Glycosylated nanostructures in sublingual immunotherapy induce long-lasting tolerance in LTP allergy mouse model

Abstract

An effective specific immunotherapy should contain elements to generate specific recognition (T-cell peptides) and to modulate the immunological response towards a Th1/Treg pattern by enhancing dendritic cells (DCs). We propose a novel sublingual immunotherapy for peach allergy, using systems, that combine Prup3-T-cell peptides with mannose dendrons (D1ManPrup3 and D4ManPrup3). Peach anaphylactic mice were treated 1, 2 and 5 nM concentrations. Tolerance was assessed one/five weeks after finishing treatment by determining in vivo/in vitro parameters after challenge with Prup3. Only mice receiving D1ManPrup3 at 2 nM were protected from anaphylaxis (no temperature changes, decrease in Prup3-sIgE and -sIgG1 antibody levels, and secreting cells) compared to PBS-treated mice. Moreover, an increase of Treg-cells and regulatory cytokines (IL-10+/IFN-γ+) in CD4+-T-cells and DCs were found. These changes were maintained at least five weeks after stopping treatment. D1ManPrup3 is an effective new approach of immunotherapy inducing protection from anaphylaxis which persists after finishing treatment.

Pru p 3‐Glycodendropeptides Based on Mannoses Promote Changes in the Immunological Properties of Dendritic and T‐Cells from LTP‐Allergic Patients

“…On the contrary, D 1 ManPrup3 does not show this capacity, inducing instead a reduced allergic response. This is in accordance with our previous studies using D 4 Prup3 and D 4 ManPrup3 …”

“…Our data suggest that the upregulation of CCR7 is necessary for full DC maturation, which will induce specific T‐cell proliferation, as has been demonstrated in other in vitro studies . Moreover, these results are associated with specific patterns of Th1/Th2 cytokine production, in agreement with a previous study from our group …”

“…The group treated with D 1 ManPrup3, was protected from anaphylaxis, as determined by both in vivo (no temperature changes or symptoms) and in vitro parameters (decreased Prup3‐sIgE and ‐sIgG1 antibody levels/secreting cells; increased Treg cells and IFN‐γ/IL‐10 cytokines). These changes were persisted during 5 weeks after stopping treatment . Whether these results can be produced in humans must be evaluated further; however, before this it is necessary to assess the immunological response to these structures using immune cells from LTP‐allergic patients.…”

“…This includes Pru p 3 T‐cell peptides and mannose molecules attached to a base structure, as shown in Figure , using either ester or ether linkers. The syntheses of the dendropeptides (DPs) without mannose (D 1 Prup3 and D 4 Prup3) and GDPs with mannose (D 1 ManPrup3 or D 4 ManPrup3) ester linkers have been published . The sequence of the Pru p 3 peptides was ASSNGIRNVNNLARTPDRQAC, based on the 26–46 region of Pru p 3, with some modifications: Cys residues at positions 27–28 replaced by Ser and with a C‐terminal non‐native Cys residue to allow conjugation to the mono‐ and tetravalent systems via a thiol‐ene click chemistry reaction.…”

“…This was confirmed by lack of change in temperature upon challenge, accompanied by a decrease in Pru p 3‐sIgE and ‐sIgG1 antibody levels and secreting cells, and an increase of Treg cells and regulatory cytokines in treated animals compared to anaphylactic animals. Moreover, these changes were maintained for at least 5 weeks after the treatment ended . However, there are no published data regarding the effects and recognition capacity of these structures on cells from LTP‐allergic patients, or how the linkers used for mannose inclusion affect this recognition.…”