Bieg S, Hanlon C, Hampe C S, Benjamin D, Mahoney C P
Department of Medicine, University of Washington, USA.
Autoimmunity. 1999;31(1):15-24. doi: 10.3109/08916939908993855.
To investigate whether GAD65 whole molecule, GAD65 p35 or insulin B chain peptide (amino acids 9-23) play an essential role in the pathogenesis of type 1 diabetes in the BioBreeding (BB) rat, we gave serial injections of GAD65, p35 or insulin B chain (9-23) to six groups of BB/Worcester rats. The individual antigens were administered either intrathymically on day 2 and intraperitoneally in MF 59-0 adjuvant 5 times during the first 5 weeks, or by intranasal instillation once neonatally and 5 days/week for the following 6 weeks. Control groups were injected with vehicle only. Age of onset of diabetes and degree of insulitis were not different between controls and antigen-treated rats. Rats that received GAD65 intrathymically and intraperitoneally developed high GAD65-antibody titers without altering diabetes development. In GAD65-treated animals, serum antibodies recognized epitopes at 3 sites on GAD65 in diabetic animals but only at 1 site in non-diabetic animals. GAD65-injected animals also showed a significant reduction of IFN-gamma mRNA expression in the thymus. This study provides evidence against the hypothesis that GAD65 and insulin B chain peptide (9-23) are primary diabetogenic autoantigens in BB rats because immunizations with these antigens and GAD65-induced immune deviation did not alter the development of diabetes.
为了研究谷氨酸脱羧酶65（GAD65）全分子、GAD65 p35或胰岛素B链肽（氨基酸9 - 23）在BioBreeding（BB）大鼠1型糖尿病发病机制中是否起关键作用，我们对六组BB/Worcester大鼠连续注射GAD65、p35或胰岛素B链（9 - 23）。在第2天经胸腺内注射，在前5周内于MF 59 - 0佐剂中腹腔注射5次给予单个抗原，或者在新生期经鼻内滴注1次，并在接下来的6周内每周5天经鼻内滴注。对照组仅注射赋形剂。对照组和抗原处理组大鼠的糖尿病发病年龄和胰岛炎程度没有差异。经胸腺内和腹腔内给予GAD65的大鼠产生了高GAD65抗体滴度，但并未改变糖尿病的发展。在GAD65处理的动物中，血清抗体在糖尿病动物的GAD65上识别3个位点的表位，但在非糖尿病动物中仅识别1个位点。注射GAD65的动物胸腺中干扰素γ mRNA表达也显著降低。本研究提供了证据反驳GAD65和胰岛素B链肽（9 - 23）是BB大鼠原发性致糖尿病自身抗原的假说，因为用这些抗原免疫以及GAD65诱导的免疫偏离并未改变糖尿病的发展。
