Several immune-based approaches are being considered for modulation of inflammatory T cells and amelioration of
autoimmune diseases. The most recent strategies include simulation of peripheral self-tolerance by injection of adjuvant free
antigen, local delivery of
cytokines by genetically altered T cells, and interference with the function of costimulatory molecules. Although promising results have been obtained from these studies that define mechanisms of T cell modulation, efficacy, practicality, and toxicity, concerns remain unsolved, thereby justifying further investigations to define alternatives for effective downregulation of aggressive T cells. In prior studies, we demonstrated that an
immunoglobulin (Ig) chimera carrying the encephalitogenic proteolipid
protein (PLP)1
peptide corresponding to amino acid sequence 139-151 of PLP, Ig-PLP1, is presented to T cells approximately 100-fold better than free PLP1. Here, we demonstrate that aggregation endows Ig-PLP1 with an additional feature, namely, induction of
interleukin (IL)-10 production by macrophages and dendritic cells, both of which are antigen-presenting cells (APCs). These functions synergize in vivo and drive effective modulation of autoimmunity. Indeed, it is shown that animals with ongoing active
experimental allergic encephalomyelitis dramatically reduce the severity of their
paralysis when treated with adjuvant free aggregated Ig-PLP1. Moreover,
IL-10 displays bystander antagonism on unrelated autoreactive T cells, allowing for reversal of disease involving multiple
epitopes. Therefore, 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-modal T cell modulation system effective for reversal of autoimmunity involving several
epitopes and diverse T cell specificities.