Seifarth C, Mack M, Steinlicht S, Hahn E-G, Lohmann T
Medizinische Klinik 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, Erlangen, Germany.
Horm Metab Res. 2006 Mar;38(3):167-71. doi: 10.1055/s-2006-925221.
The influx of autoreactive lymphocytes into the site of an autoimmune inflammation is mediated by certain chemokines. Autoimmune insulitis in type 1 diabetes is viewed as the result of destructive Th-1-cells and their corresponding antigen-presenting cells infiltrating the pancreatic islets. Blocking the chemokine receptors that mediate a Th-1-reaction has been shown to reduce autoimmunity in other experimental autoimmune disorders. We used the NOD mouse model to investigate the potency of anti-CCR2 and anti-CCR5 antibodies to inhibit the influx of Th-1-cells into the pancreatic islets, thus preventing diabetes onset. Eleven-week-old female NOD mice were treated with 500 microg of a monoclonal anti-CCR5 or anti-CCR2 or an isotype control antibody every third day over two weeks. We did not observe any preventive effect in either treatment group, but accelerated diabetes onset in the anti-CCR5 treated group. The number of autoantigen-specific Th-1-cells detected in the two treated groups was not reduced, but increased in the anti-CCR5 group. Redundancy within the chemokine system may account for this lack of prevention, or the intervention may have come too late in the disease process. Furthermore, blocking Th-1 chemokine receptors in the late autoimmune process may also inhibit regulatory T-cells, thus accelerating rather than preventing the disease.
自身反应性淋巴细胞向自身免疫性炎症部位的流入是由某些趋化因子介导的。1型糖尿病中的自身免疫性胰岛炎被视为破坏性Th-1细胞及其相应的抗原呈递细胞浸润胰岛的结果。在其他实验性自身免疫性疾病中，阻断介导Th-1反应的趋化因子受体已被证明可降低自身免疫性。我们使用非肥胖糖尿病（NOD）小鼠模型来研究抗CCR2和抗CCR5抗体抑制Th-1细胞流入胰岛从而预防糖尿病发病的效力。11周龄的雌性NOD小鼠在两周内每隔一天接受500微克单克隆抗CCR5或抗CCR2或同型对照抗体治疗。我们在两个治疗组中均未观察到任何预防效果，但在抗CCR5治疗组中糖尿病发病加速。在两个治疗组中检测到的自身抗原特异性Th-1细胞数量并未减少，而是在抗CCR5组中增加。趋化因子系统内的冗余可能是导致这种缺乏预防效果的原因，或者干预可能在疾病进程中为时已晚。此外，在自身免疫后期阻断Th-1趋化因子受体也可能抑制调节性T细胞，从而加速而非预防疾病进展。
