Preclinical studies to determine myelin peptide-specific nanoparticle tolerance mechanisms and clinical translation
Presentation Time: 02:15 PM - 03:30 PM
Poster Board Number: B684
Abstract ID: 5985
Presenting Author:
Joseph R Podojil , Research Associate Professor at Northwestern Univ. Feinberg Sch. of Med., Cour Pharma.
Abstract:
Infiltration of autoreactive T cells, subsequent tissue destruction, and the release of additional self-epitopes resulting in epitope spreading underly pathogenesis in many autoimmune diseases. Treatment with Ag-containing biodegradable poly(lactide-co-glycolide) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP/CNPs), has been shown to be safe and efficacious for the induction of Ag-specific tolerance in murine models of autoimmunity, and in a Phase Ib/IIa clinical trial for celiac disease. The present studies identified novel pathways required for Ag-specific TIMP-induced tolerance, the ability of treatment to modulate spread epitope-specific CD4+ T cell activation, and the functionality of TIMPs containing human myelin-derived peptide epitopes (CNP-102) in a pre-clinical mouse model of multiple sclerosis (MS). Following treatment, myeloid cells phagocytose TIMPs, undergo apoptosis, and Ag-specific tolerance therapy increases both FoxP3+ regulatory T cells and IL-10+ Tr1 cells via a STING/IFNAR-dependent pathway. TIMP treatment also modulates spread epitope-specific T cells associated with disease progression, but not encapsulated within the TIMP, i.e. tissue-specific tolerance. Therefore, treatment activates various Ag-specific regulatory T cell subsets capable of inhibiting disease-associated autoantigens not encapsulated within the TIMP via release of immunoregulatory cytokines, and CNP-102 has proven efficacious in preclinical mouse models of MS.
Preclinical studies to determine myelin peptide-specific nanoparticle tolerance mechanisms and clinical translation
Category
Poster and Podium (Block Symposium)