CD11c+ DCs Accelerate the Rejection of Older Cardiac Transplants via IL-17A
Background—Organ transplantation has seen an increased utilization of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplant outcomes when utilizing older donor organs represent a growing challenge.
Methods and Results—Here, we characterize the impact of donor age on solid organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when utilizing older hearts. Shorter graft survival of older hearts was independent of organ age per se, as chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells (DCs) augmenting CD4+ and CD8+ T cell proliferation and pro-inflammatory cytokine production, particularly that of IL-17A. Of note, depletion of donor CD11c+ DCs prior to engraftment, neutralization of IL-17A or transplantation of older hearts into IL-17A-/- mice delayed rejection and reduced alloimmune responses to levels observed when transplanting young hearts.
Conclusions—These results demonstrate a critical role of old donor CD11c+ DCs in mounting age-dependent alloimmune responses with an augmented IL-17A response in recipient animals. Targeting IL-17A may serve as a novel therapeutic approach when transplanting older organs.
- Received December 16, 2014.
- Revision received April 27, 2015.
- Accepted April 29, 2015.