Schlöder Janine, Berges Carsten, Luessi Felix, Jonuleit Helmut
Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany.
Department of Neurology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany.
Int J Mol Sci. 2017 Jan 28;18(2):271. doi: 10.3390/ijms18020271.
Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4⁺ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation.
多发性硬化症(MS)是一种慢性自身免疫性疾病,由自身反应性T淋巴细胞抑制不足引起。免疫控制缺失的一个原因是效应T细胞(Teff)对调节性T细胞(Treg)抑制特性的反应性降低,这一过程称为Treg抵抗。在此,我们研究了复发缓解型MS(RRMS)的疾病修饰疗法富马酸二甲酯(DMF)是否会影响患者外周血T细胞对Treg介导抑制的敏感性。我们证明,DMF在体外恢复了Teff对Treg抑制功能的反应性,可能是通过下调T细胞上的白细胞介素-6受体(IL-6R)表达来实现的。将人类免疫细胞转移到免疫缺陷小鼠体内会导致由人类CD4⁺ Teff引发的致命移植物抗宿主反应。在从接受DMF治疗的MS患者转移免疫细胞后,活化的Treg可预防这种全身炎症,但从未经治疗的MS患者注射Treg抵抗的Teff后则不能预防。此外,DMF治疗后,T细胞的增殖和扩增以及向动物脾脏的迁移会减少,并受到活化Treg的调节。总之,我们的数据表明,DMF治疗显著提高了MS患者中Teff对免疫调节的反应性。