Grönholm Juha, Pagni Philippe P, Pham Minh N, Gibson Claire B, Macomber Paul F, Vela José Luis, von Herrath Matthias, Lenardo Michael J
Molecular Development of the Immune System Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases (NIAID) and Clinical Genomics Program, NIAID, National Institutes of Health, Building 10, Room 11D14, 10 Center Drive, Bethesda, MD, 20814, USA.
Novo Nordisk Type 1 Diabetes Center, Novo Nordisk Research Center, Seattle, WA, USA.
Diabetologia. 2017 Aug;60(8):1475-1482. doi: 10.1007/s00125-017-4276-5. Epub 2017 Apr 28.
AIMS/HYPOTHESIS: Insulin is widely considered to be a driver antigen in type 1 diabetes in humans and in mouse models of the disease. Therefore, insulin or insulin analogues are candidates for tolerogenic drugs to prevent disease onset in individuals with risk of diabetes. Previous experiments have shown that autoimmune diabetes can be prevented in NOD mice by repeated doses of insulin administered via an oral, nasal or parenteral route, but clinical trials in humans have not succeeded. The hypoglycaemic activity of insulin is dose-limiting in clinical studies attempting tolerance and disease prevention. Here, we aimed to investigate the therapeutic potential of metabolically inactive insulin analogue (MII) in NOD mice.
The tolerogenic potential of MII to prevent autoimmune diabetes was studied by administering multiple i.v. or s.c. injections of MII to non-diabetic 7-12-week-old female NOD mice in three geographical colony locations. The incidence of diabetes was assessed from daily or weekly blood glucose measurements. The effect of MII on insulin autoantibody levels was studied using an electrochemiluminescence-based insulin autoantibody assay. The effect on the number of insulin-reactive CD8 and CD4 T lymphocytes in peripheral lymphoid tissue was studied with MHC class I and MHC class II tetramers, respectively.
We found that twice-weekly s.c. administration of MII accelerates rather than prevents diabetes. High-dose i.v. treatment did not prevent disease or affect insulin autoantibody levels, but it increased the amount of insulin-reactive CD4 T lymphocytes in peripheral lymphoid tissue.
CONCLUSIONS/INTERPRETATION: Our data suggest that parenteral MII, even when used in high doses, has little or no therapeutic potential in NOD mice and may exacerbate disease.
目的/假设：在人类和该疾病的小鼠模型中，胰岛素被广泛认为是1型糖尿病的驱动抗原。因此，胰岛素或胰岛素类似物是用于预防糖尿病风险个体发病的耐受性药物候选物。先前的实验表明，通过口服、鼻内或肠胃外途径重复给予胰岛素，可预防非肥胖糖尿病（NOD）小鼠发生自身免疫性糖尿病，但人类临床试验并未成功。在试图诱导耐受性和预防疾病的临床研究中，胰岛素的降血糖活性限制了其剂量。在此，我们旨在研究代谢无活性胰岛素类似物（MII）在NOD小鼠中的治疗潜力。
通过对三个地理种群位置的7至12周龄非糖尿病雌性NOD小鼠进行多次静脉内或皮下注射MII，研究MII预防自身免疫性糖尿病的耐受性潜力。通过每日或每周测量血糖来评估糖尿病的发病率。使用基于电化学发光的胰岛素自身抗体测定法研究MII对胰岛素自身抗体水平的影响。分别用I类和II类主要组织相容性复合体（MHC）四聚体研究其对外周淋巴组织中胰岛素反应性CD8和CD4 T淋巴细胞数量的影响。
我们发现，每周两次皮下注射MII会加速而非预防糖尿病。高剂量静脉注射治疗不能预防疾病或影响胰岛素自身抗体水平，但会增加外周淋巴组织中胰岛素反应性CD4 T淋巴细胞的数量。
结论/解读：我们的数据表明，肠胃外给予MII，即使高剂量使用，在NOD小鼠中也几乎没有治疗潜力，甚至可能会加重病情。
