Bonomo A, Kehn P J, Payer E, Rizzo L, Cheever A W, Shevach E M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1995 Jun 15;154(12):6602-11.
Thymectomy of 3-day-old mice results in the development of multi-organ-specific autoimmune diseases. The disease process is mediated by CD4+ T cells and is characterized by an inflammatory infiltrate in the affected organ(s) and the presence of autoantibodies. Our analysis of the phenotype of the CD4+ T cells that remain in the 3-day thymectomized animal revealed that the majority (approximately 80%) of the CD4+ lymph node cells express an activated (MEL-14low) phenotype and a smaller percentage expressed the T cell activation Ag CD69 and IL-2R alpha-chain. Thymectomized animals also had an increase in the frequency of mitogen-induced CD4+ IL-4 producers and significantly higher levels of total serum IgG. Functional studies demonstrated that lymph node T cells from 3-day thymectomized mice had an enhanced response in the syngeneic MLR and appeared to preferentially respond to syngeneic dendritic cells. To determine whether the syngeneic MLR-reactive T cells were involved in the pathogenesis of the organ-specific disease, we developed a model that mimicked the 3dTx model by grafting neonatal thymi to adult nu/nu recipients followed by removal of the thymus graft on day 3 or 4. When compared with mice transplanted with an untreated thymus, nu/nu mice transplanted with adult APC-containing thymi demonstrated a decrease in the incidence and severity of gastritis, a marked decrease in the titer of anti-parietal cell Ab, and a decrease in total serum IgG. Thus, intrathymic tolerization to complexes of self-peptides and MHC class II on adult APC prevents organ-specific autoimmune disease.
对3日龄小鼠进行胸腺切除会导致多器官特异性自身免疫性疾病的发生。疾病过程由CD4 + T细胞介导，其特征是受影响器官出现炎症浸润以及存在自身抗体。我们对3日龄胸腺切除动物体内残留的CD4 + T细胞表型进行分析，发现大多数（约80%）CD4 + 淋巴结细胞表达活化（MEL - 14low）表型，较小比例的细胞表达T细胞活化抗原CD69和IL - 2Rα链。胸腺切除动物中丝裂原诱导的CD4 + IL - 4产生细胞的频率也增加，血清总IgG水平显著升高。功能研究表明，3日龄胸腺切除小鼠的淋巴结T细胞在同基因混合淋巴细胞反应（MLR）中反应增强，并且似乎优先对同基因树突状细胞作出反应。为了确定同基因MLR反应性T细胞是否参与器官特异性疾病的发病机制，我们建立了一个模型，通过将新生胸腺移植到成年裸鼠受体，然后在第3天或第4天切除胸腺移植来模拟3日龄胸腺切除（3dTx）模型。与移植未处理胸腺的小鼠相比，移植含成年抗原呈递细胞（APC）胸腺的裸鼠胃炎的发病率和严重程度降低，抗壁细胞抗体滴度显著降低，血清总IgG水平降低。因此，成年APC上自身肽与MHC II类复合物的胸腺内耐受可预防器官特异性自身免疫性疾病。
