Multi-Component Vaccines for Suppression of Type 1 Diabetes

Many individual therapeutic strategies involving oral delivery of diabetes autoantigens such as insulin and GAD have been shown to provide partial short term suppression of organ specific type 1 diabetes autoimmunity (Weiner et al. 1991; Zhang et al. 1991; Nakayama et al. 2005). However, few individual therapies have been able to demonstrate effective, safe and persistent protection against type 1 diabetes onset or progression (Hutchings and Cooke 1998). More recently, combinatorial therapeutic strategies that incorporate immunostimulatory molecules such as the cholera toxin B subunit (CTB), linked to a diabetes autoantigen (eg. insulin or GAD), were shown to substantially enhance immune suppression of juvenile (Type 1) diabetes autoimmunity to provide more effective, safe and sustainable disease prevention (Arakawa et al. 1998; Denes et al. 2006). Combinatorial vaccines involving oral delivery of the cholera toxin B subunit (CTB) linked to pancreatic autoantigens such as proinsulin and GAD delivered together were shown to provide additive enhancement of autoantigen mediated suppression of diabetes insulitis and hyperglycemia in contrast to inoculation of prediabetic mice with CTB::GAD or CTB::proinsulin alone (Arakawa, Chong, and Langridge 1998). Most recently, combinatorial DNA vaccination experiments including genes encoding CTB::GAD together with the immunosuppressive cytokine IL-10 were shown to completely suppress type 1 diabetes onset in non-obese prediabetic (NOD) mice (Denes et al. 2010). Thus, it is now clear that combinatorial vaccination strategies have the ability to completely prevent diabetes onset in genetically susceptible mammals. However, to harness and transfer this promising combinatorial vaccination strategy for effective and safe clinical therapy in type 1 diabetes patients, cellular and molecular mechanisms underlying multi-component vaccine stimulation of immunological tolerance must be defined. Initial steps required to attain this goal, will involve identification of mechanisms responsible for vaccine interactions with cells of the innate immune system i.e., dendritic cells (DCs), involved in the initial processing vaccine autoantigens. In order to understand how multi-component vaccines may function to prevent the development of chronic islet inflammation (insulitis) progressing to high blood sugar (hyperglycemia), it will be important to understand the nature of immune responses underlying type 1 diabetes disease onset. To accomplish this goal, hypotheses must be tested that suggest how adjuvant-autoantigen fusion proteins may enhance immunotolerance e.g.