Lider O, Karin N, Shinitzky M, Cohen I R
Proc Natl Acad Sci U S A. 1987 Jul;84(13):4577-80. doi: 10.1073/pnas.84.13.4577.
An ideal treatment for autoimmune diseases would be a nontoxic means of specifically neutralizing the autoreactive lymphocytes responsible for the disease. This goal has been realized in experimental autoimmunity models by immunizing rats or mice against their own autoimmune cells such that the animals generate an immune response specifically repressive to the disease-producing lymphocytes. This maneuver, termed lymphocyte vaccination, was demonstrated to be effective using some, but not all, autoimmune helper T-lymphocyte lines. We now report that T lymphocytes, otherwise incapable of triggering an immune response, can be transformed into effective immunogens by treating the cells in vitro with hydrostatic pressure. Clone A2b, as effector clone that recognized cartilage proteoglycan and caused adjuvant arthritis in Lewis rats, is such a cell. Untreated A2b could not trigger an immune response, but inoculating rats with pressure-treated A2b induced early remission of established adjuvant arthritis as well as resistance to subsequent disease. Specific resistance to arthritis was associated with anti-idiotypic T-cell reactivity to clone A2b and could be transferred from vaccinated rats to naive recipients using donor lymphoid cells. Aggregation of T-lymphocyte membrane components appeared to be important for an immune response because the effects of hydrostatic pressure could be reproduced by treatment of A2b with chemical cross-linkers or with agents disrupting the cytoskeleton. Populations of lymph node cells from antigen-primed rats, when treated with hydrostatic pressure, could also induce suppression of disease. Thus, effective vaccines can be developed without having to isolate the autoimmune T lymphocytes as lines or clones. These results demonstrate that effector T lymphocytes suitably treated may serve as agents for specifically controlling the immune system.
自身免疫性疾病的理想治疗方法是采用无毒手段特异性中和引发该疾病的自身反应性淋巴细胞。在实验性自身免疫模型中，通过用大鼠或小鼠自身的自身免疫细胞进行免疫，使动物产生对致病淋巴细胞具有特异性抑制作用的免疫反应，这一目标已得以实现。这种操作被称为淋巴细胞疫苗接种，已证明在一些（但并非所有）自身免疫性辅助性T淋巴细胞系中有效。我们现在报告，原本无法引发免疫反应的T淋巴细胞，通过在体外对细胞施加流体静压进行处理，可转化为有效的免疫原。克隆A2b就是这样一种细胞，它作为效应克隆可识别软骨蛋白聚糖并在Lewis大鼠中引发佐剂性关节炎。未经处理的A2b无法引发免疫反应，但给大鼠接种经压力处理的A2b可诱导已确立的佐剂性关节炎早期缓解以及对后续疾病的抵抗力。对关节炎的特异性抵抗力与针对克隆A2b的抗独特型T细胞反应性相关，并且可以使用供体淋巴细胞从接种疫苗的大鼠转移至未接触过抗原的受体。T淋巴细胞膜成分的聚集似乎对免疫反应很重要，因为流体静压的作用可以通过用化学交联剂或破坏细胞骨架的试剂处理A2b来重现。用流体静压处理来自抗原致敏大鼠的淋巴结细胞群体，也可诱导疾病抑制。因此，无需将自身免疫性T淋巴细胞分离成系或克隆就可以开发出有效的疫苗。这些结果表明，经过适当处理的效应性T淋巴细胞可作为特异性控制免疫系统的制剂。
