Coupling of peripheral tolerance to endogenous interleukin 10 promotes effective modulation of myelin-activated T cells and ameliorates experimental allergic encephalomyelitis

Several immune-based approaches are being considered for modulation of infl ammatory T cells and amelioration of autoimmune diseases, the most recent s trategies include simulation of peripheral self-tolerance by injection of a djuvant free antigen, local delivery of cytokines by genetically altered T cells, and interference with the function of costimulatory molecules. Altho ugh promising results have been obtained from these studies that define mec hanisms of T doll modulation, efficacy, practicality, and toxicity, concern s remain unsolved, thereby justifying further investigations to define alte rnatives for effective downregulation of aggressive T cells. In prior studi es, we demonstrated that an immunoglobulin (Ig) chimera carrying the enceph alitogenic proteolipid protein (PLP)1 peptide corresponding to amino acid s equence 139-151 of PLP, Ig-PLP1, is presented to T cells similar to 100-fol d better than free PLP1. Here, we demonstrate that aggregation endows Ig-PL P1 with an additional feature, namely, induction of interleukin (IL)-10 pro duction by macrophages and dendritic cells, both of which aro antigen prese nting cells (APCs). These functions synergize in vivo and drive effective m odulation of autoimmunity. Indeed, it is shown that animals with ongoing ac tive experimental allergic encephalomyelitis dramatically reduce the severi ty of their paralysis when treated with adjuvant free aggregated Ig-PLP1. M oreover, IL-10 displays bystander antagonism on unrelated autoreactive T do lls, allowing for reversal of disease involving multiple epitopes. Therefor e, aggregated Ig-PLP1 likely brings together a peripheral T cell tolerance mechanism emanating from peptide presentation by APCs expressing suboptimal costimulatory molecules and IL-10 bystander suppression to drive a dual-mo dal T cell modulation system effective for reversal of autoimmunity involvi ng several epitopes and diverse T cell specificities.