Ryffel B, Car B D, Woerly G, Weber M, DiPadova F, Kammüller M, Klug S, Neubert R, Neubert D
University of Zurich, Institute of Toxicology, Schwerzenbach, Switzerland.
Blood. 1994 Apr 15;83(8):2093-102.
Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.
白细胞介素-6（IL-6）在造血和免疫反应中都被认为具有重要作用，尽管其对整体宿主防御的贡献仍知之甚少。由于先前已表明短期IL-6治疗可刺激巨核细胞生成，我们研究了长期给予IL-6对非人类灵长类动物巨核细胞生成及其他全身参数的影响。我们选择了一种小型灵长类动物狨猴（Callithrix jacchus），这使得能够长期高剂量给药。在4周和9周内以高达1000微克/千克/天的剂量给予重组人IL-6（rhIL-6），导致血小板计数持续增加两倍至三倍，在4周时达到峰值。此后，尽管继续给予IL-6，血小板计数仍下降。与对照组相比，4周和9周时骨髓巨核细胞数量未增加，但倍性等级增加，这表明IL-6的作用在体内仅限于成熟巨核细胞。首次给予IL-6后24小时内观察到急性期蛋白反应，并在以25微克/千克给予IL-6 1周后达到最大值。血清C反应蛋白、触珠蛋白和铜蓝蛋白增加，而白蛋白和转铁蛋白水平下降。急性期蛋白反应与肝细胞损伤的任何形态学证据均无关。血清中Ig和可溶性IL-2受体水平升高反映了全身免疫刺激。没有肾系膜增生性病变的证据。在2周内产生了针对rhIL-6的抗体，在研究过程中持续增加。高滴度的中和抗体与血小板计数下降和急性期蛋白下降同时出现。因此，尽管在体外观察到IL-6具有多效性，但长期给予IL-6可在狨猴中引起选择性且持续的血小板生成刺激，这种刺激仅因中和抗体的出现而消除，并且狨猴对高剂量耐受性良好。长期将IL-6靶向巨核细胞系细胞而不引发一般毒性，证实了rhIL-6对血小板减少症患者进行慢性治疗的潜在治疗价值。
