Rott O, Cash E, Fleischer B
First Department of Medicine, University of Mainz.
Eur J Immunol. 1993 Aug;23(8):1745-51. doi: 10.1002/eji.1830230802.
The phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin-mediated shock, was tested for its immunosuppressive potential on T lymphocyte activation in vitro and in vivo. POX was found to have a profound inhibitory effect on both mitogen- and antigen-induced proliferation of CD4+ T cells in vitro. This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedly in vitro stimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX could drastically down-regulate tumor necrosis factor regulate production and to a lesser extent interleukin (IL)-2 secretion in activated T cells, but an excess of exogenous IL-2 did not override the antiproliferative effect of the drug. In contrast, the same doses of POX had no inhibitory effect on spontaneous or induced IL-4 and IL-6 production by short-term cultured T lymphocytes, indicating a selective sparing of T helper type 2 (Th2)-associated lymphokine functions by the drug. To test a potential use of POX as an antiinflammatory agent in T cell-mediated autoimmune disease, the influence of POX on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) was assessed. The onset of EAE in Lewis rats could almost completely be abrogated by oral administration of POX during the induction phase of disease. Lack of clinical symptoms in POX-treated animals coincided with a marked suppression of MBP-specific T cell reactivity in vitro, without any evidence for a generalized impairment of T cell activity. Collectively, our data suggest the potential use of xanthine derivatives of the POX type as a supporting antiinflammatory therapeutic agent in Th1 CD4+ T cell-mediated autoimmune diseases in animal models and possibly in man.
磷酸二酯酶抑制剂己酮可可碱（POX）在多器官功能衰竭和内毒素介导的休克动物模型中具有药理作用，本研究对其在体外和体内对T淋巴细胞活化的免疫抑制潜力进行了测试。结果发现，POX在体外对丝裂原和抗原诱导的CD4 + T细胞增殖均有显著抑制作用。在刺激过程中用cAMP类似物处理T淋巴细胞可重现该药物的这种抑制活性。与新鲜静息淋巴细胞的反应相比，该药物和cAMP类似物对反复体外刺激细胞的反应抑制作用更强。此外，POX可显著下调活化T细胞中肿瘤坏死因子的产生，并在较小程度上下调白细胞介素（IL）-2的分泌，但过量的外源性IL-2并不能抵消该药物的抗增殖作用。相比之下，相同剂量的POX对短期培养的T淋巴细胞自发或诱导产生的IL-4和IL-6没有抑制作用，表明该药物选择性地保留了2型辅助性T细胞（Th2）相关的淋巴因子功能。为了测试POX作为T细胞介导的自身免疫性疾病抗炎剂的潜在用途，评估了POX对髓鞘碱性蛋白（MBP）诱导的实验性自身免疫性脑脊髓炎（EAE）的影响。在疾病诱导期口服POX几乎可以完全消除Lewis大鼠EAE的发病。POX处理的动物没有临床症状，这与体外MBP特异性T细胞反应性的显著抑制相一致，没有任何证据表明T细胞活性普遍受损。总体而言，我们的数据表明POX类型的黄嘌呤衍生物有可能作为动物模型以及可能在人类中Th1 CD4 + T细胞介导自身免疫性疾病的辅助抗炎治疗剂。
