Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling

Abstract

Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.

A Single Monoclonal Antibody against the Peanut Allergen Ara h 2 Protects against Systemic and Local Peanut Allergy

“…As immunotherapy (SIT) is typically thought to be allergen-specific, the preferred therapeutic concept is the use of allergen extracts for SIT to target all possible allergens. Efficacy and safety of this approach may be enhanced by using allergoids [6] or displaying allergens on virus-like particles [7] and optimizing the use of adjuvants [8]. Nevertheless, the use and standardization of allergen extracts is complex and immunogenicity/efficacy remains limited.…”

The size of micro-crystalline tyrosine (MCT®) influences its recognition and uptake by THP-1 macrophagesin vitro

“…This may be benecial with regards to the conservation of the adjuvant depot, increasing the amount of material available to interact with inltrating granulocytes and APCs, the recruitment of which has been observed as early as 4 h post immunisation with MCT®-adjuvanted vaccines. 61 Furthermore, an increase in cell-mediated translocation of antigen/antigen-adjuvant complexes to lymph nodes may serve to facilitate vaccine priming, an essential prerequisite for the development of robust adaptive immune responses. 62 The hydrodynamic size of particles within the adjuvant bolus directly inuences the rate at which they are removed from the injection site by inltrating phagocytes, with particles between 1-3 mm in size being considered optimal for recognition and engulfment by macrophages.…”

Sustained Inhibition of the IL4/IL13 Receptor Complex during Allergen Specific Immunotherapy

“…Under consideration of the controversially discussed alum (Kramer and Heath, 2014), that is widely used as depot-forming substance for AIT, the development of novel matrices (e.g. microcrystalline tyrosine) (Leuthard et al, 2018) represents a promising and relevant research field.…”