Diabetes and other autoimmune endocrine diseases
Current treatments for autoimmune disorders typically rely on the use of broadly immunosuppressive agents that increase the risk of adverse events in patients, such as cancer and opportunistic infections. Antigen (Ag)-specific immunotherapies have the potential to minimize these risks and improve efficacy by generating Ag-specific suppression to maintain immunohomeostasis. Several studies have established Ag-specific tolerance using red blood cells (RBCs) as a platform for delivery and Ag presentation in the context of eryptosis, a mechanism of RBC clearance. Here, we used the SQZ cell therapy platform to create Ag-loaded, pro-eryptotic RBCs to induce tolerance. In this approach, cells pass through constricted channels that cause transient permeation of the cell membrane and permit diffusion of cargo before the membrane reseals. In mice, we demonstrated that these highly delivered SQZ cells are rapidly cleared from circulation by splenic and liver-resident macrophages. The administration of ovalbumin (OVA)-SQZ cells led to a reduction of naïve OVA-specific T cell (OT-I/OT-II) proliferation and cytokine production. With OT-II cells that were activated ex vivo, SQZ cell treatment caused a significant decrease in T cells, particularly FOXP3-negative cells. Interestingly, FOXP3-positive OT-II cells were spared. In an autoimmune diabetes BDC2.5 T cell transfer model, mice treated with cells SQZ’d with 1040-p31 peptide delayed the onset of hyperglycemia. Additionally, SQZ cells induced tolerance in mouse models of adeno-associated virus (AAV)-gene therapy and anti-drug antibody (ADA). In summary, SQZ cells are a potentially exciting allogeneic cell therapy strategy to induce Ag-specific tolerance across a range of disease mechanisms and indications.