Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4+ and CD8+ T Cells

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.

Biomaterial-enhanced treg cell immunotherapy: A promising approach for transplant medicine and autoimmune disease treatment

“…This led to an increase in the ratio of Foxp3+/CD4+ Tregs to IFN-γ+ T cells and provided protection against T1D in mice [ 95 ]. Similar approaches were also utilized for diabetogenic peptides conjugated on ECDI-PLGA microparticles, yielding similar results [ 96 , 97 ].…”

“…To maximize the effectiveness of Treg immunotherapy, it is imperative that these cells successfully migrate to specific target tissues, maintain stability within local organs, enhance their suppressive capabilities, and ensure their continued survival while fulfilling their intended functions [ 194 , 195 ]. In pursuit of these objectives, the use of biomaterials emerges as a compelling and supportive strategy for augmenting Treg immunotherapy and addressing these formidable challenges [ 73 , 74 , 76 , 78 , 81 , 83 , 84 , 91 , 96 , 108 ]. As a result, the prospect of employing biomaterial-enhanced Treg immunotherapy holds tremendous promise as a treatment option for patients undergoing organ transplants and those grappling with autoimmune diseases in the near future.…”

“…Treating mice with EAE and T1D using these tolerogenic nanoparticles resulted in a decrease in the ability of effector T cells to produce pro-inflammatory cytokines, leading to anergy. This approach also increased the population of Foxp3+ Tregs, ultimately preventing diabetes [ [95] , [96] , [97] ] and relapsing EAE [ 93 , 96 ] in the mouse models.…”

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

“…Multiple groups have developed carboxylated PLG polymer NPs loaded with antigens relevant to autoimmunity including T1D, EAE, and model antigens. [147][148][149][150] Over several published studies, the authors have demonstrated that these NPs are able to induce T REG induction and protect against disease in an IL-10 and T REG dependent manner. In recent work, the authors also demonstrated that these particle constructs modulated CD8 responses as well-highlighting the multipronged nature of induced tolerance.…”

Antigen‐specific mRNA lipid nanoparticle platforms for the prevention and treatment of allergy and autoimmune diseases

“…[23][24][25] Different NPs have been used for this purpose; for example, biodegradable PLGA NPs loaded with proteins, peptide antigens, epitopes, or rapamycin (a tolerogenic immunomodulator) can generate antigen-specific immune tolerance in mice with encephalomyelitis, peanut allergy, or OVA-induced anaphylaxis by promoting the differentiation of naïve T cells into antigen-specific Tregs. [26][27][28][29][30] In addition to PLGA, a safe fusion peptide carrier made of a nucleic acid-gold NP conjugate containing siRNA has been used to treat psoriasis, as reported by Nemati et al [31] This fusion peptide carrier enhanced the delivery and gene silencing of siRNA in cells and skin, thereby reducing the gene expression and activity of T cells that cause psoriasislike skin lesions.…”