P-FN12, an H4R-Based Epitope Vaccine Screened by Phage Display, Regulates the Th1/Th2 Balance in Rat Allergic Rhinitis

Yuqian Wang,Jichao Sha,Heng Wang,Lifeng An,Tie Liu,Lin Li

doi:10.1016/j.omtm.2018.09.004

Abstract

Allergic rhinitis (AR) involves antigen-specific immune-inflammation of the nasal mucosa. Classical therapy for AR targets the histamine pathway, e.g., histamine receptor blockers. Histamine H4 receptor (H4R) was suggested as a novel therapeutic target due to its wide expression on almost all immune-related cells. A 12-mer random peptide library was used to select the specific epitope of the H4R. The phage clone showing the highest degree of activation was verified and translated to the corresponding peptide. The peptide FNKWMDCLSVTH, designated as P-FN12, was bound by H4R monoclonal antibody (mcAb) with high affinity. Moreover, the P-FN12 + CTB@Lipo-formulated vaccine, used as nasal drops, decreased allergic symptoms such as sneezing and nasal rubbing in a rat model. The level of ovalbumin (OVA)-specific immunoglobulin E (IgE) decreased significantly after vaccine administration. It also elicited increased levels of interferon (IFN)-γ and interleukin-2 (IL-2) but a decreased level of IL-4, and it elevated the T helper type 1 (Th1):T helper type 2 (Th2) cell ratio in peripheral blood mononuclear cell cultures. Our results indicated that the reduction of allergic inflammation by P-FN12-based vaccine was related to a decrease in production of OVA-specific IgE, Th2 immunity, and tissue eosinophilia. P-FN12 + CTB@Lipo is a promising vaccine that could suppress Th2 response and enhance the induction of Th1 cells in an AR model.

Highlights

Allergic rhinitis (AR) is a significant health issue affecting approximately 500 million people worldwide.[1]
Identification of Epitopes Using the Phage Display Library and Specificity of Phage P-FN12 In the phage display library, critical amino acid residues within an epitope can be recognized by assessing the sequence of isolated peptides for homology with the primary sequence of the protein antigen
Rats in the control group and the cholera toxin B (CTB)@Lipo group did not exhibit detectable serum-specific antibody against H4 receptor (H4R) at the serum dilutions used in the indirect ELISA, which suggests that P-FN12 + CTB@Lipo could substantially enhance H4Rspecific humoral immunity

Summary

Introduction

Allergic rhinitis (AR) is a significant health issue affecting approximately 500 million people worldwide.[1]. The histamine H4 receptor (H4R) was identified most recently, and it was shown to be involved in the recruitment and activation of cells involved in allergic inflammatory responses, including eosinophils, T cells, dendritic cells, basophils, and mast cells.[4,5] It is demonstrated that the H4R modulates inflammation in a chronic allergic dermatitis setting; it is necessary to block H4R during ontogeny and development of the allergic inflammation.[6,7] It has been demonstrated that blocking both H1R and H4R has additive effects in preventing the intestinal consequences of peanut sensitization and challenge.[8] pharmacological studies suggest the potential utility of histamine H4 antagonists in the treatment of inflammatory diseases, such as AR, asthma, atopic dermatitis, and pruritus.[9,10,11,12,13] The selective H4R antagonist JNJ7777120 showed efficacy in relieving symptoms and inflammatory conditions in animal models of AR.[11,14] these treatments are not curative and they are expensive; antihistamines may impair performance due to their side effects.[15,16]

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Conclusion