Therapeutic antigen-specific PLGA nanoparticles tolerance induces detectable changes in the spleen, blood, and disease-associate tissue 2260904

Abstract Introduction Autoreactive T cell infiltration, tissue destruction, and spread epitope-specific T cell activation underly CD4+ T cell-mediated autoimmune disease pathogenesis. Antigen (Ag)-containing biodegradable poly(lactide-co-glycolide) nanoparticle, i.e. tolerogenic immune-modifying particles/Cour Nanoparticles (TIMP/CNPs), treatment is both safe and efficacious for Ag-specific tolerance induction in mice and Phase I/IIa clinical trials in celiac disease and primary biliary cholangitis. Methods The present studies utilized the transfer of congenically marked TCR transgenic T cells (5B6 T cells) into wildtype SJL mice. These recipient mice were primed with PLP139-151/CFA and followed for disease. At the peak of acute disease, the mice were treated with either unloaded CNP or CNP-PLP139-151. At various time points post treatment, spleen, liver, CNS, and blood were collected to quantify and phenotype the 5B6 T cells. Results In continuing to identify the mechanism by which Ag-specific CNP treatment induces tolerance, the present data show that cDC2s are the APCs that present the CNP-associated Ag in a tolerogenic manner to Ag-specific CD4+ T cells. Additionally, we identify that therapeutic treatment with Ag-specific CNP significantly decreases the number of effector CD4+ T cells within the disease-associate tissue, while increasing the ratio of Ag-specific CD4+ regulatory cells (Tregs) to IFN-γ+ cells. Consequently, treatment induced an increase in the number of Ag-specific Tregs, anergic CD4+ T cells, and the ratio of Ag-specific Treg to IFN-γ+ cells present within the spleen and blood. Additionally, we have identified that the percentage of both Ag-specific and host-derived Tregs increased within the blood post Ag-specific CNP dosing. Conclusion Therefore, these data are the first to show treatment-induced increases in Ag-specific CD4+ T cells post dosing and cellular alterations across treatment relevant tissues. Funding Source This work was supported by grants to S.D.M. from Cour Pharmaceutical Development Company, NIH grant R01AI148076; and by gifts from the Johnnie Walkers MS Foundation, the Amy and David Fulton Foundation, the Crammer Family Foundation, the Thomas and Deige McLaughlin Foundation, and the Rottering Family Foundation. Topic Categories Therapeutic Approaches to Autoimmunity (THER)