Zhang Y Clare, Pileggi Antonello, Agarwal Anupam, Molano R Damaris, Powers Matthew, Brusko Todd, Wasserfall Clive, Goudy Kevin, Zahr Elsie, Poggioli Raffaella, Scott-Jorgensen Marda, Campbell-Thompson Martha, Crawford James M, Nick Harry, Flotte Terence, Ellis Tamir M, Ricordi Camillo, Inverardi Luca, Atkinson Mark A
Department of Pathology, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610-0275, USA.
Diabetes. 2003 Mar;52(3):708-16. doi: 10.2337/diabetes.52.3.708.
Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 x 10(9) infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 x 10(8) infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.
胰岛移植是1型糖尿病的一种潜在治愈方法，但目前持续存在的自身免疫和同种异体免疫限制了其临床疗效。为减轻移植胰岛的自身免疫性破坏，在将650个同基因胰岛移植到肾被膜前4周，给新诊断的非肥胖糖尿病（NOD）小鼠单次肌内注射编码小鼠白细胞介素-10（IL-10）的重组腺相关病毒载体（rAAV-IL-10）。观察到胰岛移植物呈剂量依赖性保护。接受高剂量（4×10⁹感染单位）rAAV-IL-10转导的NOD小鼠中有60%（5只中的3只）至少117天保持血糖正常，而接受低剂量rAAV-IL-10（4×10⁸感染单位；5只中的5只）的小鼠以及所有对照小鼠（5只未治疗和4只rAAV-绿色荧光蛋白转导的小鼠中的4只）在17天内糖尿病复发。血清IL-10水平与移植物存活时间延长呈正相关，与自身免疫强度呈负相关。rAAV-IL-10保护机制涉及减少淋巴细胞浸润以及诱导胰岛移植物中的抗氧化酶锰超氧化物歧化酶和血红素加氧酶1。这些研究支持了rAAV介导的免疫调节细胞因子基因治疗在1型糖尿病基于移植的治疗中预防自身免疫性疾病复发的实用性。
