Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, University of Colorado, Aurora, CO, USA.
J Control Release. 2015 May 28;206:131-9. doi: 10.1016/j.jconrel.2015.03.025. Epub 2015 Mar 21.
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.
梗阻性肾病是儿童肾脏病的主要病因。最初扩张导致的组织损伤引发巨噬细胞浸润、细胞凋亡和纤维化的有害级联反应，从而产生功能失调的组织。我们拟通过局部和持续递送白细胞介素 10（IL-10；抗炎）和抗转化生长因子β（anti-TGFβ；抗纤维化）的免疫疗法来减轻这种组织重塑过程。通过超分子主客体相互作用形成了剪切稀化、可注射的透明质酸（HA）水凝胶，并用于包含 IL-10、抗 TGFβ 或这两种分子一起。降解试验表明，扩散分子的释放与水凝胶的侵蚀有关，在体外可持续长达 3 周。通过非侵入性光学成像同样监测体内的侵蚀，观察到凝胶定位到受影响的组织，并在第 18 天几乎完全清除。水凝胶应用于慢性肾脏病的小鼠模型中，囊下水凝胶注射作为递送库。定量组织学分析（第 7、21 和 35 天）用于评估治疗效果。值得注意的是，与未治疗的单侧输尿管梗阻疾病模型相比，治疗组在第 7 天以后巨噬细胞浸润减少，在第 21 天细胞凋亡减少。在单独用 IL-10 或抗 TGFβ 治疗的组中，在第 35 天纤维化减少，但在联合治疗组中没有。相反，IL-10 和抗 TGFβ 的双重递送导致纤维化的反常加速，这需要进一步研究。局部免疫疗法是治疗肾脏病的一种新方法，有望成为一种可转化的治疗方法。
