PATHOGENESIS OF TYPE 1 DIABETES (D DABELEA, SECTION EDITOR) Antigen-Based Vaccination and Prevention of Type 1 Diabetes Leonard C. Harrison & John M. Wentworth & Yuxia Zhang & Esther Bandala-Sanchez & Ralph M. Böhmer & Alana M. Neale & Natalie L. Stone & Gaetano Naselli & Julian J. Bosco & Priscilla Auyeung & Maryam Rashidi & Petra Augstein & Grant Morahan # Springer Science+Business Media New York 2013 Abstract Insulin-dependent or type 1 diabetes (T1D) is a paradigm for prevention of autoimmune disease: Pancreatic β-cell autoantigens are defined, at-risk individuals can be identified before the onset of symptoms, and autoimmune diabetes is preventable in rodent models. Intervention in asymptomatic individuals before or after the onset of subclin- ical islet autoimmunity places a premium on safety, a require- ment met only by lifestyle–dietary approaches or autoantigen- based vaccination to induce protective immune tolerance. Insulin is the key driver of autoimmune β-cell destruction in the nonobese diabetic (NOD) mouse model of T1D and is an early autoimmune target in children at risk for T1D. In the NOD mouse, mucosal administration of insulin induces reg- ulatory T cells that protect against diabetes. The promise of autoantigen-specific vaccination in humans has yet to be realized, but recent trials of oral and nasal insulin vaccination in at-risk humans provide grounds for cautious optimism. Keywords Autoimmune . Type 1 diabetes . Islet . β cell . Preclinical . Autoantibody . T cell . Regulation . Prediction . Prevention . Vaccination . Insulin . GAD65 . Mucosa . Nasal . Oral . Immune . Suppression . Tolerance . Clinical trial . Antigen Introduction If immune responses to autoantigens are regulated physiolog- ically, the logical strategy to counter aberrant immune re- sponses leading to autoimmune disease is autoantigen-based immunotherapy. This approach has a parallel in allergen- specific immunotherapy, which has been practiced for decades and shown in multiple randomized trials to be efficacious in allergic asthma, rhinitis, and other conditions. The aim of the administration of autoantigens to induce protective immune tolerance, “negative vaccination” [1], is to boost or restore autoantigen-specific immunoregulatory mechanisms and avert pathological autoimmunity. In animal models of auto- immune disease, this has been achieved in several ways: administration of autoantigen by a “tolerogenic” route (mu- cosal, dermal), cell type (resting dendritic cell), mode (with blockade of costimulation molecules), or form (as an “altered peptide ligand”)[2, 3]. Mechanisms of antigen-induced toler- ance include deletion and/or anergy of effector T cells and induction of regulatory T cells (Treg). Treg cells stand center stage following their renaissance as CD4 + CD25 + cells programmed by the transcription factor forkhead box P3 (FOXP3) and the unequivocal evidence that they are required naturally to prevent autoimmune disease [4], exemplified by the immune dysregulation, polyendocrinopathy, and X-linked (IPEX) syndrome due to FOXP3 mutations [5]. Two subsets of Treg express FOXP3: natural Treg (nTreg) and induced Treg (iTreg) [reviewed in ref. 6]. Like conventional T cells (Tconv), nTreg cells are thymus derived, whereas iTreg cells differentiate in the periphery from naïve Tconv under “tolerogenic” conditions of antigen presentation, such as in the presence of transforming growth factor (TGF)-β in the gut [7]. Of importance clinically is the ability of Treg to exert antigen-nonspecific “bystander” or “linked” suppression. Thus, Treg generated in response to epitopes within a specific antigen, presented by different human leukocyte antigen (HLA) molecules to heterogeneous T-cell receptors (TCRs), may impair (by direct cell contact and/or the release of soluble immunosuppressive factors) the ability of local antigen- presenting dendritic cells to elicit effector T-cell responses to the same or another antigen presented locally at the site of the lesion or in the draining lymph nodes. Bystander suppression L. C. Harrison (*) : J. M. Wentworth : Y. Zhang : E. Bandala-Sanchez : R. M. Böhmer : A. M. Neale : N. L. Stone : G. Naselli : J. J. Bosco : P. Auyeung : M. Rashidi : P. Augstein : G. Morahan Walter & Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3052, Victoria, Australia e-mail: harrison@wehi.edu.au Curr Diab Rep DOI 10.1007/s11892-013-0415-7