Teng Y T, Gorczynski R M, Hozumi N
Department of Microbiology & Immunology, the University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Cell Immunol. 1998 Nov 25;190(1):51-60. doi: 10.1006/cimm.1998.1389.
Innocent bystander suppression has been demonstrated in experimental models of transplantation tolerance and oral tolerance. This phenomenon is associated with expression of cytokines such as TGF-beta or/and type II cytokines (e.g., IL-4, IL-10). However, the mechanism responsible for bystander suppression is poorly understood, as is its role in antigen-specific self-tolerance. Here, we describe a series of investigations using an antigen coimmunization strategy to examine the outcome of bystander suppression in vivo in a well-characterized physiological model, using beef insulin transgenic (BI-Tg) mice, for self-tolerance. Our results demonstrate that: (1) T-cell-mediated peripheral hyporesponsiveness, or CD4(+) regulatory type II Th cell-mediated adoptive transfer of peripheral hyporesponsiveness (defined by an ELISA antibody assay), is antigen-specific at induction but effector-nonspecific (bystander suppression) when the self-antigen (BI) and a control antigen (chicken ovalbumin) are coadministered in BI-Tg mice; (2) bystander suppression is manifest as a local and transient, rather than a systemic and long-term, phenomenon; (3) bystander suppression is both time and antigen dose dependent; and (4) anti-TGF-beta Mab abolishes the effect of bystander suppression in vivo. We suggest that TGF-beta-mediated innocent bystander suppression associated with physiological self-tolerance thus produces no major biological consequence for general immune responsiveness. It may prevent the activation of auto(or cross)-reactive lymphocytes.
在移植耐受和口服耐受的实验模型中已证实存在无辜旁观者抑制现象。这种现象与细胞因子如转化生长因子-β（TGF-β）或/和II型细胞因子（如白细胞介素-4、白细胞介素-10）的表达有关。然而，导致旁观者抑制的机制及其在抗原特异性自身耐受中的作用仍知之甚少。在此，我们描述了一系列研究，采用抗原共免疫策略，在一个特征明确的生理模型中，即使用牛肉胰岛素转基因（BI-Tg）小鼠，检测体内旁观者抑制的结果，以研究自身耐受情况。我们的结果表明：（1）T细胞介导的外周低反应性，或CD4(+)调节性II型Th细胞介导的外周低反应性的过继转移（通过酶联免疫吸附测定抗体法定义），在诱导时是抗原特异性的，但当自身抗原（BI）和对照抗原（鸡卵白蛋白）在BI-Tg小鼠中共给药时，效应是非特异性的（旁观者抑制）；（2）旁观者抑制表现为局部和短暂的现象，而非全身性和长期的现象；（3）旁观者抑制具有时间和抗原剂量依赖性；（4）抗TGF-β单克隆抗体可消除体内旁观者抑制的效应。我们认为，与生理性自身耐受相关的TGF-β介导的无辜旁观者抑制对一般免疫反应性不会产生重大生物学后果。它可能会阻止自身（或交叉）反应性淋巴细胞的激活。
