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. APPs^TM 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).

« Back to 2018 American Transplant Congress