Treatment of glomerulonephritis: Will we ever have options other than steroids and cytotoxics?
Treatment of glomerulonephritis: Will we ever have options other than steroids and cytotoxics?
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DOI：
10.1111/j.1523-1755.2005.00266.x
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发表时间：
2005-05-01
影响因子：
19.6
通讯作者：
Quigg, RJ
中科院分区：
文献类型：
--
作者：
Javaid, B;Quigg, RJ
肾小球肾炎是指一组原发和继发于系统性疾病的肾脏疾病，其特征都是肾小球内的炎症。考虑到这些疾病的潜在免疫学性质，它们通常使用皮质类固醇和各种细胞毒剂进行治疗。虽然在许多情况下，这种疗法是成功的，但它们与严重的发病率有关；因此，替代疗法显然是必要的。我们对免疫性肾小球疾病发病机制的了解显著增长，这在很大程度上是通过对啮齿类疾病模型的研究。每一种疾病的基础都是抗原特异性免疫反应的发展，随后是炎症的效应阶段。为了阻断免疫反应，可以使用抗原特异性治疗来诱导耐受，例如通过在狼疮性肾炎中使用双链DNA分子。由于其他抗原系统的特性不是很好，通过阻断共刺激分子CD40-CD154和CD28-CD80/R6来诱导更广泛的免疫反应障碍是治疗各种免疫疾病和移植的一种日益增长的方法。为了减轻肾小球炎症，多种效应系统被作为靶点，包括补体、细胞因子/趋化因子、黏附分子和细胞增殖的介质。其中，针对补体系统中CS的抗体，以及肿瘤坏死因子-α(TNF-α)的抗体和受体拮抗剂已经被用于治疗肾小球疾病，前景看好。对由血小板衍生生长因子和细胞周期蛋白刺激的受体介导的事件的特异性较低的阻断可能很快就会应用于肾小球肾炎。最后，阻断纤维形成途径，导致肾小球硬化和间质纤维化，是所有肾小球肾炎终末期常见的，是可能产生有效生物疗法的紧张努力的主题。尽管有这些进展，我们仍然依赖类固醇和细胞毒素来治疗肾小球肾炎。为了克服这一点，我们必须投入大量资源，在基础研究实验室中进行观察，以开发治疗方法，并证明其在人类疾病中的有效性。
Glomerulonephritis refers to a collection of primary renal disorders and those secondary to a systemic disease, all characterized by inflammation within the glomerulus. Given the underlying immunologic nature of these disorders, they arc routinely treated with corticosteriods and various cytotoxic agents. Although in many instances such therapies are successful, they are associated with significant morbidity; as such, alternatives are clearly necessary. Our understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably, in large part from the study of rodent disease models. Fundamental to each disorder is the development of an antigen-specific immune response followed by the effector stage of inflammation. To block the immune response, antigen-specific therapy can be used to induce tolerance, such as through the use of double-stranded DNA molecules in lupus nephritis. Since other antigen systems are less well characterized, inducing a more generalized impairment in the immune response by blocking costimulatory molecules CD40-CD154 and CD28-CD80/R6 is a growing approach to treat various immunologic disorders and transplantation. To reduce glomerular inflammation, a variety of effector systems have been targeted, including complement, cytokines/chemokines, adhesion molecules, and mediators of cellular proliferation. Of these, antibodies targeting CS in the complement system, and antibody and receptor antagonists of tumor necrosis factor-alpha (TNF-alpha) have already been used in glomerular disorders with some promise. Less specific blockade of receptor-mediated events stimulated by platelet-derived growth factors and cell cycle proteins may soon be applied to glomerulonephritis. Finally, interruption of (fibrosing pathways, which lead to glomerulosclerosis and interstitial fibrosis common to the end-stage of all glomerulonephritis, is the subject of intense effort which may yield effective biologic therapies. In spite of all these advances, we still are dependent on steroids and cytotoxics to treat glomerulonephritis. To get past this, we must devote significant resources to take observations made in basic research laboratories to develop therapeutics and prove their utility in human disease.