Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall 4EF
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 ROS, including H202 that initiates inflammation and significantly contributes to allograft loss. APPsTM are potent, site-specific, self-limiting therapeutics that mitigate inflammation by reducing localized oxidative stress. Here, we show that APP-103 can mitigates IRI incurred during transplant surgery by reducing inflammation.
Methods: Lew kidneys were stored at 4[deg]C after procurement. Recipients received APP-103 (i.v./15mg/Kg) or vehicle (PBS). Kidney function was assessed by serum creatinine (SCrea) measured at POD1 and 7. Local inflammation was determined by histology and qPCR for pro-and anti-inflammatory cytokines.
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 day 1). Pathological analysis confirmed a significant reduction in interstitial fibrosis and tubular atrophy on POD1 and 7. Prolonged cold ischemia had been mitigated by APP-103 with significantly SCrea reductions. Treatment with APP-103 resulted in reduced intragraft mRNA levels of pro-inflammatory cytokines TNF-a and IL-6, inhibition of T cell proliferation cytokine IL-2; notably a significant increase of the anti-inflammatory cytokine IL-10 was observed. Flow cytometry revealed a 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, frequencies of CD4+ and CD8+ IFNγ+ cells were significantly reduced when DCs were cocultivated in presence of APP-103 suggesting a potential to impact alloimmune responses.
Conclusion: APP-103 is a novel and safe therapeutic that targets on-site ROS showing impressive improvements of graft function and structure while dampening inflammatory responses linked to IRI.
CITATION INFORMATION: Minami K., Uehara H., Elkhal A., Weins A., Bae S., Reder J., Houser B., Kang P., Tullius S. The Novel Polymer Pro-Drug APP-103 Reduces 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, Weins A, Bae S, Reder J, Houser B, Kang P, Tullius S. The Novel Polymer Pro-Drug APP-103 Reduces I/R Injury and Improves Graft Function in a Pre-Clinical Renal Transplant Model [abstract]. https://atcmeetingabstracts.com/abstract/the-novel-polymer-pro-drug-app-103-reduces-i-r-injury-and-improves-graft-function-in-a-pre-clinical-renal-transplant-model/. Accessed March 8, 2021.
« Back to 2018 American Transplant Congress