Date: Tuesday, May 2, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
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 APP-103 to mitigate IRI injury incurred during transplant surgery by reducing inflammation and improving graft function.
Methods: Lew kidneys kept at 4[deg]C until transplanted. 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.
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.
CITATION INFORMATION: Minami K, Uehara H, Elkhal A, Bae S, Reder J, Houser B, Kang P, Tullius S. The Polymer Pro-Drug APP-103 Mitigates I/R Injury and Improves Graft Function in a Pre-Clinical Renal Transplant Model. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Minami K, Uehara H, Elkhal A, Bae S, Reder J, Houser B, Kang P, Tullius S. The Polymer Pro-Drug APP-103 Mitigates I/R Injury and Improves Graft Function in a Pre-Clinical Renal Transplant Model. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/the-polymer-pro-drug-app-103-mitigates-ir-injury-and-improves-graft-function-in-a-pre-clinical-renal-transplant-model/. Accessed September 30, 2020.
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