Recently, it has been shown that Dendritic Cells (DCs) of old organs accelerate graft rejection by orchestrating IL-17A-mediated T cell responses. Moreover, cell-free DNA has lately been implicated as a novel biomarker for graft injury and rejection. Here, we investigated whether aging is altering the release of mitochondrial-DNA (mt-DNA) and tested effects on graft immunogenicity.

Circulating mitochondrial DNA levels were measured by quantitative PCR. DC activation in young (2 mths) and old (18 mths) C57BL/6 (B6) mice was characterized by flow cytometry analysis. Fully mismatched heart grafts from young (2 mths) or old (18 mths) B6 were transplanted into young (2 mths) DBA/2J recipient mice.

Circulating mitochondrial DNA was highly elevated in naive old mice while young animals, in sharp contrast, had no detectable circulating mt-DNA (p=0.02). Consistent with those findings, we found increased frequencies of DCs in the periphery of old mice vs. DC frequencies in young animals (p<0.0001). Next we co-cultured naive T cells with DCs to test their capacity on CD4⁺ T cell activation. Strikingly, T cells cultured with old DCs expressed more Th1/Th17 cytokines vs. young animals (p< 0.05). To confirm our observation in vivo, we performed adoptive transfers of old DCs and observed an increased priming of T cells. Additionally, we analyzed age-dependent inflammatory responses of DCs subsequent to LPS injection in vivo (2.5mg/kg). Of note, old DCs displayed an increased cytokine expression of IL-1β and TGF-β (p=0.02). To confirm the relevance of DC age in transplantation, we adoptively transferred either old or young DCs prior to heart transplantation and observed that the transfer of young DCs prolonged graft survival while, conversely, transfer of old DCs reduced graft survival (p=0.02).

Those data show that aging is linked to augmented amounts of circulating mitochondrial DNA that may impact a more potent immunogenicity of older DCs. Those aspects of clinical relevance when transplanting older organs and may provide novel therapeutic avenues.

CITATION INFORMATION: Seyda M, Li H, Liu G, Quante M, Uehara H, Schuitenmaker J, Elkhal A, Tullius S. Dendritic Cells and Damage-Associated Molecular Patterns in Aging. Am J Transplant. 2016;16 (suppl 3).

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