Reconstruction of Immune Tissues and Repair/Reinforcement of Immune Surveillance

免疫监视系统不仅在伯内特博士首次提出的癌症控制中起着至关重要的作用，而且在预防严重感染以及调节自身反应性免疫反应方面也起着至关重要的作用。该特别项目的目标是通过人工构建新型淋巴组织来恢复因严重感染、癌症或自身免疫性疾病而受损的免疫监视系统。我们以前证明，人工淋巴结（aLN）可以通过移植基质细胞包埋的生物相容性支架到小鼠的肾包膜下空间。在aLN中形成的T和B细胞结构域在免疫应答中具有与正常淋巴组织的滤泡相似的功能。aLN可移植到幼稚正常以及严重联合免疫缺陷（SCID）小鼠，其中它们有效地诱导二次免疫应答。抗原特异性二次反应强烈诱导aLN，甚至四周后移植。携带aLN的SCID小鼠中的抗原特异性抗体应答是巨大的，达到7- 8 mg/ml。抗原攻击后应答随时间维持，表明aLN可以支持骨髓中的记忆B细胞和长寿浆细胞。记忆型CD 4 + T细胞在携带aLN的SCID小鼠的aLN和脾脏中高度富集。我们的研究结果表明，aLN强烈支持免疫缺陷小鼠的抗原特异性二次抗体应答，并提示未来临床应用的可能性。最近，我们成功地构建了具有肿瘤抗原特异性细胞毒活性的aLN，其通过从CD 8+细胞、CD 4+细胞和NK/NKT细胞分泌γ FN来实现。这些aLN表现出很强的肿瘤免疫力。

Immune Surveillance system plays a crucial role not only in the control of cancer as first proposed by Dr. Burnet, but also in the prevention of severe infection as well as the regulation of autoreactive immune responses. The objective of this special project is to recover the impaired immune surveillance system by such as severe infection, cancers or autoimmune diseases by artificially constructing novel lymphoid tissues. We previously demonstrated that artificial lymph nodes (aLNs) could be generated by the transplantation of stromal cell-embedded biocompatible scaffolds into the renal subcapsular space in mice. T and B cell domains that form in the aLNs have a similar function in the immune response as the follicles of normal lymphoid tissue. The aLNs were transplantable to naive normal as well as to severe combined immunodeficient (SCID) mice where they efficiently induced secondary immune responses. Antigen-specific secondary responses were strongly induced in aLNs even four weeks after their transplantation. The antigen-specific antibody responses in SCID mouse carrying aLNs were enormous, reaching 7-8mg/ml. Responses were maintained with time after antigen challenge, indicating that aLNs can support memory B cells and long-lived plasma cells in bone marrow. Memory type CD4+ T cells were highly enriched in the aLNs and spleen of SCID mice carrying aLNs. Our results indicate that the aLNs support strongly the antigen-specific secondary antibody responses in immunodeficient mice, and suggest the possibility for clinical apprication in future. Recently, we have succeeded to construct aLNs which display the tumor antigen specific cytotoxic activities by secreting gammalFN from CD8+ cells, CD4+ cells and NK/NKT cells. These aLNs exhibit a strong tumor immunity.