Abstract
Current treatments for autoimmune disorders rely on non-specific immunomodulatory and global immunosuppressive drugs, which show a variable degree of efficiency and are often accompanied by side effects. In contrast, strategies aiming at inducing antigen-specific tolerance promise an exclusive specificity of the immunomodulation. However, although successful in experimental models, peptide-based tolerogenic “inverse” vaccines have largely failed to show efficacy in clinical trials. Recent studies showed that repetitive T cell epitopes, coupling of peptides to autologous cells, or peptides coupled to nanoparticles can improve the tolerogenic efficacy of peptides, suggesting that size and biophysical properties of antigen constructs affect the induction of tolerance. As these materials bear hurdles with respect to preparation or regulatory aspects, we wondered whether conjugation of peptides to the well-established and clinically proven synthetic material polyethylene glycol (PEG) might also work. We here coupled the T cell epitope OVA323–339 to polyethylene glycols of different size and structure and tested the impact of these nano-sized constructs on regulatory (Treg) and effector T cells in the DO11.10 adoptive transfer mouse model. Systemic vaccination with PEGylated peptides resulted in highly increased frequencies of Foxp3+ Tregs and reduced frequencies of antigen-specific T cells producing pro-inflammatory TNF compared to vaccination with the native peptide. PEGylation was found to extend the bioavailability of the model peptide. Both tolerogenicity and bioavailability were dependent on PEG size and structure. In conclusion, PEGylation of antigenic peptides is an effective and feasible strategy to improve Treg-inducing, peptide-based vaccines with potential use for the treatment of autoimmune diseases, allergies, and transplant rejection.
Highlights
The limited efficacy and increased risk of opportunistic infection associated with classical immunosuppressants or modern biologics still represent a challenge in the therapy of immunemediated diseases such as autoimmunity, allergy, and transplant rejection
In order to test whether T cell stimulation capacity is preserved after conjugation to different polyethylene glycol (PEG) carriers, the model peptide ovalbumin peptide 323–339 was either monovalently conjugated to linear PEG molecules [PEG20 (20 kDa) or PEG40
DO11.10 mice were cultured with irradiated antigen-presenting cells (APCs) (1:3) for four days. pOVA and equimolar amounts of pOVA-PEG conjugates were added as indicated
Summary
The limited efficacy and increased risk of opportunistic infection associated with classical immunosuppressants or modern biologics still represent a challenge in the therapy of immunemediated diseases such as autoimmunity, allergy, and transplant rejection. Numerous studies have demonstrated that the administration of soluble antigens or immunodominant peptides under noninflammatory conditions can induce a state of unresponsiveness. Induction of anergy, or modification in the cytokine profile of pro-inflammatory effector cells and, notably, induction and expansion of regulatory T cells (Tregs) were discussed as possible mechanisms in induced tolerance [3,4,5,6,7,8]. Tregs play a pivotal role in maintaining selftolerance and in modulating immune responses in inflammatory diseases. Foxp3+ Tregs are generated either as a distinct lineage in the thymus during T cell development (tTregs) or in the periphery by conversion of conventional naive Foxp3- T cells (pTregs) upon antigen exposure [9]
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