Reconstruction of Immune Tissues and Repair/Reinforcement of Immune Surveillance

免疫监视系统不仅在Burnet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和调节自身反应性免疫反应方面也起着至关重要的作用。本课题的目标是通过人工构建新的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。我们之前已经证明，将基质细胞包埋的生物相容性支架移植到小鼠肾包膜下空间可以产生人工淋巴结。在aln中形成的T和B细胞结构域在免疫应答中与正常淋巴组织的滤泡具有相似的功能。aln可移植到幼稚正常和严重联合免疫缺陷（SCID）小鼠身上，在那里它们能有效地诱导继发性免疫反应。即使在移植后4周，抗原特异性的二次反应也在aln中被强烈诱导。携带aLNs的SCID小鼠抗原特异性抗体反应巨大，可达7-8mg/ml。抗原激发后，反应持续一段时间，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CD4+ 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，aLNs在免疫缺陷小鼠中强烈支持抗原特异性二抗反应，并为未来的临床应用提供了可能性。最近，我们成功地从CD8+细胞、CD4+细胞和NK/NKT细胞中通过分泌gammalFN构建了具有肿瘤抗原特异性细胞毒活性的aln。这些碱性磷酸酶具有很强的肿瘤免疫能力。

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.