Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell–dependent induction of CD4+CD25+FoxP3+ Treg

Low cost delivery of proteins bioencapsulated in plant cells to human non-immune or immune modulatory cells

“…Our strategy of oral tolerance induction to autoantigens and to therapeutic proteins used in replacement therapy of genetic disorder (such as hemophilia and lysosomal storage disorders) has in part relied on efficient targeting of gut epithelial cells with CTB followed by transmucosal delivery and proteolytic cleavage, resulting in the release of the antigen from the CTB tag and uptake by DCs [7, 9, 10, 11, 33, ]. However, DCs and macrophages also directly sample antigen in the gut lumen, and M cells may shuttle intact antigen across the epithelium to areas rich in DCs.…”

“…Recently, we demonstrated that oral tolerance induction to coagulation factors in hemophilic mice upon delivery of bioencapsulated CTB-fusion antigens was associated with increased CD103 + DC frequency, antigen uptake by CD103 + DC, and induction of several subsets of Treg [9, 10]. Also increased were plasmacytoid DC, which also have important immune modulatory functions [33]. Recently, DC peptide (DCpep) has been developed as a ligand to mucosal DCs [26].…”

Phenotype and function of tissue-resident unconventional Foxp3-expressing CD4+ regulatory T cells

“…Depending on the stimulus such as TGF-b, IL-10, IL-35 and rapamycin, non-Treg cells can develop into a subpopulation of suppressive inducible Tregs [1,[16][17][18]. Of note, unlike conventional Treg cells, CD4 + Treg cells induced by IL-35 lack expression of Foxp3, and mediate suppressive activity independently of IL-10 and TGF-b [17].…”

Complexity of immune responses to AAV transgene products – Example of factor IX

“…Induced Treg are more resistant to blockage of the mTOR pathway by rapamycin because they utilize alternative signaling and metabolic pathways (that are independent of mTOR) [52]. Shifting the balance from Teff to Treg responses can be further enhanced by addition of other molecules such as the cytokines IL-10 or Flt3L [53, 54]. Such protocols were successful in prevention and reversal of antibody responses against FIX in muscle gene transfer in hemophilia B mice with F9 gene deletion [54, 55].…”

“…FLt3L does not aid in the induction of Treg but expands existing Treg in vivo indirectly through DC expansion [56]. Interestingly, in the presence of rapamycin, FLt3L enhances Treg induction through selective expansion of plasmacytoid DCs (pDCs), when dosed properly [53]. Although FL3L-Flt3 signaling occurs through the mTOR pathway, pDC have an up-regulated mTOR pathway and are therefore more resistant to rapamycin due to a miRNA expression pattern that is distinct from other DCs [57].…”