Abstract
Purpose Ischemia-reperfusion injury (IRI) is the strongest non-HLA factor that augments allogenicity of transplanted organs. Damage subsequent to IRI is critically linked to an abundance of reactive oxygen species (ROS), including H202 that initiates inflammation and significantly contributes to allograft loss. Antioxidant Polymer Prodrugs, or APPs™, are potent, site-specific, self-limiting therapeutics that mitigate inflammation by reducing localized oxidative stress. APPs are innovative, highly effective, and safe antioxidative and anti-inflammatory therapies. Here, we show that APP-103 is able to mitigate IRI incurred during transplant surgery by reducing inflammation and improving graft function. Methods Lew kidneys were stored at 4°C after procurement. Recipients received APP-103 (i.v./15mg/Kg) or vehicle (PBS); time for anastomosis was 25±5 minutes. Kidney function was assessed by serum creatinine (SCrea) measured at days 1 and 7 after transplantation. Local inflammation was determined by histology and qPCR for pro-and anti-inflammatory cytokines. Dosing at -1 and +2hrs after transplant was based on pharmacokinetic studies that revealed a 3-hr half-life for APP-103. Results APP-103 ameliorated IRI in prior studies of warm ischemia (kidney, heart and limb injury). Here, we demonstrate that APP-103 restores graft function following renal transplantation in syngeneic rat models by early mitigation of inflammatory responses. Recipients treated with APP-103 had 40% improved graft function (SCrea at days 1 and 7). Pathological analysis confirmed a significant reduction in interstitial fibrosis and tubular atrophy on POD days 1 and 7. Extended cold ischemia conditions were also mitigated by APP-103 with >50% SCrea reduction. Treatment with APP-103 resulted in reduced intragraft mRNA levels of the pro-inflammatory cytokines TNF-a and IL-6, inhibition of T cell proliferation cytokine IL-2, and a significant increase of the anti-inflammatory cytokine IL-10.Of further clinical relevance, APP-103 had no associated toxicity at the highest administrable dose. Flow cytometry revealed a significant decrease in surface expression of activation and maturation markers including CD40, CD80, and CD86 on DCs treated with APP-103 during stimulation with LPS. Moreover, flow cytometry indicated that frequencies of CD4+ and CD8+ IFNγ+ cells were significantly reduced when DCs were cocultivated in presence of APP-103. Conclusion APP-103 is a novel and safe therapeutic that targets on-site ROS showing impressive preservation of graft structure and function while dampening the initial inflammatory response linked to IRI.
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