title: Local immunotherapy via delivery of interleukin-10 and transforming growth factor β antagonist for treatment of chronic kidney disease.
abstract: Obstructive nephropathy is the leading cause of kidney disease in children. The tissue injury resulting from initial dilation precipitates a deleterious cascade of macrophage infiltration, apoptosis, and fibrosis to produce a resultant dysfunctional tissue. We propose to abate this tissue remodeling process through immunotherapy administered via the local and sustained delivery of interleukin-10 (IL-10; anti-inflammatory) and anti-transforming growth factor β (anti-TGFβ; anti-fibrotic). Shear-thinning, injectable hyaluronic acid (HA) hydrogels were formed through supramolecular guest-host interactions and used to contain IL-10, anti-TGFβ, or both molecules together. Degradation assays demonstrated that diffusive molecule release was associated with concurrent hydrogel erosion and was sustained for up to 3weeks in vitro. Erosion was likewise monitored in vivo by non-invasive optical imaging, where gel localization to the affected tissue was observed with near complete clearance by day 18. Hydrogels were applied to a murine model of chronic kidney disease, with subcapsular hydrogel injections acting as a delivery depot. Quantitative histological analysis (days 7, 21, and 35) was used to evaluate treatment efficacy. Notably, results demonstrated reduced macrophage infiltration beyond day 7 in treatment groups and reduced apoptosis at day 21, relative to untreated unilateral ureteral obstruction disease model. Fibrosis was reduced at the 35day timepoint in groups treated with IL-10 or anti-TGFβ alone, but not with the combination therapy. Rather, dual delivery of IL-10 and anti-TGFβ resulted in a paradoxical hastening of fibrosis, warranting further investigation. Localized immunotherapy is a novel approach to treat kidney disease and shows promise as a translatable therapy.
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: crodell@seas.upenn.edu.
authors: Christopher B
authors: CB
authors: Rodell
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: rai.reena@gmail.com.
authors: Reena
authors: R
authors: Rai
authors: Department of Medicine, University of Colorado, Aurora, CO, USA. Electronic address: sarah.faubel@ucdenver.edu.
authors: Sarah
authors: S
authors: Faubel
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: burdick2@seas.upenn.edu.
authors: Jason A
authors: JA
authors: Burdick
authors: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA; Departments of Pediatrics and Bioengineering, University of Colorado, Aurora, CO, USA. Electronic address: Danielle.Soranno@childrenscolorado.org.
authors: Danielle E
authors: DE
authors: Soranno
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000737:chemistry*; D016503:Drug Delivery Systems; D005355:Fibrosis / Q000150:complications / Q000473:pathology / Q000628:therapy; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D020100:Hydrogels / Q000737:chemistry; D007167:Immunotherapy; D016753:Interleukin-10 / Q000008:administration & dosage* / Q000627:therapeutic use; D007668:Kidney / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000473:pathology / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D020100:Hydrogels; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D006820:Hyaluronic Acid
keywords: Anti-transforming growth factor β; Chronic kidney disease; Drug delivery; Hydrogel; Immunotherapy; Interleukin-10