Tolerance Induction by Exosomes from Immature Dendritic Cells and Rapamycin in a Mouse Cardiac Allograft Model

Abstract

BackgroundDendritic cells (DCs) release bioactive exosomes that play an important role in immune regulation. Because they express low levels of class I major histocompatibility complex (MHC) and co-stimulatory molecules, exosomes derived from donor immature DCs (imDex) prolong allograft survival by inhibiting T-cell activation. However, this effect is limited and does not induce immunological tolerance when imDex are administered alone. Thus, we tested the effect of combined treatment with donor imDex and low-dose rapamycin on inducing tolerance in a mouse cardiac transplantation model.MethodsImDex were obtained from the culture supernatant of immature DCs derived from donor mouse (C57BL/6) bone marrow and were injected with suboptimal doses of rapamycin into recipient mouse (BALB/c) before and after transplantation. The capacity of this treatment to induce immune tolerance was analyzed in vitro and in vivo using the mouse cardiac transplantation model.ResultsDonor imDex expressed moderate levels of MHC class II and low levels of MHC class I and co-stimulatory molecules, but neither imDex nor subtherapeutic rapamycin dose alone induced cardiac allograft tolerance. Combined treatment with imDex and rapamycin, however, led to donor specific cardiac allograft tolerance. This effect was accompanied by decreased anti-donor antigen cellular response and an increased percentage of spleen CD4+CD25+ T cells in recipients. Furthermore, this donor specific tolerance could be further transferred to naïve allograft recipients through injection of splenocytes, but not serum, from tolerant recipients.ConclusionCombined with immunosuppressive treatment, donor imDex can prolong cardiac allograft survival and induce donor specific allograft tolerance.

Stabilization of Exosome-targeting Peptides via Engineered Glycosylation

“…Biologically derived nanoparticles are an emerging subset of lipid nanoparticles that have been shown to effectively deliver a wide range of functional biomolecules, evade or dampen immune responses, and accumulate in tumors (2)(3)(4). In particular, exosomes, which are endosomally derived secreted vesicles, have shown great promise as therapeutic delivery vehicles (5,6).…”

“…In contrast, displaying targeting ligands on exosomes is relatively simple because peptide ligands can be genetically fused to the extra-exosomal termini of exosomal membrane proteins. This strategy has been applied to target exosome uptake by neurons by fusing a rabies viral glycoprotein (RVG) 3 peptide to the N terminus of lysosomal associated membrane protein 2b (Lamp2b) (7). Such a fusion resulted in RVG peptide being displayed on the surface of exosomes, leading to exosome uptake via the nicotinic acetylcholine receptor.…”

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

“…Importantly, exosomes from a variety of cell populations can mediate either immune activation or immune suppression based on the individual immunological microenvironment. [34][35][36][37] In autoimmunity, it has also been suggested that exosomes play a role in the chronic inflammatory response and that the cellular origin of exosomes will differentially influence the immune response in autoimmune disease. 6,38,39 Our data are important because they emphasize that co-stimulatory molecules play a pivotal role in APC-mediated immune responses, particularly T-cell activation and proliferation.…”

Exosome-mediated immune regulation and its clinical application

“…Immature DCs release exosomes more vigorously than mature DCs [22,23] . Immature DC exosomes exhibit a potent role in Treg cell activation [23,24] , suggesting maintenance of homeostasis by suppressing autoimmune reactions and excessive inflammations. Whereas, mature DCs release exosomes to facilitate tumoricidal immune reactions.…”