Development of The Endogenous Protease Inhibitor for the Treatment of Allergic Diseases

变态反应性疾病以白细胞浸润和血管通透性增加为主要特征，可能与多种蛋白酶系统有关。本研究的目的是纯化各种内源性蛋白水解酶抑制物，研究这些抑制物如何参与变态反应性疾病的体内调节，最终开发治疗人类变态反应性疾病的手段。皮肤中的蛋白酶抑制剂。激肽释放酶抑制剂和大白蛋白(&lt；α2&gt；-MA)分别存在于正常皮肤和结核菌素皮肤部位。发现这两种抑制物与血浆中各自的抑制物完全相同。血浆蛋白水解酶抑制剂。血浆-α_2-MA纯度高，可抑制由激活的Hageman因子引起的血管通透性(IVP)升高，在豚鼠皮肤和诱导的IVP。豚鼠皮肤注射α_2-MA抗原后，对牛-丙种球蛋白和结核菌素引起的迟发型超敏反应(DHR)无明显抑制作用。而在血管内注射抗-α2-MA兔抗体所致的耗竭豚鼠中，0小时的IVP明显受到抑制。提示α2-MA参与了DHR IVP的调节，有待进一步研究。高纯度血浆激肽释放酶抑制剂可抑制激肽释放酶注射所致的IVP，但对DHR无抑制作用。在体内实验中需要在各种条件下进行进一步的研究。血浆类胰蛋白酶抑制物参与巨噬细胞趋化因子的产生。激肽释放酶抑制剂在体外抑制了该蛋白水解酶的活性，但在体内检测其对巨噬细胞浸润的调节活性仍有待进一步研究。

Allergic diseases consist of leukocyte infiltration and increased vascular permeability, in which various protease system are suggested to be involved. The purpose of this study is to purify the various endogenous protease inhibitors, to study how the inhibitors are involved in the in vivo regulation of allergic diseases, and finally to develop the curative means of human allergic diseases.1. Protease inhibitors in the skin. Kallikrein inhibitors and <alpha_2> -macroalbumin ( <alpha_2> -MA) were found in the normal and tuberculin skin sites, respectively. These two inhibitors were found to be identical to the respective inhibitors in plasma.2. Plasma protease inhibitors. Plasma <alpha_2> -MA was highly purified and was found to inhibit increased vascular permeability(IVP) induced by activated Hageman Factor, which was found in the guinea pig skin and induced IVP. <alpha_2> -MA, when injected into guinea pig skin with antigen, did not suppress IVP in delayed hypersensitivity reaction(DHR) to bovine <gamma> -globulin and tuberculin. However, in the <alpha_2> -MA-depleted guinea pig, induced by intravascular injection of anti- <alpha_2> -MA rabbit antibody, IVP at 0 hour was strongly suppressed. This suggest the involvement of <alpha_2> -MA in the regulation of IVP in DHR, and needs further study. Highly purified plasma kallikrein inhibitor suppressed IVP induced by kallikrein injection, but found no suppressive activity in DHR. It needs further study under various conditions in in vivo experiments.3. Plasma inhibitor for trypsin-like protease which invovlved in the generation of chemotactic factor for macrophages. Kallikrein inhibitor suppressed the protease activity in vitro, however, in vivoexperiment to detect the regulatory activity in the macrophage infiltration remains to be done.