Reconstruction of Immune Tissues and Repair/Reinforcement of Immune Surveillance

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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.