Schmied M, Duda P W, Krieger J I, Trollmo C, Hafler D A
Laboratory of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Clin Immunol. 2003 Mar;106(3):163-74. doi: 10.1016/s1521-6616(03)00020-2.
Glatiramer acetate (GA; Copaxone) is a random sequence polypeptide used in the treatment of relapsing remitting multiple sclerosis (RR MS). We have recently demonstrated that prior to treatment, GA induces proliferation of resting T cells and is not cross-reactive with myelin antigens. Daily GA injections induce a significant loss of this GA responsiveness, which is associated with the induction of highly cross-reactive Th2-type T cells potentially capable of suppressing inflammatory responses. The mechanism of action by which GA induces T cell nonresponsiveness leading to T cell receptor degeneracy in patients with RR MS is unknown. Here, we examined the effects of daily GA administration on the induction of T cell hyporesponsiveness. The frequency of GA-reactive T cells in peripheral blood of seven patients with RR MS was measured by limiting dilution analysis prior to and during 6 months of treatment. In addition, a model in which GA-reactive T cells were stimulated in vitro was developed to better characterize the selection of T cell populations over time. In vivo treatment with GA induced a decrease in GA-reactive T cell frequencies and hyporesponsiveness of CD4(+) T cell reactivity to GA in vitro that was only partially reversed by the addition of IL-2. These data suggest that T cell peripheral tolerance to GA was achieved in vivo during treatment. Thus, our in vitro data suggest that the underlying changes in GA-reactive CD4(+) T cell reactivity could be explained by the induction of T cell anergy and clonal elimination.
醋酸格拉替雷（GA；考帕松）是一种随机序列多肽，用于治疗复发缓解型多发性硬化症（RR MS）。我们最近证明，在治疗前，GA可诱导静息T细胞增殖，且与髓鞘抗原无交叉反应。每日注射GA会导致这种GA反应性显著丧失，这与诱导高度交叉反应的Th2型T细胞有关，这些T细胞可能能够抑制炎症反应。GA在RR MS患者中诱导T细胞无反应性并导致T细胞受体退化的作用机制尚不清楚。在此，我们研究了每日给予GA对诱导T细胞低反应性的影响。通过有限稀释分析法在7例RR MS患者治疗前及治疗6个月期间测量外周血中GA反应性T细胞的频率。此外，还建立了一个体外刺激GA反应性T细胞的模型，以更好地描述随着时间推移T细胞群体的选择情况。GA的体内治疗导致GA反应性T细胞频率降低，以及体外CD4(+) T细胞对GA反应性的低反应性，而添加IL-2只能部分逆转这种情况。这些数据表明，治疗期间在体内实现了T细胞对GA的外周耐受。因此，我们的体外数据表明，GA反应性CD4(+) T细胞反应性的潜在变化可以通过诱导T细胞无能和克隆清除来解释。
