Abstract
Autoimmune diseases such as type 1 diabetes (T1D) involve the loss of regulatory mechanisms resulting in increased tissue-specific cytotoxicity. The result is destruction of pancreatic insulin-producing β-cells and loss of glucose homeostasis. We are developing a novel oral vaccine using live attenuated Salmonella to deliver TGFβ, IL10, and the diabetic autoantigen preproinsulin combined with low-doses of anti-CD3 mAb. Here we show that oral administration of Salmonella-based anti-CD3 mAb combined therapy reverses new-onset T1D in non-obese diabetic (NOD) mice. The therapeutic effect of the combined therapy was associated with induction of immune suppressive CD4+CD25+Foxp3+ Treg and CD4+CD49b+LAG3+ Tr1 cells. In adoptive transfer experiments, adding or depleting Treg or Tr1 cells indicated that both are important for preventing diabetes in combined therapy-treated mice, but that Tr1 cells may have a more central role. Furthermore, induced Tr1 cells were found to be antigen-specific responding to peptide stimulation by secreting tolerance inducing IL10. These preclinical data demonstrate a role for Treg and Tr1 cells in combined therapy-mediated induction of tolerance in NOD mice. These results also demonstrate the potential of oral Salmonella-based combined therapy in the treatment of early T1D.
Highlights
Type 1 diabetes (T1D) is a tissue-specific autoimmune disease resulting from lymphocyte destruction of pancreatic islet insulin-producing β-cells [1,2,3]
We previously developed an oral Salmonella-based delivery system (SPI2-TTSS) that was found to be effective in delivering autoantigen in combination with TGFβ to prevent diabetes in non-obese diabetic (NOD) mice [37]
Our studies showed that the co-administration of a short-course of anti-CD3 mAb along with a reduced dose of Salmonella-based vaccine (PPI+TGFβ+IL10) preserved insulin-positive cells, reduced insulitis and prevented autoimmune diabetes in NOD mice [38]
Summary
Type 1 diabetes (T1D) is a tissue-specific autoimmune disease resulting from lymphocyte destruction of pancreatic islet insulin-producing β-cells [1,2,3]. The loss of islet β-cell function leads to insulin deficiency and high blood glucose levels (hyperglycemia) [4]. Multiple approaches have and are being pursued to correct or limit this process including monoclonal antibodies, autoantigen immunization, Treg-based immunotherapy and systemic immunosuppressive drugs targeting T cells or antigen presenting cells. Most of these interventions have been complicated by severe immune suppression or have shown a lack of efficacy [6,7,8].
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