Evaluation of in vivo tolerogenicity of genetically modified recipient dendritic cells (syngeneic DC) pulsed with immunogenic peptides (allopeptides) derived from donor HLA molecule in HLA class I transgenic mouse.

评估 HLA I 类转基因小鼠中用源自供体 HLA 分子的免疫原性肽（同种肽）脉冲的转基因受体树突状细胞（同基因 DC）的体内耐受性。

• 批准号: 12671142
• 负责人: BECK Yoshifumi
• 金额: $ 2.18万
• 依托单位: The University of Tokyo.
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671142/
• 关键词: HLA; Peptide; Genetic modification; Dendritic Cell; DC; Mouse; Transplantation; Tolerance; 免疫制御; トランスジェニックマウス; 異所性心移植モデル; HLAクラスI抗原

T cells of C3H.B51 recognize HLA-B^*3501 molecules expressed on C3H.B35 as allo-MHC class I antigens and rejects vascularized C3H. B35 grafts by cellular mechanism. HLA-B^*3501 derived peptide induces long-term heart graft survival in C3H.B35 into C3H.B51 cardiac transplantation model by intra-thymic injection. (Transplant proceedings, 30, 3890-3891, 1998.) We plan to clarify the putative tolerogenic capability of DC involved with HLA molecules based on this HLA TGM heart transplant model. Application of syngeneic (recipient : C3H.B51) DC exposed to allo-antigen (HLA-B*3501 derived peptides) with some modification is expected to establish donor(C3H.B35) specific tolerance. C3H.B35 and C3H.B51 HLA transgenic mouse : So far, after several months of breeding management, the specific TGM strains have been successfully recovered from cryo-preservation. The allogeneic response, which is the key factor in this study, has been confirmed by both in vitro and in vivo study. In brief, mean survival of skin graft from C3H.B35 on C3H.B51 was 15 days and survival of heterotopic heart graft was 24 days. These findings coincides with our previous report (Ando and Beck et al., Transplantation 68, 904-908, 1999.). C3H.B35 specific cytotoxic T cell was generated from splenocytes obtained from C3H.B51 primed by C3H.B35 skin grafting and co-cultured with irradiated C3H.B35 splenocytes. The specific %lysis was more than 50% at the E : T ration of 80 : 1. DC : DC obtained from mouse bone marrow cells after removal of adherent cells followed by GM-CSF and IL4 addition showed marked allo-stimulatory effect in mixed leukocyte reaction.We plan to investigate the possibility of regulating the allo-immune-response between the TGM strain by modified DC propagated from TGM.

C3H.B51的T细胞将C3H.B35上表达的HLA-B^*3501分子识别为allo-MHC I类抗原，并排斥血管化的C3 H。B35细胞移植机制。HLA-B^*3501衍生肽通过胸腺内注射诱导C3H.B35到C3H.B51心脏移植模型中的长期心脏移植物存活。（移植程序，30，3890-3891，1998。）我们计划在此HLA-TGM心脏移植模型的基础上阐明与HLA分子相关的DC的致耐受性能力。应用暴露于具有一些修饰的同种抗原（HLA-B*3501衍生肽）的同基因（受体：C3H.B51）DC预期建立供体（C3H.B35）特异性耐受。C3H.B35和C3H.B51 HLA转基因小鼠：到目前为止，经过几个月的饲养管理，已经成功地从冷冻保存中回收了特定的TGM品系。同种异体反应是本研究的关键因素，已通过体外和体内研究得到证实。简言之，C3H.B35皮肤移植物在C3H.B51上的平均存活时间为15天，异位心脏移植物的平均存活时间为24天。这些发现与我们以前的报告（Ando和Beck等人，Transplantation 68，904-908，1999.）。从通过C3H.B35皮肤移植物致敏的C3H.B51获得的脾细胞产生C3H.B35特异性细胞毒性T细胞，并与照射的C3H.B35脾细胞共培养。在80：1的E：T比下，特异性%裂解大于50%。华盛顿特区：从小鼠骨髓细胞中分离出DC，经GM-CSF和IL-4修饰后，在混合白细胞反应中显示出明显的同种异体刺激效应，本研究拟探讨经修饰的DC调节TGM株间同种异体免疫反应的可能性。

项目成果

Qin.L.Ding, Y, Tahara, H, et al.: "Viral IL-10-induced Immunosuppression Requires Th2 Cytokines and Impairs APC Function Within the Allograft"J Immunol. 166. 2385-2393 (2001)

Qin.L.Ding, Y, Tahara, H, et al.：“病毒 IL-10 诱导的免疫抑制需要 Th2 细胞因子并损害同种异体移植物内的 APC 功能”J 免疫学杂志。

Takayama T, Tahara H, et al.: "Refrarirally transduced myeloid cells expressing mammalian orviral IL-10 differentially affect cell mediated immunity and growth of iransplantable tumors"Transplant Proceedings. 33. 590 (2001)

Takayama T、Tahara H 等人：“表达哺乳动物或病毒 IL-10 的转导骨髓细胞对细胞介导的免疫和可移植肿瘤的生长有不同影响”移植论文集。

Takayama T, Tahara H, Thomson AW: "Differential effects of myeloid dendritic cells retrovirally transduced to express mammlian or viral IL-10 on CTL and NK cell activities and resistance to tumor growth"Transplantation. 71. 1334-40 (2001)

Takayama T、Tahara H、Thomson AW：“逆转录病毒转导表达哺乳动物或病毒 IL-10 的骨髓树突状细胞对 CTL 和 NK 细胞活性以及对肿瘤生长的抵抗力的不同影响”移植。

Takayama T, Tahara, H, et al.: "Differential effects of myeloid dendritic cells retrovirally transduced to express mammalian or viral IL-10 on CTL and NK cell functions and resistance to tumor growth"Transplantation. 71. 1334-1340 (2001)

Takayama T、Tahara、H 等人：“逆转录病毒转导表达哺乳动物或病毒 IL-10 的骨髓树突状细胞对 CTL 和 NK 细胞功能以及对肿瘤生长的抵抗力的不同影响”移植。

Takayama T, Tahara, H, et al.: "Mammalian and Viral IL-10 Enhance C-C Chemokine Receptor 5 but Down-Regulate C-C Chemokine Receptor 7 Expression by Myeloid Dendritic Cells : Impact on Chemotactic Responses and In Vivo Homing Ability"J Immunol. 166. 7136-7

Takayama T、Tahara、H 等人：“哺乳动物和病毒 IL-10 增强 C-C 趋化因子受体 5，但下调髓样树突状细胞的 C-C 趋化因子受体 7 表达：对趋化反应和体内归巢能力的影响”J 免疫学杂志。