Introduction: Solid organ transplantation has seen a increase in the utilization of older organs. Here, we investigate how aging-associated kinetics of damage associated molecular patterns (DAMPs) including mtDNA are driving the augmented susceptibility of older organs to IRI through dendritic cells (DCs) with subsequent inferior graft survival.

Methods: Old and young mice underwent bilateral clamping of the renal pedicles (22 min ischemic time). mtDNA, cytokine and senescence marker levels were tested by qPCR; DC and T cell activation were characterized by FACS. Old and young DCs were adoptively transferred into young recipients that subsequently received young or old cardiac allografts.

Results: DCs of old naïve mice showed higher frequencies and levels of maturation in parallel to increased baseline levels of mtDNA. Importantly, renal IRI induced a prominent release of mtDNA into the circulation of old animals (after 48h; p=0.019) and an increased IFN-γ expression in splenic CD8⁺ T cells (p=0.0001). Isolated DCs showed a dose-dependent up-regulation of CD40 with augmented amounts of IL-6 in the presence of mtDNA; the addition of a TLR9 antagonist attenuated this pro-inflammatory response of old DCs. In addition, old DCs promoted IFN-γ and IL-17 responses of allogeneic T cells in vitro. Of particular relevance, adoptive transfer of old but not young DCs prior to transplantation shortened cardiac allograft survival (p<0.0001).

Treatment with the senolytic agents Dasatinib (5mg/kg) and Quercetin (50mg/kg) not only reduced local expression of senescence marker p16 and p21 in kidneys, but also reduced local and systemic mtDNA levels in old mice. Levels of IFN-γ and IL-17 and systemic frequencies of CD8⁺IFN-γ⁺ and CD4⁺IL-17⁺ T cells were reduced subsequent to the treatment. These in-vitro effects translated into prolonged survivals of old cardiac allografts that underwent pretreatment with senolytic agents (p<0.0280).

Conclusion: Our results suggest a pivotal role for mtDNA in driving allogeneic immune responses to old donor organs, critically affecting graft survival. Senolytic treatment reduced mtDNA release.

CITATION INFORMATION: Minami K., Seyda M., Heinbokel T., Nian Y., Quante M., Liu G., Abdi R., Tchkonia T., Kirkland J., Elkhal A., Tullius S. Senolytic Drug Treatment Attenuates mtDNA-Mediated Inflammatory Injury in Old Donors and Prolongs Cardiac Allograft Survival Am J Transplant. 2017;17 (suppl 3).

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