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Abstract

While clinical vaccination has long been used to promote protective adaptive immunity, clinicians lack similar tools to specifically prevent immune reactions or to induce specific immunological tolerance. Available medicines, such as glucocorticoids, can suppress inflammation and benefit patient quality of life. However, they are not curative and leave patients with compromised immune systems, vulnerability to infections, and risk of cancer. There have long been efforts in pursuit of induction of antigen-specific immunological tolerance, with efforts including delivery of apoptotic cells or targeting antigen to tolerogenic organs. We sought to induce antigen-specific immunological tolerance by fusing antigen with efferocytic mediators, which facilitate the clearance of dying cells and modulate immunity. We designed two recombinant proteins with ovalbumin (OVA) as the model antigen: GAS6-OVA and MFGE8-OVA. We tested their immunomodulatory effects both in vitro and in vivo. GAS6-OVA and MFGE8-OVA demonstrated preferential binding to phosphatidylserine, a marker of apoptotic cells, and were rapidly taken up by bone-marrow-derived dendritic cells. GAS6-OVA-pulsed BMDCs presented antigen to OT I and OT II cells, driving robust proliferation. We also examined GAS6-OVA and MFGE8-OVA using the in vivo OT adoptive transfer model of antigen-specific immune responses. GAS6-OVA and MFGE8-OVA either reduced the number and activity of OVA-specific CD4+ and CD8+ T cells or induced signs of anergy, a state of unresponsiveness to antigen stimulation. Finally, when examined in the context of allergic airway inflammation, prophylactic administration of GAS6-OVA demonstrated benefit in reduction of multiple pathological mediators, including eosinophilia in the airway, goblet cell metaplasia, and mucus hypersecretion. Directly targeting antigen to efferocytosis pathways via GAS6 or MFGE8 has demonstrated potential for applications in cases where antigen-specificity is both feasible and desirable, such as allergies to a known immunodominant allergen. It is conceivable that this approach could enhance nanoparticle delivery of antigen or other payloads.

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