Inflammatory bowel diseases
Inflammatory bowel disease results from a loss of tolerance to commensal microbiota within the mucosal environment. Immunoregulatory T cell costimulation by programmed death 1 (PD- 1) receptor and PD ligand 1 (PD-L1) can provide a negative signal to inhibit T cell proliferation, mediate tolerance and prevent auto-inflammation. Therefore, we hypothesize that modulation of PD-L1 levels in the gastrointestinal tract (GIT) provides a novel mechanism to control intestinal tolerance. We have developed a novel dually-derivitized (DD) chitosan to package plasmid DNA into nanoparticles for delivery to the GIT for treatment of mucosal disease, such as IBD. Codon optimized gene sequences of human full-length PD-L1 or PD-L1-Fc were sub-cloned into an expression plasmid and formulated in DD-chitosan. In vitro potency of the PD-L1 constructs was assessed by inhibition of T cell activation and a receptor binding assay. In vivo expression of PD-L1 mRNA was confirmed and disease outcome was evaluated in the T cell transfer model of colitis. Following transfer of CD4+CD25-CD45RBhi naive T cells, significant effect on weight loss, survival and clinical signs was observed with mice treated with PD-L1-PPs relative to controls. A significant increase in FOXP3 expression was observed in CD4+CD25+FOXP3+ cells in PD-L1-PP treated mouse lymphoid tissues relative to controls. Our data suggest that local expression of PD-L1 improves clinical manifestations of murine IBD. Our findings provide a strong foundation for exploring the therapeutic effect of local delivery of T-cell inhibitory checkpoint proteins to treat IBD using the DD-chitosan-based gene vector platform optimized for gut delivery of DNA.