Vial T, Descotes J
Laboratoire d'Immunotoxicologie Fondamentale et Clinique, INSERM U80, Faculté de Médecine Alexis Carrel, Lyon, France.
Toxicology. 1995 Dec 20;105(1):31-57. doi: 10.1016/0300-483x(95)03124-x.
A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
自上世纪九十年代以来，已经积累了大量关于细胞因子给药不良反应的临床经验。细胞因子治疗性使用后报告的副作用表明，免疫反应的激活有时可能产生有害后果。一些效应是细胞因子诱导的免疫激活的直接结果，例如流感样反应、血管渗漏综合征。细胞因子诱导的基础疾病加重或免疫失调是其他日益受到关注的并发症。现在已经明确，α-干扰素（IFN-α）治疗与几种自身抗体或自身免疫性疾病（甲状腺炎、系统性红斑狼疮、血液系统疾病、胰岛素依赖型糖尿病）的加重或发生，或涉及细胞介导免疫功能改变的疾病（炎症性皮肤病、肾炎、肺炎、结肠炎）有关。相比之下，IFN-β和IFN-γ的免疫副作用很少被报道。然而，这两种细胞因子的临床经验范围仍然非常有限。白细胞介素-2（IL-2）也与各种可能涉及免疫病理过程的疾病有关（甲状腺疾病、类风湿性关节炎、皮肤病、间质性肾炎）。生长因子通过中性粒细胞、单核细胞/巨噬细胞或嗜酸性粒细胞的激活，更具体地与皮肤炎症性疾病的发展或加重有关（例如皮肤血管炎和全身性皮疹、Sweet综合征、大疱性皮疹、银屑病）。仅粒细胞-巨噬细胞集落刺激因子（GM-CSF）被描述可加重自身免疫性甲状腺炎。细胞因子的免疫原性也具有重要意义，并且已经报道了结合IFN-α和IFN-β、IL-2和GM-CSF的抗体的出现。虽然非中和抗体的临床意义尚未明确确定，但在产生中和抗体的患者中已经描述了无反应或临床疗效逆转的情况。最后，最近有几份单独的报告表明，IFN-α治疗可能与几种免疫抑制作用有关，而IL-2在临床上与感染并发症的发生率增加有关。
