Adoptive transfer of tolerized dendritic cells—a potential new strategy for the prevention of AKI

According to new data from a study by Li Li and colleagues, adoptive transfer of dendritic cells tolerized with the selective adenosine 2A-receptor (A_2AR) agonist, ATL313, protects the kidneys of wild-type mice from ischaemia–reperfusion injury (IRI)—a model that mimics acute kidney injury (AKI) in humans. The researchers suggest that administration of dendritic cells tolerized using A_2AR agonists could be a new therapeutic strategy for the prevention of AKI.

Previously, the researchers showed that dendritic cells and natural killer T (NKT) cells had a critical role in the initiation of the immune response to IRI in murine kidneys. In addition, activation of A_2ARs on immune cells using a selective agonist protected the kidneys of wild-type mice from IRI. “We hypothesised that blocking dendritic-cell-mediated NKT-cell activation could provide a new therapeutic strategy for prevention of AKI”, explains principal investigator Mark Okusa.

In the present study, the researchers generated mice with selective knockout of A_2ARs on their dendritic cells. These A_2AR-knockout mice were more susceptible to surgery-induced kidney IRI than were wild-type mice, and the renoprotective effect of treatment with ATL313 was abrogated. The researchers concluded that activation of A_2ARs expressed on dendritic cells by either endogenously released adenosine or selective A_2AR agonists protects against tissue injury.

“Because systemic administration of drugs may have untoward side effects, we wondered whether the renoprotective effect of A_2AR agonists might be realized using an alternative approach”, says Okusa. The researchers found that by treating dendritic cells ex vivo with ATL313 and the NKT cell glycolipid antigen αGC, they were able to produce tolerogenic dendritic cells that were specifically targeted to block dendritic-cell–NKT-cell interactions. Adoptive transfer of these tolerized dendritic cells into wild-type mice inhibited IRI-induced kidney inflammation and NKT-cell activation. Moreover, administration of the tolerized dendritic cells as early as 7 days before or as late as 6 h after surgery protected the kidneys from IRI.

“In our model, we demonstrated that A_2AR-agonist-induced dendritic cell tolerance has strong biological activity, which prevents NKT-cell-mediated innate immune activation and provide protection from kidney IRI”, concludes Okusa. “Thus, we have now provided the proof-of-principle for pharmacologically tolerizing dendritic cells for use in the prevention of AKI.”