Research Associate Professor Northwestern Univ. Feinberg Sch. of Med., United States
Disclosure(s):
Joseph Podojil, PhD: No relevant disclosure to display
Introduction/Rationale: 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-+ 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-+ 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.
