Investigation into regulation of immune responses by NK cells and NKT cells

我已经分析了NK细胞和NKT细胞的靶标识别和细胞毒性机制，以阐明这些细胞和/或其功能分子调节免疫应答的可能性。肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）是未成熟NK细胞的关键细胞毒分子，在幼鼠的自我防御中起重要作用。我们还证明了成年小鼠肝脏中表达TRAIL的NK细胞是未成熟的NK细胞，有可能发育成成熟的NK细胞。TRAIL是NK细胞介导的肿瘤监视中的关键分子。为了将TRAIL应用于肿瘤治疗，我们新近建立了针对DR 5（death-inducing TRAIL receptor）的激动性单克隆抗体（MD5-1）。用MD5-1处理通过凋亡诱导诱导对TRAIL敏感的肿瘤细胞的肿瘤排斥，并且还诱导肿瘤特异性T细胞应答，并且这导致对TRAIL抗性肿瘤变体的排斥.我们证明IOCS在NKT细胞活化中作为共刺激分子发挥作用，增加细胞因子的产生和细胞毒活性.特异性配体激活的NKT细胞暂时内化抑制性NK细胞受体（CD 94/NKG 2），当用α-半乳糖神经酰胺（NKT细胞特异性配体）再刺激时，这些NKT细胞表现出显著增加的细胞因子产生和抗肿瘤作用。我们还证明了这种调节是由IFN-γ介导的。这些结果表明，联合应用NKT细胞特异性配体和/或抑制NK细胞受体介导的信号增强了NKT细胞介导的抗肿瘤效应.我们报道了TRAIL在BCG治疗的人膀胱癌中肿瘤浸润T细胞上的表达，并提出了TRAIL对BCG治疗效果的可能贡献. TWEAK与TRAIL同属TNF超家族，表达于巨噬细胞表面，在抑制肿瘤生长和肿瘤免疫监视中起重要作用。

I have been analyzed target-recognizing and cytotoxic mechanisms of NK cells and NKT cells to elucidate the possibility to regulate immune responses by these cells and/or their functional molecules.1. TNF-related apoptosis-inducing ligand (TRAIL) is the critical cytotoxic molecule of immature NK cells, and which play critical roles in self-defense of infant mice. We also demonstrated that TRAIL-expressing NK cells in the liver of adult mice are immature NK cells potentially developing into mature NK cells.2. TRAIL is a critical molecule in NK cell mediated tumor surveillance. To utilize TRAIL to tumor therapy, we newly established agonistic monoclonal antibody to DR5 (death-inducing TRAIL receptor) (MD5-1). Treatment with MD5-1 induces tumor rejection of TRAIL-sensitive tumor cells by apoptosis induction, and also induces tumor specific T cell responses, and which results in the rejection of TRAIL-resistant tumor variants.3. We demonstrated that IOCS play a role as costimulatory molecules in NKT cell activation, which augments cytokines production and cytotoxic activity.4. Specific ligand-activated NKT cells temporally internalize inhibitory NK cell receptor (CD94/NKG2), and these NKT cells demonstrate dramatically augmented cytokines production and anti-tumor effects when re-stimulated with α-Galactosylceramide (NKT cell specific ligand). We also demonstrated that this regulation is mediated by IFN-γ. These results suggested that combined therapy of NKT cell specific ligand and/or inhibition of NK cell receptor-mediated signal augments NKT cell mediated anti-tumor effects.5. We reported that TRAIL is expressed on tumor infiltrating T cells in BCG-treated bladder cancers in human, and suggested the possible contribution of TRAIL to therapeutic effect of BCG therapy.6. TWEAK, one of the member of TNF super family as TRAIL, is expressed on macrophages and plays important roles in inhibition of tumor growth and immunological tumor surveillance.