Fukushima Atsuki, Yamaguchi Tomoko, Ishida Waka, Fukata Kazuyo, Mittler Robert S, Yagita Hideo, Ueno Hisayuki
Department of Ophthalmology, Kochi Medical School, Nankoku-city, Japan.
J Immunol. 2005 Oct 15;175(8):4897-903. doi: 10.4049/jimmunol.175.8.4897.
The 4-1BB receptor acts as a costimulator in CD8(+) T cell activation. Agonistic stimulation through this molecule by treatment with anti-4-1BB Abs has been demonstrated to inhibit various experimentally induced diseases in animals. However, the effect of anti-4-1BB Abs on experimental allergic diseases has not been reported. We investigated the effect of anti-4-1BB Abs on the development and progression of experimental allergic conjunctivitis in mice. To examine the effects of Abs during the induction or effector phase, actively immunized mice or passively immunized mice by splenocyte transfer were treated with agonistic anti-4-1BB Abs, blocking anti-4-1BB ligand Abs, or normal rat IgG. Eosinophil infiltration into the conjunctiva was significantly reduced in wild-type mice by the anti-4-1BB Ab treatment during either induction or effector phase. Th2 cytokine production by splenocytes and total serum IgE were significantly reduced by the anti-4-1BB Ab treatment, while IFN-gamma production was increased. The anti-4-1BB Ab treatment induced a relative increase of CD8-positive cell numbers in the spleens. Moreover, inhibition of eosinophil infiltration by the treatment with anti-4-1BB Abs was also noted in actively immunized IFN-gamma knockout mice. Taken altogether, in vivo treatment with agonistic anti-4-1BB Abs in either induction or effector phase inhibits the development of experimental allergic conjunctivitis, and this inhibition is likely to be mediated by suppression of Th2 immune responses rather than up-regulation of IFN-gamma.
4-1BB受体在CD8(+) T细胞活化过程中作为共刺激分子发挥作用。通过用抗4-1BB抗体处理经该分子进行激动剂刺激已被证明可抑制动物中各种实验诱导的疾病。然而，抗4-1BB抗体对实验性变应性疾病的影响尚未见报道。我们研究了抗4-1BB抗体对小鼠实验性变应性结膜炎的发生和发展的影响。为了检查抗体在诱导期或效应期的作用，对主动免疫的小鼠或通过脾细胞转移进行被动免疫的小鼠用激动性抗4-1BB抗体、阻断性抗4-1BB配体抗体或正常大鼠IgG进行处理。在诱导期或效应期，抗4-1BB抗体处理可使野生型小鼠结膜中的嗜酸性粒细胞浸润显著减少。抗4-1BB抗体处理可使脾细胞产生的Th2细胞因子和血清总IgE显著减少，而IFN-γ的产生增加。抗4-1BB抗体处理可使脾脏中CD8阳性细胞数量相对增加。此外，在主动免疫的IFN-γ基因敲除小鼠中也观察到抗4-1BB抗体处理对嗜酸性粒细胞浸润的抑制作用。综上所述，在诱导期或效应期用激动性抗4-1BB抗体进行体内处理可抑制实验性变应性结膜炎的发展，这种抑制作用可能是通过抑制Th2免疫反应而不是上调IFN-γ介导的。
