Mellergård Johan, Havarinasab Said, Hultman Per
Division of Molecular and Immunological Pathology, Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden.
Toxicology. 2004 Mar 15;196(3):197-209. doi: 10.1016/j.tox.2003.10.004.
Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2(s)) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2(s)) mice were given 6 mg HgCl(2)/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.
由于利用啮齿动物体内许多存在于人类自身免疫中的特征能够轻松且可靠地诱发疾病状态，汞诱导的自身免疫（mHgAI）在啮齿动物中是一种理想的自身免疫模型。基因易感（H-2(s)）小鼠在接触汞（Hg）后会产生一种全身性自身免疫状态，伴有针对蛋白质纤维原蛋白的抗核仁抗体（ANoA）、短暂的多克隆B细胞活化、高免疫球蛋白血症以及全身性免疫复合物（IC）沉积。为了研究免疫调节药物治疗对HgAI疾病参数的短期和长期影响，将B10.S（H-2(s)）小鼠分组，给予含6 mg HgCl₂/l的饮用水，持续22周。用环孢素A（CyA）、高剂量他克莫司（HD他克莫司）或抗CD4单克隆抗体（a-CD4）进行为期三周的初始治疗可抑制Hg诱导的ANoA和IC沉积。在随后的19周小鼠仅接受Hg治疗时，这种效果持续存在。用抗IL-4单克隆抗体（a-IL-4）进行为期三周的初始治疗可抑制Hg诱导的IgE和IC沉积，但不能抑制ANoA。然而，随后在没有a-IL-4的情况下用Hg治疗19周会诱导IC沉积。T细胞调节药物加重了一些HgAI疾病参数：a-CD4刺激多克隆B细胞活化，a-IL-4增加IgG抗染色质抗体反应，低剂量他克莫司（LD他克莫司）增强ANoA、多克隆B细胞活化和IC沉积。我们得出结论，用a-CD4或CyA进行短期初始治疗可有效预防全身性自身免疫的诱导，并持续较长时间。然而，一些T细胞调节药物，尤其是低剂量他克莫司，不仅在持续治疗期间，而且在停止使用这些药物治疗后都会加重自身免疫表现。
