Tolerance induction of alloreactive T cells and regulation of graft rejection

同种异体反应性 T 细胞的耐受诱导和移植物排斥的调节

• 批准号: 04454207
• 负责人: FUJIWARA Hiromi
• 金额: $ 4.29万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04454207/
• 关键词: tolerance; transplantation immunology; helper T cells; DST; immunosuppresive drugs; アロ抗原反応性T細胞; 拒絶反応

One of major issues in transplantation immunology is to develop methods to regulate allograft responses. This study investigated an approach to regulate allograft responses by either a single DST(donor-specific transfusion), repeated administrasion of immunosuppressive drugs (FK506 or rapamycin) or the combination of these. The follwing were revealed : (1)Allo class 1 MHC-reactive helper T cells (Th) consist of (a)CD4^+ and CD8^+ Th with the capacity to produce high levels of IL-2 and (b) CD4^+ Th with the limited capacity of IL-2 production. The former is susceptible to donor-specific transfusion (DST) and rendered easily tolerant by a single DST, whereas the latter is DST-resistant. (2)In the donor-host combination involving the DSP-susceptible and DST-resistant Th subsets, the induction and maintenance of tolerance of the former is inhibited by the operation of the DSP-resistant subset, indicating the modulation of allograft responses based on cellular interactions. (3)It was found that FK506 or rapamycin at suboptimal deses was effective for suppressing allograft rejection responses by the combination with a single DST under which either of these treatments alone failed to inhibit rejection responses. Thus, by presenting a practical approach for producing a beneficial effect on immunomodulation of allograft responses using DST and by demonstrating cellular mechanisms underlying such an immunomodulation, the present study may provide a significant contribution to transplantation immunology.

移植免疫学的主要问题之一是发展调节同种异体移植物反应的方法。本研究探讨了一种通过单次DST（供体特异性输血）、反复使用免疫抑制药物（FK506或雷帕霉素）或这些药物联合使用来调节同种异体移植物反应的方法。结果显示：(1)Allo 1类mhc反应性辅助性T细胞（Th）由(a)CD4^+和CD8^+ Th组成，具有产生高水平IL-2的能力；(b) CD4^+ Th具有有限的IL-2产生能力。前者易受供体特异性输血（DST）的影响，单次DST即可使其产生耐受性，而后者则具有DST抗性。(2)在涉及dsp敏感和dst耐药Th亚群的供体-宿主结合中，前者耐受的诱导和维持被dsp耐药Th亚群的操作所抑制，表明同种异体移植物反应的调节是基于细胞相互作用的。(3)发现FK506或雷帕霉素在次优剂量下与单一DST联合可有效抑制同种异体移植物的排斥反应，而单独使用这两种治疗均不能抑制排斥反应。因此，通过提出一种实用的方法，利用DST对同种异体移植物反应的免疫调节产生有益的影响，并通过展示这种免疫调节的细胞机制，本研究可能为移植免疫学做出重大贡献。

项目成果

Sugihara, S et al.: "Thyroiditis-inducing T cell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatory T cell subset." 150. 683-694 (1993)

Sugihara, S 等人：“甲状腺炎诱导 T 细胞系和克隆源自通过消除调节性 T 细胞亚群在小鼠中诱导的自身免疫性甲状腺炎病变。”

Kita,Y.,et.al.: "Thymic stroma-derived T cell inhibitory factor(TSTIF).I.TSTIF induces inhibition of antigen-stimulated T cell proliferation." Thymus-J.of T cell Biology. 21. 159-175 (1993)

Kita,Y.,et.al.：“胸腺基质来源的 T 细胞抑制因子 (TSTIF)。I.TSTIF 诱导抗原刺激的 T 细胞增殖的抑制。”

Iwata,H.,et.al.: "Suppression of allograft responses by combining allo-antigen-specifici.v.presensitization with suboptimal doses of rapamycin." International Immunol.6. 93-99 (1994)

Iwata, H., et.al.：“通过将同种异体抗原特异性预敏化与次优剂量的雷帕霉素相结合来抑制同种异体移植反应。”

Sugihara,S.,et.al.: "Thyroiditis-inducing T cell lines and clones derived from autoimmune thyroiditis lesions induced in mice by the elimination of regulatory T cell subset." J.Immunol.150. 683-694 (1993)

Sugihara,S.,et.al.：“甲状腺炎诱导 T 细胞系和克隆源自通过消除调节性 T 细胞亚群在小鼠中诱导的自身免疫性甲状腺炎病变。”

Iwata,H.,et.al.: "Suppression of allograft responses by combining donor alloantigen-specific i.v.presensitization with suboptimal doses of FK506." Transplantation. 56. 173-180 (1993)

Iwata, H., et.al.：“通过将供体同种异体抗原特异性静脉内预敏化与次优剂量的 FK506 相结合来抑制同种异体移植物反应。”