Targeted immunomodulatory strategies that induce antigen-specific regulation of pathogenic T cells is an attractive paradigm for treatment of autoimmune diseases. One such strategy is to use the natural process of antigen-presentation by dendritic cells (DCs) to control the balance of pathogenic T cells vs. regulatory T cells. Currently, there is a lack of safe and effective therapeutic strategies that induce antigen-specific T cell regulation. We describe a liposome-based therapeutic approach, in which peptide antigen and an NF-KB inhibitor are co-delivered to DCs to expand auto-regulatory cell populations and establish antigen-specific tolerance.

Egg phosphatidylcholine liposomes of 90-130 nm encapsulating 1,25 dihydroxycholecalciferol (calcitriol), and OVA_323-339 or aggrecan_89-103 peptide, were prepared by thin film hydration. Subcutaneous administration of liposomes passively targeted dermal migratory and inflammatory dendritic cells in draining lymph nodes (dLN). Five hours post-delivery, liposomes in the dLN were distributed within MHC class II+ cells adjacent to the afferent lymphatic vessel and in the paracortex. After transfer of OVA-specific DO11.10 T cells and s.c. administration of OVA-calcitriol liposomes, transferred OVA-specific naïve and memory T cells were deleted. Residual OVA-specific cells were enriched in Foxp3+ peripheral Treg and FoxP3- T cells expressing CD73 and PD1 anergic markers. In response to OVA/QuilA immunization, OVA-specific cells accumulated at high frequencies and secreted high levels of IFNg in control mice, but these effector functions were suppressed in OVA-calcitriol liposome-pre-treated mice. In the proteoglycan-induced arthritis model of rheumatoid arthritis, s.c. administration of liposomes co-encapsulating the dominant aggrecan epitope and calcitriol, reduced disease severity in an antigen-specific manner with concomitant reductions in antigen-specific CD4+ T cells identified with pMHCII tetramers. Hence, our data describe a broadly-adaptable nanoparticle system for the passive targeting of dendritic cells resulting in antigen-specific immune tolerance. This system represents a suitable translational therapy for the treatment of human autoimmune diseases.