Lynes M A, Borghesi L A, Youn J, Olson E A
Department of Molecular and Cell Biology, University of Connecticut, Storrs 06269.
Toxicology. 1993 Dec 31;85(2-3):161-77. doi: 10.1016/0300-483x(93)90040-y.
Extracellular metallothionein (Zn,Cd-MT) has previously been shown to be a potent inducer of lymphocyte proliferation and to synergize with polyclonal activators in proliferation assays. In this report, the effects of metallothionein on the development of humoral responsiveness are examined. In vivo, the specific anti-ovalbumin (OVA) IgG response was diminished by co-injection of Zn, Cd-MT, while total IgG levels remained unchanged. A similar reduction was also observed when Zn,Cd-MT was administered during the development of an anti-sheep red blood cell (sRBC) humoral response. When amounts of Zn and Cd equimolar to that associated with the Zn, Cd-MT were co-injected with OVA, humoral responsiveness was enhanced, in contrast to the suppression seen with Zn, Cd-MT. Apothionein lacking the available thiols associated with native Zn, Cd-MT had no effect on the development of humoral immunity. These results point to the thiols associated with the protein as the important determinants in the observed immunosuppression and this is supported by the capacity of UC1MT, a new monoclonal anti-MT antibody, to reverse MT mediated immunosuppression. No evidence was found to suggest that Zn,Cd-MT was interacting directly with OVA. Finally, in vitro experiments with LPS-stimulated splenocyte production of IgM correlated with the in vivo observations of Zn,Cd-MT. These data provide evidence for a significant role for MT in the development of metal-mediated immunomodulation and suggest that MT may also possess immunomodulatory functions under circumstances where MT is synthesized in the absence of heavy metal stress. Furthermore, it may be possible to take advantage of this system to exogenously manipulate the development of the immune response.
细胞外金属硫蛋白（Zn,Cd-MT）先前已被证明是淋巴细胞增殖的有效诱导剂，并在增殖试验中与多克隆激活剂协同作用。在本报告中，研究了金属硫蛋白对体液反应性发展的影响。在体内，共注射Zn,Cd-MT可降低特异性抗卵清蛋白（OVA）IgG反应，而总IgG水平保持不变。在抗绵羊红细胞（sRBC）体液反应发展过程中给予Zn,Cd-MT时，也观察到了类似的降低。当与Zn,Cd-MT中锌和镉等摩尔量的锌和镉与OVA共注射时，与Zn,Cd-MT引起的抑制相反，体液反应性增强。缺乏与天然Zn,Cd-MT相关的可利用硫醇的脱辅基金属硫蛋白对体液免疫的发展没有影响。这些结果表明，与该蛋白质相关的硫醇是观察到的免疫抑制中的重要决定因素，这得到了一种新的单克隆抗MT抗体UC1MT逆转MT介导的免疫抑制能力的支持。没有发现证据表明Zn,Cd-MT与OVA直接相互作用。最后，用脂多糖刺激脾细胞产生IgM的体外实验与Zn,Cd-MT的体内观察结果相关。这些数据为MT在金属介导的免疫调节发展中的重要作用提供了证据，并表明在没有重金属应激的情况下合成MT时，MT也可能具有免疫调节功能。此外，利用该系统对外源性操纵免疫反应的发展可能是可行的。
