Ischemia reperfusion injury (IRI) evokes major intra-graft inflammatory responses that markedly augment alloimmune responses. Understanding mechanisms involved is critical for the development of novel therapeutic regimens that prevent/ameliorate organ IRI while mitigating graft immunogenicity. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DC). While autophagy serves as a protective survival mechanism for ischemic DC, the production of IL6 by ischemic DC, in turn, promotes CD4⁺ alloreactive T cells. Of note, allograft derived Dendritic Cells (ADDC) lacking the autophagy related gene Atg5, experienced higher rates of death post transplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice, in which DCs lack Atg5 protein showed also marked reduction of intra graft IL6 as compared to controls (n=3mice/group, p<0.05)). To antagonize the effect of intragraft IL6, we synthesized novel anti-IL6 nanoparticles that have the capacity for controlled release of anti-IL6 over time. Localized nanodelivery of anti-IL6 was found to be far superior to systemic delivery of anti-IL6 in reducing IRI related induced chronic rejection by histology.

These data carry high clinical significance to improve the outcome of organ transplantation by devising innovative targeted-strategies to manipulate organs prior to transplantation that diminish intra graft inflammation.

CITATION INFORMATION: Uehara M, Solhjou Z, Bahmani B, Maarouf O, Ichimura T, Brooks C, Xu W, Kasinath V, Banouni N, Elkhal A, Guleria I, McGrath M, Tullius S, Abdi R. Novel Application of Localized Nanodelivery of Anti-IL6 Protects Organ Transplant from Ischemia Reperfusion Injuries. Am J Transplant. 2017;17 (suppl 3).

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