Novel Application of Localized Nanodelivery of Anti–Interleukin-6 Protects Organ Transplant From Ischemia–Reperfusion Injuries

Abstract

Ischemia reperfusion injury (IRI) evokes intra-graft inflammatory responses, which markedly augment alloimmune responses against the graft. Understanding the mechanisms underlying these responses is fundamental to develop therapeutic regimens to prevent/ameliorate organ IRI. Here, we demonstrate that IRI results in a marked increase in mitochondrial damage and autophagy in dendritic cells (DC). While autophagy is a survival mechanism for ischemic DC, it also augments their production of IL6. Allograft derived dendritic cells (ADDC) lacking autophagy related gene 5 (Atg5) showed higher death rates post-transplantation. Transplanted ischemic hearts from CD11cCre/Atg5 conditional knockout mice showed marked reduction in intra-graft expression of IL6 as compared to controls. To antagonize the effect of IL6 locally in the heart, we synthesized novel anti-IL6 nanoparticles with capacity for controlled release of anti-IL6 over time. As compared to systemic delivery of anti-IL6, localized delivery of anti-IL6 significantly reduced chronic rejection with a markedly lower amount administered. Despite improved allograft histology, there were no changes to splenic T cell populations, illustrating the importance of local IL6 in driving chronic rejection after IRI. These data carry potential clinical significance, by identifying an innovative, targeted strategy to manipulate organs prior to transplantation to diminish inflammation, leading to improved long term outcomes.

Ischemia augments alloimmune injury through IL-6-driven CD4+ alloreactivity

“…DCs are highly specialized to absorb oxidative stress signals and increase alloimmune activation via multiple routes including enhanced expression of MHC class II and positive costimulatory molecules, and the secretion of inflammatory cytokines 19 . Our group has previously shown that ischemic dendritic cells increase IL-6 production via activation of autophagy pathways 48 and ischemic allografts from mice lacking autophagy-related gene-5 in DCs had a marked reduction in IL-6 expression 48 . Furthermore, in vitro , IL-6 production by ischemic DCs leads to increased proliferation and pro-inflammatory cytokine production by allospecific CD4 + T cells 16 , 18 .…”

“…However, CTLA4Ig treatment has been complicated by an increased rate of early acute rejection episodes 69 , 71 and increased alloimmune activation of ischemic organs could increase the risk of rejection in CTLA4Ig treated patients. While we have previously shown the utility of anti-IL-6 in a class II mismatch model, here, we used a more clinically relevant, full MHC mismatch model of prolonged ischemia, where we investigated the synergistic effects of anti-IL-6 with CTLA4Ig 72 . Our data indicate a significant decrease in heart graft survival following severe IRI in sCTLA4Ig treated recipients, and adding anti-IL-6 abrogates this effect, by alleviating inflammation, decreasing immune cell trafficking to the ischemic organ and decreasing vascular injury; resulting in similar graft survival as control non-ischemic grafts.…”

Anti-IL-6 eluting immunomodulatory biomaterials prolong skin allograft survival

“…A growing body of evidence highlights the importance of novel strategies that can reduce intra-graft inflammatory responses effectively 13,14 . Intra-graft inflammatory responses have increasingly received attention as an instigator of the alloimmune response 15–19 .…”

Organ preservation with targeted rapamycin nanoparticles: a pre-treatment strategy preventing chronic rejection in vivo

“…Taken together, these data support the use of rapamycin encapsulated as a targeted nanotherapeutic micelle to abrogate transplant fibrosis and vasculopathy when used as a donor organ preservation pre-treatment strategy. In a recent study by Solhjou et al , novel controlled-release IL-6-containing nanoparticles were utilized as a pre-treatment method in experimental cardiac allografts to blunt early IRI injury and chronic rejection responses 31. In the novel studies presented here, we approach the problem of vasculopathy in a similar fashion in the preservation phase of transplantation prior to implantation of the allograft.…”