von Herrath M G, Coon B, Lewicki H, Mazarguil H, Gairin J E, Oldstone M B
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 1998 Nov 1;161(9):5087-96.
We tested the in vivo potential of a MHC class I-restricted blocking peptide to sufficiently lower an anti-viral CTL response for preventing virus-induced CTL-mediated autoimmune diabetes (insulin-dependent diabetes mellitus (IDDM)) in vivo without affecting systemic viral clearance. By designing and screening several peptides with high binding affinities to MHC class I H-2Db for best efficiency in blocking killing of target cells by lymphocytic choriomeningitis virus (LCMV) and other viral CTL, we identified the peptide for this study. In vitro, it selectively lowered CTL killing restricted to the Db allele, which correlated directly with the affinity of the respective epitopes. Expression of the blocking peptide in the target cell lowered recognition of all Db-restricted LCMV epitopes. In addition, in vitro expansion of LCMV memory CTL was prevented, resulting in decreased IFN-gamma secretion. In vivo, a 2-wk treatment with this peptide lowered the LCMV Db-restricted CTL response by over threefold without affecting viral clearance. However, the CTL reduction by the peptide treatment was sufficient to prevent LCMV-induced IDDM in rat insulin promoter-LCMV-glycoprotein transgenic mice. Following LCMV infection, these mice develop IDDM, which depends on Db-restricted anti-self (viral) CTL. Precursor numbers of splenic LCMV-CTL in peptide-treated mice were reduced, but their cytokine profile was not altered, indicating that the peptide did not induce regulatory cells. Further, non-LCMV-CTL recognizing the blocking peptide secreted IFN-gamma and did not protect from IDDM. This study demonstrates that in vivo treatment with a MHC class I blocking peptide can prevent autoimmune disease by directly affecting expansion of autoreactive CTL.
我们测试了一种MHC I类限制性阻断肽在体内的潜力，它能够充分降低抗病毒CTL反应，从而在不影响全身病毒清除的情况下，预防病毒诱导的CTL介导的自身免疫性糖尿病（胰岛素依赖型糖尿病（IDDM））。通过设计和筛选几种与MHC I类H-2Db具有高结合亲和力的肽，以实现最佳效率阻断淋巴细胞性脉络丛脑膜炎病毒（LCMV）和其他病毒CTL对靶细胞的杀伤，我们确定了本研究使用的肽。在体外，它选择性地降低了仅限于Db等位基因的CTL杀伤，这与各个表位的亲和力直接相关。阻断肽在靶细胞中的表达降低了对所有Db限制性LCMV表位的识别。此外，还阻止了LCMV记忆CTL在体外的扩增，导致IFN-γ分泌减少。在体内，用这种肽进行为期2周的治疗可使LCMV Db限制性CTL反应降低三倍以上，而不影响病毒清除。然而，肽治疗引起的CTL减少足以预防大鼠胰岛素启动子-LCMV-糖蛋白转基因小鼠中LCMV诱导的IDDM。LCMV感染后，这些小鼠会发生IDDM，这依赖于Db限制性抗自身（病毒）CTL。肽处理小鼠脾脏中LCMV-CTL的前体细胞数量减少，但其细胞因子谱未改变，表明该肽未诱导调节性细胞。此外，识别阻断肽的非LCMV-CTL分泌IFN-γ，且不能预防IDDM。这项研究表明用MHC I类阻断肽进行体内治疗可通过直接影响自身反应性CTL的扩增来预防自身免疫性疾病。
