本橋 新一郎

Background: Certain immune functions are known to be impaired in human beings exposed to Antarctic winter; in particular, decreased amounts of serum proinflammatory cytokines, such as TNF-alpha and IL-1, were noted. It is not known, however, whether this exposure has any effect on T-cell-mediated acquired immune functions. Objectives: This study aims to investigate whether exposure to Antarctic winter has any effect on T cell-dependent immune functions. Methods: We assessed changes in various immunologic indicators. including serum levels of various cytokines, peripheral blood Valpha24Vbeta11 natural killer T cell numbers, and T(H)1/T(H)2 ratios of 40 Japanese personnel exposed to an Antarctic winter. Also, a 2-month inland traverse was executed during the isolation, and the effect on the above indicators was assessed. Results: All subjects were healthy during the Antarctic isolation. The levels of serum TNF-alpha, IL-1Ra, IL-6, and IL-1beta were dramatically reduced and remained at low levels throughout the isolation. The decrease in the levels of TNF-alpha and IL-1Ra was more pronounced during the inland traverse than during the rest of the isolation. The percentage of Valpha24Vbeta11 natural killer T cells was significantly increased at the midpoint of the isolation. Most interestingly, T(H)1/T(H)2 ratio was increased significantly, and this T(H)1 bias was most prominent at the late point of the isolation. Conclusions: Exposure to an Antarctic winter appeared to induce T(H)1-skewed immunity in human beings. (J Allergy Clin Immunol 2003;111:1353-60.).

We report the case of a 60-year-old woman referred to us after chest X-ray and mobile computed tomography screening detected an 8-mm nodule in right S2. Transbronchial aspiration cytology suggested a pulmonary metastasis from colorectal cancer. Therefore, we performed a colonoscopy and found a polypoid lesion, 2 cm in diameter, in the sigmoid colon. An analysis of a biopsy specimen from this polypoid lesion confirmed adenocarcinoma. Surgical resection of the primary sigmoid colon cancer was subsequently performed, followed 4 weeks later by a right S2 segmentectomy to remove the lung metastasis. The patient is currently well without any clinical signs of recurrence, 44 months after her operation.

Human Valpha24 NKT cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-GalCer, in a CD1d-dependent manner. Here, we demonstrate decreased numbers of circulating Valpha24 NKT cells in patients with primary lung cancer compared to healthy volunteers. However, Valpha24 NKT cells and DCs from lung cancer patients were functionally normal, even in the presence of tumor. Furthermore, levels of Valpha24 NKT cells in surgically resected lung tissue appeared to be equivalent to those of Valpha14 NKT cells in the mouse lung. Levels of Valpha24 NKT cells in the tumor tissue itself were increased about 2.5 times. Administration of alpha-GalCer-pulsed DCs expanded Valpha14 NKT cells in the lung more than 10 times, and the increased levels were sustained for 1 week. This may explain the previous finding that alpha-GalCer-pulsed DCs exerted strong antitumor activity in mouse lung tumor metastatic models. The potential use of alpha-GalCer-pulsed DCs for immunotherapy aimed at activating endogenous Valpha24 NKT cells in the lung of cancer patients is discussed. (C) 2002 Wiley-Liss, Inc.

NKT cells, a novel murine lymphoid lineage bearing an invariant T cell receptor encoded by Valpha14 and Jalpha281 gene segments, recognize a specific ligand glycolipid, alpha-galactosylceramide (alpha-GalCer) in a CD1d-dependent manner. Recent research has revealed that activated Valpha14 NKT cells have dramatic antitumor effects against a wide variety of tumor cell lines in vivo and in vitro. Here, we demonstrate strong in vivo antitumor effects brought about by treatment with alpha-GalCer-pulsed dendritic cells in comparison with in vitro-activated Valpha14 NKT cells. Furthermore, we show a significant expansion of endogenous Valpha14 NKT cells in the lung following the administration of alpha-GalCer-pulsed dendritic cells. The feasibility of immunotherapy with alpha-GalCer-pulsed dendritic cells is discussed.

A unique lymphocyte lineage, the V alpha 14 NKT cells, expresses both NK1.1 and an invariant antigen receptor encoded by V alpha 14 and J alpha 281 gene segments. Va14 NKT cells play crucial roles in various immune responses, including autoimmune diseases, allergic reactions and anti-tumor immunity. V alpha 14 NKT cells were demonstrated to be essential for anti-tumor effect of IL-12 in vivo. Here, we report that adoptive transfer of IL-12-activated Va alpha 14 NKT cells prevents hepatic metastasis of B16 melanoma. The injection of large amounts of IL-2, IL-4, and IFN-gamma, which are cytokines produced by activated V alpha 14 NKT cells, exhibited no significant inhibition of the metastasis of this melanoma. The cells prepared from the liver of IL-12-injected mice expressed a potent cytotoxic activity on B16 melanoma cells in vitro. Although the adoptive transfer of IL-12-activated V alpha 14 NKT cells prevents hepatic metastasis of B16 melanoma, activated NK cells from IL-12-injected RAG-I-/- mice failed to inhibit the metastasis of this melanoma. Thus, the anti-tumor effect of IL-12 can be replaced by adoptive transfer of IL-12-activated Va14 NKT cells but not by IL-12-activated NK cells, suggesting a minor role of NK cells for the IL-12-mediated anti-tumor effect in this experimental system. Moreover, our studies have suggested the involvement of direct cytotoxic mechanisms rather than cytokine-mediated immune responses at the effector phase of the V alpha 14 NKT cell-mediated anti-tumor activity. (C) 2001 Wiley-Liss, Inc.

Purpose: The majority of lung carcinoma patients requiring resection have smoking habits prior to surgical treatment, and the correlation of smoking with postoperative complications is well known, However, few studies have investigated the correlation between long-term survival and cigarette smoking in patients with primary, resected lung carcinoma. We analyzed the relationship between clinical factors, including cigarette smoking before surgery, and 10-year survival in stage I nan-small-cell lung carcinoma (NSCLC). Patients and Methods: Cigarette smoking habit and other factors influencing either the overall survival or the disease-specific survival rates of patients with stage I primary, resected NSCLC were evaluated according to the Cox proportional hazards model using a total of 369 patients with stage I-NSCLC, Results: Comparison of the cause of death in patients with 30 or more pack-years and patients with less than 30 pack-years showed significant differences in the prevalence of recurrent disease and onset of nonmalignant disease, Multivariate analysis demonstrated significant correlations between overall survival and age and pack-years. Disease-specific survival showed significant correlations with age, tumor classification, and visceral pleural invasion. Conclusion: Smoking pack-years is an important clinical prognostic factor in evaluating overall long-term survival in patients with stage I primary, resected NSCLC. (C) 1999 by American Society of Clinical Oncology.

症例は26才男性で1992年11月左上腕の滑膜肉腫にて上腕の切断術を行った.術前術後化学療法を実施したが無効で翌年2月胸部CTにて異常陰影が認められ, 手術目的で同年7月当科に紹介された.入院時胸部CTにて両側肺野に多発性腫瘤陰影を認めた.入院後, 抗癌剤化学療法および開胸術4回施行するも, 効果なく, 1994年2月よりIL-2, LAK細胞による養子免疫療法を追加した.その後1997年4月までに3回の開胸術と化学療法に加えて18クールのIL-2, LAK療法を施行し, 4年後の現在健在である.養子免疫療法の副作用は主に発熱, 悪寒, 戦慄であるが2～3日で回復する.術後の化学療法を含めた養子免疫療法により再発までの期間の延長と転移数の減少が期待できると考えられた.