Engineering Programmed Death Ligand-1/Cytotoxic T-Lymphocyte-Associated Antigen-4 Dual-Targeting Nanovesicles for Immunosuppressive Therapy in Transplantation

Abstract

T cell activation by immune allorecognition is a major contributing factor toward the triggering of organ rejection. Immunosuppressive drugs have to be taken after organ transplantation, but long-term use of these drugs increases the risks of infection and other serious disorders. Here, we showed dysregulation of programmed cell deathligand 1/programmed cell death 1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated protein 4/cluster of differentiation 80 (CTLA-4/CD80) in the spleen of two organ transplantation models. Using a bioengineering approach, cellular exosome-like nanovesicles (NVs) displaying PD-L1/CTLA-4 dual-targeting cargos were designed, and their specificity to bind their ligands PD-1 and CD80 on T cell and dendritic cell surfaces was confirmed. These NVs consequently enhanced PD-L1/PD-1 and CTLA-4/CD80 immune inhibitory pathways, two key immune checkpoints to co-inhibit T cell activation and maintain peripheral tolerance. It was also confirmed that PD-L1/ CTLA-4 NVs led to the reduction of T cell activation and proliferation in vitro and in vivo. Finally, it was demonstrated that PD-L1/CTLA-4 NVs reduced density of CD8 + T cells and cytokine production, enriched regulatory T cells, and prolonged the survival of mouse skin and heart grafts. Taken together, these data supported the idea that PD-L1/CTLA-4 dual-targeting NVs exert immune inhibitory effects and may be used as a prospective immunosuppressant in organ transplantation.

Placental Immune Tolerance and Organ Transplantation: Underlying Interconnections and Clinical Implications

“…In brief, the PD-1/PD-L1 axis can induce tolerance in organ transplantation through PD-1 and CD28 gates and influence the effector T cells. Xu et al (62) reported that cellular exosome-like nanovesicles could inhibit the proliferation of mononuclear cells in peripheral blood (76% vs. 2%, P < 0.001) through the interaction of PD-1/PD-L1 and CTLA-4/CD80, which would subsequently decrease the density and activation of CD8 + T cells, downregulate cytokine production (HEK293T cells), and prolonged the survival of mouse skin and heart grafts. The blocked PD-1/PD-L1 axis could lead to a high rejection rate [37% to 80% (63)] for transplanted organs.…”

Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

“…The secretome including soluble proteins and extracellular vesicles are highlighted as an acellular regenerative therapy for liver disease [ 78 ]. EVs are as expected from the nature of EVs, the recent study indicates that EVs or EV-like nanovesicles will be useful for the potential therapeutic usage as a prospective immunosuppressant, and proposed the possible usage of dual-targeting vesicles, composed of programmed cell death-ligand 1/programmed cell death 1 (PD-L1/PD-1) and cytotoxic T-lymphocyte-associated protein 4/cluster of differentiation 80 (CTLA-4/CD80) [ 79 ].…”

Combined Application of Nanotechnology and Multiple Therapies with Tumor Immune Checkpoints

“…[24] Concentrating the dose on the relevant cells in place can enhance the therapeutic index and promote the effectiveness of immune checkpoint blocking therapy. [25] ( Figure 2)…”

“…Nanotechnology can improve the safety and effectiveness of immunomodulatory compounds by changing their spatiotemporal release profiles [24] . Concentrating the dose on the relevant cells in place can enhance the therapeutic index and promote the effectiveness of immune checkpoint blocking therapy [25] . (Figure 2)…”