Loser Karin, Balkow Sandra, Higuchi Tetsuya, Apelt Jenny, Kuhn Annegret, Luger Thomas A, Beissert Stefan
Department of Dermatology, University of Münster, Münster, Germany.
J Invest Dermatol. 2006 Jun;126(6):1307-15. doi: 10.1038/sj.jid.5700185.
Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.
自身免疫是由控制自身反应性的机制丧失所致。自身免疫性疾病发挥着越来越重要的作用，免疫活性细胞上的CD40 - CD40配体（CD40L）相互作用能够打破已建立的免疫耐受。为了研究钙调神经磷酸酶抑制剂FK506对CD40L诱导的全身性自身免疫的影响，在明显的自身免疫发作后，用FK506治疗自发发展为混合性结缔组织样疾病的CD40L转基因（tg）小鼠。有趣的是，用FK506治疗的CD40L tg小鼠的自身免疫性皮炎评分显著降低，病变部位浸润白细胞数量明显减少。这一发现与FK506治疗引起的淋巴结病减轻有关。此外，FK506抑制了细胞毒性/自身反应性CD8(+) T细胞的发育，这在经治疗的CD40L tg小鼠中T细胞活化标志物表达降低得到证明。重要的是，FK506使CD40L tg动物血清中的自身抗体滴度显著降低。由于CD40L tg小鼠会发展为肾炎导致肾功能丧失，在注射FK506后测定蛋白尿情况。值得注意的是，FK506治疗恢复了肾功能，这在经治疗的CD40L tg小鼠尿蛋白浓度显著降低中得到体现。总之，这些发现表明FK506对治疗CD40L诱导的自身免疫具有有益的治疗效果。此外，这些结果表明FK506能够抑制正在进行的严重自身免疫反应。
