Tregitope-linked Refined Allergen Vaccines for Immunotherapy in Cockroach Allergy

Abstract

Allergen-specific immunotherapy (AIT) facilitates long-term resolution of allergic morbidity resulting in reduced drug use and increased refractoriness to new sensitization. AIT effectiveness has been demonstrated in seasonal and perennial allergies, and insect stings. However, data and studies in AIT relative to cockroach (CR) allergy are relatively scarce. In this study, mice allergic to American CR (Periplaneta americana) were treated with a liposome (L)-entrapped vaccine made of mouse Tregitope289-Per a 9 of the CR, Tregitope167-Per a 9, or Per a 9 alone – or placebo. Allergic mice that received an individual vaccine intranasally had reduced Th2 response, reduced lung inflammation, and reduced respiratory tissue remodeling. However, only L-Tregitope289-Per a 9 and L-Tregitope167-Per a 9 induced expression of immunosuppressive cytokine genes (IL-10, TGF-β, and IL-35 for L-Tregitope289-Per a 9, and IL-10 and TGF-β for L-Tregitope167-Per a 9) and increment of idoleamine-2,3-dioxygenase 1 (IDO1), indicating that these vaccines caused allergic disease suppression and reversal of respiratory tissue remodeling via generation of regulatory lymphocytes. Liposome entrapped-recombinant Per a 9 (L-Per a 9) did not cause upregulation of immunosuppressive cytokine genes and IDO1 increment; rather, L-Per a 9 induced high expression of IFN-γ in lungs of treated mice, which resulted in mitigation of allergic manifestations. This study provides compelling evidence that both liposome-entrapped vaccines made of single refined major allergen alone and single refined major allergen linked with Tregitopes are effective for reducing allergen-mediated respiratory tissue inflammation and remodeling, but through different mechanisms.

Specificity of the T Cell Response to Protein Biopharmaceuticals

“…Presentation of these peptides might lead to deletion of effector CD4 T cells ( Figure 3 c), which explains why CD4 T cell epitopes are not found in the constant parts of IgG, and also to selection of specific tTregs ( Figure 3 d). These Tregitopes have been shown to suppress multiple kinds of immune responses, including humoral ( 82 , 85 ) and cellular ( 86 ), but were also shown to be poorly active in this regard in an alternative study ( 87 ). No BP-specific tTregs have been cloned and characterized yet and the mechanism of suppression remains to be determined.…”

All the small things: How virus‐like particles and liposomes modulate allergic immune responses

“…Reduced type 2 inflammation was also obtained upon treatment with all Per a 9 containing liposomal preparations (recombinant Per a 9 alone and Tregitope Per a 9 liposomes); however, induction of Treg cells was exclusively observed when Tregitopes were present. Liposomes exclusively containing allergen were unable to induce a Treg signature but, instead, induced high levels of IFN-γ production [128].…”

Therapeutic administration of Tregitope-Human Albumin Fusion with Insulin Peptides to promote Antigen-Specific Adaptive Tolerance Induction

“…Specific to the “ASATI” hypothesis under investigation here, previous studies in murine models have demonstrated the ability of Tregitopes to induce antigen-specific tolerance (including conversion of epitope-specific Teff to Treg) in DO11.10 mice 18 , to modulate antigen-specific transplant rejection 19 and to reduce immune responses to allergens in vitro and in vivo 19,20 . T cells responding to Tregitopes exhibit a T regulatory phenotype in mice (CD4 + CD25 + FoxP3+) 13 .…”