The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance
The role of interleukin-4 in the induction phase of allogeneic neonatal tolerance
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DOI：
10.1097/00007890-199612270-00029
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发表时间：
1996-12-27
期刊：
影响因子：
6.2
通讯作者：
Field, EH
中科院分区：
文献类型：
--
作者：
Gao, QL;Chen, NX;Field, EH
我们以前曾报道过，在移植耐受小鼠中，移植物存活时间延长与Th 2/Th 1细胞因子增强有关。为了确定Th 2 CD 4细胞是否在耐受中起作用，我们研究了在新生儿抗原暴露期间使用抗白细胞介素（IL）-4单克隆抗体治疗是否可以通过阻断Th 2 CD 4成熟来预防耐受。抗IL-4治疗恢复了BALB/c小鼠排斥A/J皮肤移植物的能力，并通过多种机制阻断了耐受的诱导。抗IL-4治疗阻断了供体微嵌合体的发展，并恢复了小鼠的增殖能力，并以剂量依赖性方式对A/J产生适当的迟发型超敏反应（DTH）和细胞毒性T淋巴细胞（CTL）反应。低剂量抗IL-4恢复DTH反应和干扰素（IFN）-γ的产生，但未能完全阻止IL-4的产生或恢复CTL活性。在这些小鼠中未检测到A/J反应性IFN-γ产生性CD 8细胞。相反，用较高剂量的抗IL-4处理的小鼠产生针对A/J的正常CTL应答，并且含有A/J反应性IFN-γ产生性CD 8细胞。CTL应答和产生IFN-γ的CD 8细胞的恢复与Th 2细胞因子产生的更完全阻断相关。因此，IL-4的存在可能在诱导新生儿免疫耐受中发挥重要作用，其通过使CD 4细胞的成熟向Th 2细胞转移而远离Th 1细胞，并且还通过阻止同种异体反应性CD 8 CTL细胞的成熟。
We previously reported that prolonged graft survival in neonatally tolerant mice was associated with enhanced Th2/Th1 cytokines. To determine whether Th2 CD4 cells function in tolerance, we examined whether we could prevent tolerance by blocking Th2 CD4 maturation, using anti-interleukin (IL)-4 monoclonal antibody treatment during neonatal antigen exposure. Anti-IL-4 treatment restored the ability BALB/c of mice to reject A/J skin grafts and blocked the induction of tolerance through multiple mechanisms. Anti-IL-4 treatment blocked the development of donor microchimerism and recovered the ability of mice to proliferate and to generate appropriate delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) responses against A/J in a dose-dependent manner. Low-dose anti-IL-4 recovered DTH responses and interferon (IFN)-gamma production, but failed to completely prevent IL-4 production or to recover the CTL activity. No A/J-reactive IFN-gamma-producing CD8 cells were detected in these mice. In contrast, mice treated with higher doses of anti-IL-4 generated normal CTL responses against A/J, and contained A/J-reactive IFN-gamma-producing CD8 cells. The recovery of CTL responses and IFN-gamma-producing CD8 cells was associated with a more complete blocking of Th2 cytokine production. Therefore, the presence of IL-4 may play an important role in the induction of neonatal tolerance by shifting maturation of CD4 cells toward Th2 cells and away from Th1 cells, and also by preventing maturation of alloreactive CD8 CTL cells.