Tregitopes Improve Asthma by Promoting Highly Suppressive and Antigen-Specific Tregs

Abstract

Tregitopes (T regulatory epitopes) are IgG-derived peptides with high affinity to major histocompatibility complex class II (MHCII), that are known to promote tolerance by activating T regulatory cell (Treg) activity. Here we characterized the effect of IgG Tregitopes in a well-established murine model of allergic asthma, demonstrating in vivo antigen-specific tolerance via adoptive transfer of Tregitope-and-allergen-activated Tregs. Asthma is a heterogeneous chronic inflammatory condition affecting the airways and impacting over 300 million individuals worldwide. Treatment is suppressive, and no current therapy addresses immune regulation in severely affected asthmatics. Although high dose intra-venous immunoglobulin (IVIg) is not commonly used in the asthma clinic setting, it has been shown to improve severe asthma in children and in adults. In our laboratory, we previously demonstrated that IVIg abrogates airway hyperresponsiveness (AHR) in a murine model of asthma and induces suppressive antigen-specific T-regulatory cells. We hypothesized that IgG-derived Tregitopes would modulate allergic airway disease by inducing highly suppressive antigen-specific Tregs capable of diminishing T effector cell responses and establishing antigen-specific tolerance. Using ovalbumin (OVA-) and ragweed-driven murine models of allergic airway disease, we characterized the immunoregulatory properties of Tregitopes and performed Treg adoptive transfer to OVA- and ragweed-allergic mice to test for allergen specificity. Treatment with Tregitopes attenuated allergen-induced airway hyperresponsiveness and lung inflammation. We demonstrated that Tregitopes induce highly suppressive allergen-specific Tregs. The tolerogenic action of IgG Tregitopes in our model is very similar to that of IVIg, so we foresee that IgG Tregitopes could potentially replace steroid-based treatment and can offer a synthetic alternative to IVIg in a range of inflammatory and allergic conditions.

Autophagy functions in lung macrophages and dendritic cells to suppress TH17 responses and neutrophil accumulation during allergic airway inflammation

“…Loss of autophagy in lung macrophages and DCs also resulted in the accumulation of Tregs in the lungs following HDM challenge. Although Tregs are well-known to suppress the inflammatory responses during asthma [100][101][102][103] , Treg accumulation is also reported to be increased during severe asthma 104,105 . Higher Treg accumulation during severe asthma is associated with higher TH17 responses, where the transfer of purified TH17 cells promoted the expansion of Tregs in mice 106 .…”

Systems biology and artificial intelligence analysis highlights the pleiotropic effect of IVIg therapy in autoimmune diseases with a predominant role on B cells and complement system

“…De Groot and coworkers (121) described a DC-dependent mechanism where promiscuous IgGderived T-cell epitope peptides (Tregitopes) increases protolerogenic cytokine production (IL-10) and converts naïve conventional T cells to T regulatory cells (122). Treg would then inhibit effector Th1, Th2 and Th17 cellular activity in inflammatory microenvironments and secrete antiinflammatory cytokines (112,(123)(124)(125). Overall, the presence of Tregitopes might in part explain the success of IVIg therapy in treating autoimmune diseases (122,126).…”

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

“…Treatment with Tregitopes inhibited allergen-induced airway hyperresponsiveness and lung inflammation [ 132 ]. To direct Tregs towards asthma associated antigens, Skuljec et al applied CAR technology.…”