Mechanism of Action of Oral Salmonella -Based Vaccine to Prevent and Reverse Type 1 Diabetes in NOD Mice

• Published in: Vaccines (Basel) Vol. 12; no. 3; p. 276
• Main Authors: Cobb, Jacob, Rawson, Jeffrey, Gonzalez, Nelson, Singer, Mahmoud, Kandeel, Fouad, Husseiny, Mohamed I
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.03.2024; MDPI
• Subjects: Antigens; Autoimmune diseases; Bacteria; Beta cells; CD25 antigen; CD3 antigen; CD4 antigen; Chemokines; Cytokines; Diabetes; Diabetes mellitus (insulin dependent); Foxp3 protein; Gene expression; Genetic modification; Granulocyte-macrophage colony-stimulating factor; Immune response; Immune system; Immunological tolerance; Immunomodulation; Immunomodulators; Inflammation; Insulin; Interleukin 10; Lymphatic system; Lymphocytes; Monocyte chemoattractant protein 1; oral vaccination; Peptides; Preproinsulin; regulatory cells; Salmonella; Salmonella-based vaccine; Serum levels; tolerance; tolerogenic dendritic cell (Tol-DC); type 1 diabetes (T1D); Vaccines; γ-Interferon; Minneapolis Minnesota; United States > US; oral vaccination; tolerogenic dendritic cell (Tol-DC); Salmonella-based vaccine; tolerance; type 1 diabetes (T1D); regulatory cells
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines12030276

A combination therapy of preproinsulin (PPI) and immunomodulators (TGFβ+IL10) orally delivered via genetically modified and anti-CD3 promoted glucose balance in in NOD mice with recent onset diabetes. The bacteria were modified to express the diabetes-associated antigen PPI controlled by a bacterial promoter in conjunction with over-expressed immunomodulating molecules. The possible mechanisms of action of this vaccine to limit autoimmune diabetes remained undefined. In mice, the vaccine prevented and reversed ongoing diabetes. The vaccine-mediated beneficial effects were associated with increased numbers of antigen-specific CD4 CD25 Foxp3 Tregs, CD4 CD49b LAG3 Tr1-cells, and tolerogenic dendritic-cells (tol-DCs) in the spleens and lymphatic organs of treated mice. Despite this, the immune response to infection was not altered. Furthermore, the vaccine effects were associated with a reduction in islet-infiltrating lymphocytes and an increase in the islet beta-cell mass. This was associated with increased serum levels of the tolerogenic cytokines (IL10, IL2, and IL13) and chemokine ligand 2 (CCL2) and decreased levels of inflammatory cytokines (IFNγ, GM-CSF, IL6, IL12, and TNFα) and chemokines (CXCL1, CXCL2, and CXCL5). Overall, the data suggest that the -based vaccine modulates the immune response, reduces inflammation, and promotes tolerance specifically to an antigen involved in autoimmune diabetes.