Strategies for tolerance induction among B cells responding transplantation-associated carbohydrate antigens (with the aim of success in clinical ABO-incompatible transplantation and xenotransplantation

B 细胞响应移植相关糖抗原的耐受诱导策略（目的是在临床 ABO 不相容移植和异种移植中取得成功

• 批准号: 13470237
• 负责人: ASAHARA Toshimasa
• 金额: $ 9.22万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470237/
• 关键词: Organ Transplantation; ABO-incompatible transplantation; Xenotransplantation; Tolerance; B cells; Immuno-toxin; 移植; 抗体性拒絶反応; 免疫抑制; 血液型不適合; 血液型A、B抗原; Gal抗原; ABO不適合移植; 抗体; 免疫制御

The specific and persistent inhibition of antibody (Ab) production against blood group A or B carbohydrate determinants would be required to succeed ABO-incompatible transplantation. We here demonstrated a novel strategy for specific elimination of B cells responding to A-carbohydrates. Resembling to human blood group O or B individuals, mice had naturally occurring Abs against human blood group A-carbohydrates in their sera. By surface staining with fluoresceine-labeled synthetic A-carbohydrates (GalNAcα1-3 Fucα1-2Gal) conjugated to bovine serum albumin (BSA), we have demonstrated that B cells bearing receptors recognizing A-carbohydrates in mice belong to CD5^+ CD11b^+ B-1a subset, similarly to the phenotypic property of those in humans. Such B cells could be temporarily eliminated by single injection of synthetic A-carbohydrates conjugated with BSA and anti-BSA Abs. Administration of such A-carbohydrates into the circulation resulted in its specific binding to the corresponding B cell receptors, and consequently depleted the B cells with the anti-A-carbohydrates specificity via the interaction with the cytotoxic constituent without affecting B cell clones with other specificity. Subsequent treatment with cyclosporin A, which could block differentiation to B-1a, completely inhibited reappearance of B cells bearing receptor for A-carbohydrates. This strategy thereby prevented production of anti-A Abs even after immunization with human group A erythrocytes, while maintaining total serum IgM and IgG levels.

要成功进行ABO血型不合的移植，需要针对A或B血型碳水化合物决定簇的抗体(Ab)产生的特异性和持续性抑制。我们在这里展示了一种新的策略，可以特异性地消除对A-碳水化合物有反应的B细胞。与人类O型或B型人相似，小鼠在其血清中自然产生了抗人A型碳水化合物的抗体。用荧光素标记的合成A-碳水化合物(GalNAcα1-3Fucα1-2Gal)与牛血清白蛋白偶联进行表面染色，我们证明了小鼠体内带有识别A-碳水化合物的受体的B细胞属于CD5^+CD11b^+B-1a亚群，与人类的表型特征相似。这种B细胞可以通过一次注射与BSA和抗BSA抗体结合的合成A-碳水化合物来暂时消除。这种A-碳水化合物进入血液循环，导致其与相应的B细胞受体特异性结合，从而通过与细胞毒性成分的相互作用而耗尽具有抗A-碳水化合物专一性的B细胞，而不影响具有其他专一性的B细胞克隆。随后用环孢菌素A处理，可以阻断向B-1a的分化，完全抑制带有A-碳水化合物受体的B细胞的重现。因此，这种策略即使在人类A组红细胞免疫后也能防止抗-A抗体的产生，同时保持血清总IgM和免疫球蛋白G水平。

项目成果

Yuka Tanaka: "Enzyme-linked immunospot assay for detecting cells secreting antibodies against human blood group A epitopes"Transplantation Proceedings. 35. 555-556 (2003)

Yuka Tanaka：“用于检测分泌针对人血型 A 表位的抗体的细胞的酶联免疫斑点测定”移植论文集。

Fudaba Y, Ohdan H, Asahara T, et al.: "Geranylgeranylacetone, a heat shock protein inducer, prevents primary graft nonfunction in rat liver transplantation"Transplantation. 7(2). 184-189 (2001)

Fudaba Y、Ohdan H、Asahara T 等人：“香叶基香叶基丙酮，一种热休克蛋白诱导剂，可防止大鼠肝移植中的原发性移植物无功能”移植。

Yuka Tanaka: "Multiparameter flow cytometric approach for simultaneous evaluation of proliferation and cytokine-secreting activity in T cells responding to allo-stimulation"Immunological Investigations. (in press). (2004)

Yuka Tanaka：“多参数流式细胞术方法同时评估 T 细胞对同种异体刺激的增殖和细胞因子分泌活性”免疫学研究。

Yuka Tanaka: "Enzyme-linked immunospot assay for detecting cells secreting antibodies against human blood group A epitopes"Transplant Proc. (35). 9-18 (2003)

Yuka Tanaka：“用于检测分泌针对人血型 A 表位的抗体的细胞的酶联免疫斑点测定”Transplant Proc。

Hayamizu K, Shinozaki K, Asahara T et al.: "IL-1-transduction of liver allografts ilduces antiinflammatory monocytes in long-term-surviving hosts"Transplantation Proceeding. 33. 335 (2001)

Hayamizu K、Shinozaki K、Asahara T 等人：“肝脏同种异体移植物的 IL-1 转导在长期存活的宿主中诱导抗炎单核细胞”移植论文集。