Zheng X X, Steele A W, Nickerson P W, Steurer W, Steiger J, Strom T B
Harvard Medical School, Department of Medicine, Boston, MA, USA.
J Immunol. 1995 May 15;154(10):5590-600.
Numerous studies have suggested the potential application of IL-10 as an anti-inflammatory and as an antirejection agent. Unfortunately, cytokines have short circulating t1/2 We developed a murine IL-10/Fc gamma 2a immunoligand that possesses the biologic functions of IL-10 and the long circulating t1/2 in vivo, characteristic of Igs. We mutated the Fc gamma 2a fragment to render the immunoligand ineffective in directing Ab-dependent cell-mediated cytotoxicity and complement-directed cytolysis (noncytolytic IL-10/Fc (IL-10/Fc2-)). In terms of IL-10 activity, IL-10/Fc2- was as effective as rIL-10 mole per mole in preventing lethal septic shock, but the immunoligand had a prolonged period of efficacy in accord with its extended circulating half-life. Contrary to expectations, IL-10/Fc2- treatment tended to accelerate the destruction of islet cell allografts and increase the levels of granzyme B gene expression in local draining lymph nodes. These data suggest that the enhanced cytotoxic activity of allograft-destroying CTLs may contribute to the accelerated allograft rejection. Finally, our studies suggest that a noncytolytic IL-10/Fc fusion protein provides a useful tool to study the biologic effects of IL-10 in vivo and may provide a useful agent for the prevention and treatment of septic shock.
大量研究表明白细胞介素-10（IL-10）具有作为抗炎剂和抗排斥剂的潜在应用价值。不幸的是，细胞因子的循环半衰期较短。我们开发了一种小鼠IL-10/Fcγ2a免疫配体，它具有IL-10的生物学功能且在体内具有Ig的长循环半衰期特征。我们对Fcγ2a片段进行了突变，以使免疫配体在介导抗体依赖性细胞介导的细胞毒性和补体介导的细胞溶解方面无效（非细胞溶解型IL-10/Fc（IL-10/Fc2-））。就IL-10活性而言，在预防致死性脓毒症休克方面，每摩尔IL-10/Fc2-与重组IL-10（rIL-10）一样有效，但该免疫配体因其延长的循环半衰期而具有更长的疗效期。与预期相反，IL-10/Fc2-治疗倾向于加速胰岛细胞同种异体移植物的破坏，并增加局部引流淋巴结中颗粒酶B基因的表达水平。这些数据表明，同种异体移植物破坏型细胞毒性T淋巴细胞（CTL）增强的细胞毒性活性可能导致同种异体移植物排斥加速。最后，我们的研究表明，一种非细胞溶解型IL-10/Fc融合蛋白为研究IL-10在体内的生物学效应提供了一种有用的工具，并且可能为脓毒症休克的预防和治疗提供一种有用的药物。
