**3. DNA vaccine immunotherapies**

Plasmid DNA vaccine-based immunotherapy is a promising therapeutic field for treatment of type 1 diabetes. Clinical proof of concept has already been provided with results from phase I/II trials where individuals with new-onset type 1 diabetes were treated with proinsulinencoding plasmid DNA [15]. Nevertheless, although beneficial effects were observed, it is clear that efficacy must be significantly improved. Improving efficacy will be likely dependent on the ability to modulate both the innate immune system, through activation of tolerogenic antigen-presenting cells like dendritic cells, and the adaptive immune system, through activation of various populations of regulatory cells. DNA vaccines are particularly well positioned to achieve this goal because plasmid DNA is information-based, and can encode molecules that affect the immune system in different manners. The challenge is to identify which combination of functions should be delivered together with a pancreatic autoantigen to treat disease with maximum efficacy and safety.

Several beta cell autoantigens have been tested in mice for induction of immune tolerance by DNA vaccines and will be discussed in this section. Immune mechanisms associated with the therapeutic effects of DNA vaccines can be complex because of the variety of cells that can process the information encoded by plasmid DNA. Regardless, the major goals are to induce diabetic suppressive dendritic cells, T regulatory lymphocytes, and the cell death and inacti‐ vation of T effector lymphocytes that destroy pancreatic beta cells.


mune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn disease, and autoimmune diabetes [55, 56]. For example, a single intramuscular injection of 300 microgram of vasoactive intestinal polypeptide-encoding plasmid DNA significantly reduced the incidence of cyclophosphamide accelerated diabetes in female nonobese diabetic mice, from 70% in control to 30% on day 33 post delivery in 8-10-week-old mice [57]. A subsequent report in a different model system indicated that injection of the peptide

Section 1 covers plasmid DNA encoding small protein molecules like cytokines, chemokines, peptides and other immune cell-manipulating agents with therapeutic effects on preclinical type 1 diabetes (Table 1). These approaches belong to systemic treatments and inevitably bear the risks associated with nonspecific immune suppression and chronic complications resulting from interference with the host immune system. Nonetheless, if used as adjuvants or supple‐ ments to pancreatic autoantigen-targeting therapies like DNA vaccines, these approaches could be used selectively in DNA-based combination therapies. We provide examples of such

Plasmid DNA vaccine-based immunotherapy is a promising therapeutic field for treatment of type 1 diabetes. Clinical proof of concept has already been provided with results from phase I/II trials where individuals with new-onset type 1 diabetes were treated with proinsulinencoding plasmid DNA [15]. Nevertheless, although beneficial effects were observed, it is clear that efficacy must be significantly improved. Improving efficacy will be likely dependent on the ability to modulate both the innate immune system, through activation of tolerogenic antigen-presenting cells like dendritic cells, and the adaptive immune system, through activation of various populations of regulatory cells. DNA vaccines are particularly well positioned to achieve this goal because plasmid DNA is information-based, and can encode molecules that affect the immune system in different manners. The challenge is to identify which combination of functions should be delivered together with a pancreatic autoantigen

Several beta cell autoantigens have been tested in mice for induction of immune tolerance by DNA vaccines and will be discussed in this section. Immune mechanisms associated with the therapeutic effects of DNA vaccines can be complex because of the variety of cells that can process the information encoded by plasmid DNA. Regardless, the major goals are to induce diabetic suppressive dendritic cells, T regulatory lymphocytes, and the cell death and inacti‐

host disease in a mouse model of allogeneic bone marrow transplantation [58].

CD25high T regulatory cells and protect against acute graft-versus-

could activate FoxP3+

542 Type 1 Diabetes

**2.4. Summary of Section 2**

approaches in Section 2 of this chapter.

**3. DNA vaccine immunotherapies**

to treat disease with maximum efficacy and safety.

vation of T effector lymphocytes that destroy pancreatic beta cells.

CD4+

**Table 1. Plasmid DNA Based Immunotherapies for Type 1 Diabetes.** The table summarizes plasmid DNA based immunotherapies under two categories: Gene therapies and DNA vaccines. Immunotherapies are listed according to their category, type of immune response and trial. Abbreviation: IL, interleukin; CD, cluster of differentiation; PRPIII, pancreatic regenerating protein III; CGRP, calcitonin gene-related peptide; VIP, vasoactive intestinal polypeptide; HSP, heat shock protein; GAD, glutamic acid decarboxylase. IA, insulinoma associated protein; Tregs, T regulatory cells; DCs: dendritic cells.
