Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL-4 increases safety

Abstract

Administration of autoantigens through DNA immunizations or via the oral route can prevent progression of islet destruction and lower the incidence of type 1 diabetes in animal models. This beneficial effect is mediated by autoreactive regulatory CD4 lymphocytes, and it is known that their induction depends on the precise dose and route of antigen administration. However, it is not clearwhich endogenous factors determine when such immunizations lead to activation of regulatory versus aggressive autoreactive lymphocytes and how a deleterious outcome can be avoided. Here we describenovel observations made in an animal model for virally induced type 1 diabetes, showing that the endogenous expression levels of the islet antigens and glutamic acid decarboxylase determine whetherimmunization with these antigens is beneficial or detrimental. Lower expression levels in β‐cells support immune regulation resulting in induction of autoreactive, regulatory cells characterized by increased IL‐4 production (Th2‐like), whereas higher levels favor Th1‐like autoaggressive responses characterized by augmented IFN‐γ generation. Co‐immunization with an IL‐4‐expessing plasmid reduces the risk of augmenting autoaggression and in this way increases the safety margin of this immune‐based therapy. Our findings will be of importance for designing safe antigen‐specific interventions for human type 1 diabetes.

Minimal Impact of a De Novo–Expressed β-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

“…It is thus possible that only certain autoantigens are capable of inducing "driver" populations that significantly impact disease; possible examples of such autoantigens are IGRP (17) and proinsulin (32). This consideration will be important for devising immune-based preventions in type 1 diabetes, and we propose that induction of regulatory lymphocytes that can act as bystander suppressors for multiple antigenic autoaggressive specificities rather than elimination of targeted specificities might be a more effective strategy as long as the initiating autoantigens and driver epitopes, if existent, remain elusive in human type 1 diabetes pathogenesis (8,9,33,34).…”

Tolerizing DNA vaccines for autoimmune arthritis

“…It is well established that delivery of IL-4 via gene therapy or administration of recombinant protein ameliorates arthritis in CIA [30,31]. These data combined with the potentiating effect of DNA encoding IL-4 in tolerizing DNA vaccines for EAE [6,10] and NOD [19] provide the rationale for testing its potential to augment CIIencoding DNA vaccines for CIA. In contrast to the results in EAE and NOD mice, co-treatment with DNA encoding CII plus IL-4 did not provide benefit over treatment with CII DNA alone.…”

Genetic vaccination for re-establishing T-cell tolerance in type 1 diabetes

“…67,72 Accordingly, one approach has been to co-administer pDNA encoding antigen and anti-inflammatory cytokines to "shape" the nature of the T cell response. [67][68][69]80 Intramuscular injection of pDNA encoding GAD65-IgFc and IL-10 suppresses β cell autoimmunity and protects syngeneic islet …”