Fc receptor gene analysis and immunotherapy with bispecific antibody for periodontal disease

Fc受体基因分析及双特异性抗体免疫治疗牙周病

• 批准号: 12557191
• 负责人: YOSHIE Hiromasa
• 金额: $ 6.59万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557191/
• 关键词: Fc receptor; Bispecific antibody; Immunothearpy; Periodonlal disease; r40kDa OMP; Porphyromonas gingivalis; Neutrophils; Porphyromonas gingivalis; 二極特異的抗体; 歯肉溝滲出液

- Diagnosis of periodontisis risk with Fc receptor gene polymorphisms :The association of FcR polymorphisms with severity of chronic periodontitis (CP) was examined by means of allele-specific polymerase chain reactions. A significant over-representation of FcRIIIa-158V allele in severe CP patients as compared to moderate AP patients (P = 0.03). In addition, we found a strong association between CP severity and FcR composite genotype comprising FcRIIIA-158V plus FcRIIIB-NA2 (odds ratio 4.7, P = 0.002). The association study consisted of 60 SLE patients, age-matched 42 healthy subjects with periodontitis, and 42 healthy subjects without periodontitis indicated FcγRIIa-R131 allele to be a common risk factor for SLE and periodontitis. Variation screening of neutrophil-specific FcRIIIB and B cell-specific FcRIIB genes showed new one and seven single nucleotide polymorphisms, respectively, and documented the association of FcRIIB nt 775T/C with aggressive periodontitis risk. These results suggest FcR genotype to be associated with susceptibility to periodontitis.- Immunotherapy of periodontitis with human monoclonal antibody :Human immunoglobulin (Ig)-producing mice were immunized by intraperitoneal injection of recombinant 40-kDa outer membrane protein (r40-kDa OMP) of Porphyromonas gingivalis. Total 99 clones of human monoclonal antibodies (hMAb) specific for r40-kDa OMP were obtained, all of which was IgG isotype (IgG1 : 84 clones ; IgG2 : 11 clones ; IgG4 : 4 clones). The binding activity of hMAb to r40-kDa OMP was shown to be almost same as that of human polyclonal antibody (60 times higher in concentration). The opsonophagocytic activity of hMAb clones were also indicated to be almost same as that of human polyclonal antibody (10000 times higher in concentration). This hMAb was shown to enhance neutrophil phagocytosis of P. gingivalis.

-用Fc受体基因多态性诊断牙周病风险：通过等位基因特异性聚合酶链式反应检测FCR基因多态性与慢性牙周炎(CP)严重程度的关系。FcRIIa-158V等位基因在重度CP组明显高于中度AP组(P=0.03)。此外，我们还发现CP的严重程度与FcRIIIA-158V+FcRIIIB-Na2的FCR复合基因型有很强的相关性(优势比为4.7P=0.002)。60例系统性红斑狼疮患者、42例年龄匹配的健康牙周炎患者和42例健康非牙周炎患者的关联研究表明，Fc-γRIIA-R131等位基因是系统性红斑狼疮和牙周炎的共同危险因素。中性粒细胞特异的FcRIIIB和B细胞特异的FcRIIB基因的变异筛查分别显示了新的1个和7个单核苷酸多态，并证明了FcRIIB NT 775T/C与侵袭性牙周炎的风险有关。这些结果表明，FCR基因与牙周炎的易感性有关。人的单抗用于牙周炎的免疫治疗：人免疫球蛋白(Ig)产生的小鼠通过腹膜注射牙龈卟啉单胞菌的重组40-kDa外膜蛋白(R40-kDa OMP)进行免疫。共获得99个针对R40-kDa OMP的人源单抗克隆，均为免疫球蛋白亚型(IgG1：84个，IgG2：11个，IgG4：4个)。HMAb与R40-kDa OMP的结合活性与人多克隆抗体的结合活性几乎相同(浓度高60倍)。HMAb克隆的吞噬细胞活性与人多克隆抗体的吞噬活性几乎相同(浓度高10000倍)。此hMAb可增强牙龈假单胞菌的中性粒细胞吞噬功能。

项目成果

Keiko Yasuda, et al.: "Seven single nucleotide substitutions in human Fcγ receptor IIB gene"Tissue Antigens. Vol.58,No.5. 339-342 (2001)

Keiko Yasuda 等：“人 Fcγ 受体 IIB 基因中的七个单核苷酸取代”Tissue Antigens，第 58 卷，第 339-342 期（2001 年）。

Tetsuo Kobayashi et al.: "Risk of Periodontitis in Systemic Lupus Erythematosus is Associated with Fcγ Receptor Polymorphisms"Journal of Periodontology. Vol.74,No.3. 378-384 (2003)

Tetsuo Kobayashi 等：“系统性红斑狼疮的牙周炎风险与 Fcγ 受体多态性相关”，牙周病学杂志第 74 卷，第 378-384 期（2003 年）。

T. Kobayashi, K. Yamamoto, N. Sugita, A. B. van Spriel, S. Kaneko, J. G. J. van de Winkel, H. Yoshie.: "Effective In Vitro Clearance of Porphyromonas gingivalis by Fcα Receptor I (CD89) on Gingival Crevicular Neutrophils"Infection and Immunity. Vol.69, No

T. Kobayashi、K. Yamamoto、N. Sugita、A. B. van Spriel、S. Kaneko、J. G. J. van de Winkel、H. Yoshie.：“Fcα 受体 I (CD89) 对牙龈沟中性粒细胞有效体外清除牙龈卟啉单胞菌”感染与免疫。第 69 卷，第 1 期。

T. Kobayashi, K. Yamamoto, N. Sugita, W-L. van der Pol, K. Yasuda, S. Kaneko, J. G. J. van de Winkel, H. Yoshie: "The Fcγ Receptor Genotype as a Severity Factor for Chronic Periodontitis in Japanese Patients"Journal of Periodontology. Vol.72, No.10. 1324-

T. Kobayashi、K. Yamamoto、N. Sugita、W-L van der Pol、K. Yasuda、S. Kaneko、J. G. J. van de Winkel、H. Yoshie：“Fcγ 受体基因型作为日本患者慢性牙周炎的严重因素” “牙周病学杂志。第 72 卷，第 10 期。1324-

N. Sugita, T. Kobayashi, Y. Ando, A. Yoshihara, K. Yamamoto, J. G. J. van de Winkel, H. Miyazaki, H. Yoshie: "Increased Frequency of FcγRIIIb-NA1 Allele in Periodontitis-resistant Subjects in an Elderly Japanese Population"Journal of Dental Research. Vol.

N. Sugita、T. Kobayashi、Y. Ando、A. Yoshihara、K. Yamamoto、J. G. J. van de Winkel、H. Miyazaki、H. Yoshie：“牙周炎抵抗受试者中 FcγRIIIb-NA1 等位基因的频率增加日本老年人口”牙科研究杂志。卷。