (OVA323–339 -specific) transgenic T cells are sequestered in secondary lymphoid tissue following treatment with PLG nanoparticles loaded with their respective cognate antigen
Summary
LCMV GP33–41 (KAVYNFATM) (referred to as GP33) was purchased from Anaspec (Fremont, CA, USA). OVA323–339 (ISQAVHAAHAEINEAGR) (referred to as OVA323) and. Institute Peptide Synthesis Core (Chicago, IL, USA). MOG35–55 (MEVGWYRSPFSRVVHLYRNGK) (referred to as MOG35) was purchased from Genemed Synthesis
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