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Dendritic cells (DCs) play a crucial role in maintaining the immune system. Although DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, clinical efficacies have been still unsatisfactory. To improve the clinical outcome of DC-based cancer immunotherapy, we are now focusing on 1) increase of numbers of therapeutic immune cells, i.e., DCs, and 2) the development of new methods for stimulating them. We have recently established a possible breakthrough, a simple cytokine-based culture method to realize a log-scale order of functional myeloid-type murine/human DCs. Moreover, we demonstrated that DCs activated by replication-deficient recombinant Sendai virus (rSeV) were highly effective than that seen in the use of current DC vaccine stimulated by conventional cytokines etc., for immunotherapy against malignancies. Therefore, our study strongly suggests that these improvements could overcome the current limitations of DC-based immunotherapy for malignancies.

Besides blood flow restoration, neuroprotection is essential for treating strokes at an acute stage. Both neurotrophic factors (NTFs) and free radical scavengers can act as neuroprotective agents with abilities to inhibit cell death and facilitate cell survival under cerebral ischemia. For example, topical application of glial cell line-derived neurotrophic factor (GDNF) remarkably reduced infarct size and brain edema after middle cerebral artery (MCA) occlusion in rats. Reduction in the infarct size was not found to be related to a change in the cerebral blood flow (CBF), but was accompanied by marked reduction in BrdU-positive cells in the affected area after TdT-mediated dUTP-biotin nick end labeling (TUNEL) for caspses. Thus, GDNF elicited a direct protective effect against ischemic brain damage, but without improving CBF. Sendai virus vectors harboring the GDNF gene led to a remarkable reduction in infract volume without affecting regional CBF but reduced the translocation of apoptosis inducible factor (AIF) from the mitochondria to cytoplasm. Regenerative therapy involving neural stem cells which are intrinsically activated or exogenously transplanted, is an important treatment strategy. To facilitate stem cell migration, an artificial scaffold can be implanted into the injured brain for promoting ischemic brain repair. Addition of NTFs greatly enhanced an intrinsic migration or invasion of stem cells into the scaffold: this strategy could be used in the future for enhancing regenerative potential of brain cells after chronic ischemia-induced brain damage.

Ultraviolet-inactivated, replication-defective Sendai virus particles (Hemagglutinating virus of Japan envelope, HVJ-E) injected into murine colon carcinoma (CT26) tumors growing in syngeneic Balb/c mice eradicated 60-80% of the tumors and obviously inhibited the growth of the remainder. Induced adaptive anti-tumor immune responses were dominant in the tumor eradication process because the effect was abrogated in severe combined immunodeficient (SCID) mice. Murine and human dendritic cells (DCs) underwent dose-dependent maturation by HVJ-E in vitro. Profiles of cytokines secreted by DCs after HVJ-E stimulation showed that the amount of IL-6 released was comparable to that elicited by live HVJ. Real-time RT-PCR and immunohistochemistry revealed that HVJ-E induced a remarkable infiltration of DCs, CD4+ and CD8+ T cells into tumors and CT26 specific cytotoxic T lymphocytes (CTL) were induced. On the other hand, conditioned medium from DCs stimulated by HVJ-E (H-DCCM) rescued CD4+CD25- effector T cell proliferation from Foxp3+CD4+CD25+ regulatory T cell (Treg) mediated suppression and IL-6 was presumably dominant for this phenomenon. We also confirmed such rescue in mice treated with HVJ-E in vivo. Moreover, anti-tumor effect of HVJ-E was significantly reduced by an in vivo blockade of IL-6 signaling. Depending on cancer cell types, it is also expected that HVJ-E eradicates tumor by its direct cytotoxity against cancer cells or activating NK cells. Because it can enhance anti-tumor immunity and simultaneously remove Treg mediated suppression, HVJ-E shows promise as a novel therapeutic for cancer immunotherapy.