本橋 新一郎

The aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC). The methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD. IL-12R beta 2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16(INK4A) and WNT antagonist genes was a negative prognostic factor in the non-COPD group. Novel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

The aim of this clinical trial was to investigate the feasibility of intra-arterial infusion of in vitro-expanded V alpha 24 natural killer T (NKT) cells combined with submucosal injection of alpha-galactosylceramide (KRN7000; alpha GalCer)-pulsed antigen-presenting cells (APC). A phase I clinical study was carried out in patients with head and neck squamous cell carcinoma (HNSCC). Patients with locally recurrent HNSCC refractory to standard therapy were eligible. Eight patients received super-selective transcatheter intra-arterial infusion of activated V alpha 24 NKT cells into tumor-feeding arteries and nasal submucosal injections of alpha GalCer-pulsed APC twice with a 1-week interval. V alpha 24 NKT cell-specific immune responses, safety, and antitumor effects were evaluated. The number of V alpha 24 NKT cells and interferon-gamma-producing cells in peripheral blood mononuclear cells increased in seven out of eight patients enrolled. Grade 3 toxicity with a pharyngocutaneous fistula related to local tumor reduction was observed in one patient and mild adverse events with grade 1-2 symptoms occurred in seven patients. Regarding the clinical responses, three cases exhibited a partial but significant response, four were classified as stable disease, and one patient continued to develop progressive disease. The use of the intra-arterial infusion of activated V alpha 24 NKT cells and the submucosal injection of alpha GalCer-pulsed APC has been shown to induce significant antitumor immunity and had beneficial clinical effects in the management of advanced HNSCC. The use of such therapeutic modalities may be helpful in the management of tumors and therefore needs to be explored in further detail. The clinical trial registration number was UMIN000000722. (Cancer Sci 2009; 100: 1092-1098).

Several studies have described p16(INK4A) and prostaglandin E2 (PGE2) co-alterations in various solid tumors, including non-small cell lung cancer (NSCLC). In this study, we examined the correlation between PGE2 receptor 2 (EP2) expression and p16(INK4A) methylation in NSCLC, and the association with clinicopathological features and prognostic significance. We retrospectively reviewed 88 NSCLC patients who underwent resection from July 1993 to May 1997. The tumors included 43 adenocarcinomas, 39 squamous cell carcinomas, and 6 large cell carcinomas. EP2 expression was determined by immunostaining, and p16(INK4A) methylation was analyzed by methylation specific PCR. EP2 was overexpressed in 44% of NSCLC patients, 61% of adenocarcinoma cases, 28% of squamous cell carcinoma cases, and 33% of large cell carcinoma cases. EP2 expression positively correlated with lymph node metastasis (P=0.034), especially in patients with squamous cell carcinoma (P < 0.009). Methylation of p16(INK4A) was detected in 34% of NSCLC patients, 23% of adenocarcinoma cases, 44% of squamous cell carcinoma cases, and 50%, of large cell carcinoma cases. In patients with squamous cell carcinoma, EP2 overexpression correlated with poor prognosis with a relative risk of 2.4 (confidence interval 2.1-51.8, P < 0.003), and positively correlated with p16(INK4A) methylation (P < 0.024). Adenocarcinoma patients with p16(INK4A) methylation had poor prognosis with a relative risk of 2.4 (confidence interval 1.8-69.7, P < 0.009), but this was not. correlated with EP2 expression. In conclusion, EP2 overexpression was common in NSCLCs, especially in adenocarcinomas. Synchronous alteration of p16(INK4A) and EP2 may accelerate progression of squamous cell carcinomas. These two alterations may differentially affect pathogenesis among subtypes of NSCLC.

To evaluate the safety, immune responses, and antitumor responses after the administration of a-galactosylceramide (alpha GalCer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. alpha GalCer-pulsed IL-2/GM-CSF-cultured PBMCs (I X 10(9)/m(2)) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of aGalCer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-gamma-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-gamma-producing cells (>= 2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poor-responder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test,p = 0.0015). The administration of aGalCer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT cell-dependent immune responses. The increased IFN-gamma-producing cells that result from aGalCer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy. The Journal of Immunology, 2009, 182: 2492-2501.

Human invariant Valpha24 Natural Killer T (NKT) cells are unique lymphocyte subsets, characterized by an invariant T-cell receptor Valpha24 chain paired with Vbeta11. Recent findings have highlighted the role of NKT cells in tumor immunity. Valpha24 NKT cells are activated by a specific glycolipid ligand, alpha-Galactosylceramide and rapidly produce high levels of cytokines upon stimulation, thereby modulating other immune cells such as NK cells antigen-specific CD4+ and CD8+ T cells and dendritic cells. Abnormalities in the numbers and functions of Valpha24 NKT cells have been observed in patients with various malignant diseases. Therefore, therapeutic strategies have recently focused on the reconstitution of an adequate number of functionally sufficient Valpha24 NKT cells which is thought to be logical and reasonable for cancer treatment. The quantitative alteration and functional impairment of circulating Valpha24 NKT cells are herein reviewed in various cancer-bearing patients and the progress to date in the clinical applications of NKT cell-based tumor immunotherapy is summarized.

Human V alpha 24 invariant natural killer T (iNKT) cells are a distinct lymphocyte population, characterized by an invariant T-cell receptor V alpha 24 chain paired mainly with V alpha 11. V alpha 24 iNKT cells are activated by a glycolipid ligand - alpha-galactosylceramide - and produce a large amount of Th1 and Th2 cytokines, thereby modulating the function of other cells. iNKT cells have the capability to control a wide variety of immune responses, including antitumor immunity. Abnormalities in the number and function of V alpha 24 NKT cells have been observed in patients with malignant diseases accompanied with a poor clinical outcome. Therefore, therapeutic strategies that focused on the restoration of V alpha 24 iNKT cell population and function would be a reasonable rationale for the treatment of cancer. In this article, the progress to date in the clinical studies of iNKT cell-based immunotherapy is briefly reviewed and the role of V alpha 24 iNKT cells in cancer immunotherapy is highlighted.

Chemokines play an important role in the pathogenesis of non-small cell lung cancer (NSCLC). However, aberrant methylation of CXCL12 has not been examined in NSCLC. CXCL12 mRNA expression and methylation were examined in 17 NSCLC cell lines by RT-PCR and methylation-specific PCR (MSP). MSP was performed on 236 tumor specimens from NSCLC patients who received curative intent surgery. CXCL12 and CXCR4 protein expression was examined in 90 of the 236 NSCLC specimens by immunohistochernistry. Down-regulation of CXCL12 expression was found in 10 of 17 (59%) NSCLC cell lines compared with normal bronchial cells. Treatment of 8 expression-negative cell lines with a demethylating agent restored expression in all cases. Twelve cell lines (71%) showed aberrant methylation, and good concordance between methylation and expression was present. Aberrant methylation occurred in 85 out of 236 (36%) primary NSCLCs in a tumor-specific manner. In multivariate analysis, CXCL12 methylation correlated strongly and independently with prognosis both in all patients with NSCLCs and in those with stage I NSCLCs (hazard ratio=1.68, P=0.015 and hazard ratio=3.58, P=0.017). Secreted protein CXCL12 and its receptor CXCR4 were abundant in NSCLC cells (72 out of 90, 80%; 57 out of 90, 63%) and correlated with the progression of NSCLCs. In conclusion, epigenetic silencing of CXCL12 is a frequent event in NSCLCs, and could be an independent and powerful prognostic marker in patients with NSCLCs and those with stage I disease. Analysis for CXCL12 may provide novel opportunities for prognosis and therapy of resected NSCLCs.

Human invariant V alpha 24 natural killer T (NKT) cells are a novel, distinct lymphocyte population, characterized by an invariant T-cell receptor V alpha 24 chain paired with V beta 11. V alpha 24 NKT cells are activated by a specific glicolipid ligand, alpha-GalCer, and rapidly produce a large amount of Th1 and Th2 cytokines, thereby modulating other immune cells such as antigen-specific CD4 and CD8 T cells, NK cells, and dendritic cells. Recent studies have shown that NKT cells play pivotal regulatory roles in many immune responses, including antitumor immunity. We herein review the quantitative alteration and functional deterioration of circulating V alpha 24 NKT cells in various cancer-bearing patients. We also summarize the recent progress in the clinical studies of NKT cell-based tumor immunotherapy. Novel immunological results including the increased peripheral blood V alpha 24 NKT cells and IFN-producing cells after the immunotherapy were revealed. The details of the safety profile and the antitumor responses were also disclosed. Although the objective clinical responses still remain unclear, some encouraging results have emerged. Therefore, NKT cell-based immunotherapy may potentially be an effective strategy for the treatment of cancer patients.

Background Human V alpha 24 natural killer T (NKT) cells are activated by the specific ligand, alpha-galactosylceramide (alpha-GalCer), in a CD1d-dependent manner. Potent anti-tumor activity of activated NKT cells has been previously demonstrated. Methods We conducted a phase I study with alpha-GalCer-pulsed antigen presenting cells (APCs) administered in the nasal submucosa of patients with head and neck cancer, and evaluated the safety and feasibility of such a treatment. Nine patients with unresectable or recurrent head and neck cancer received two treatments 1 week apart, of 1 x(8) of alpha-GalCer-pulsed autologous APCs into the nasal submucosa. Results During the clinical study period, no serious adverse events (Common Terminology Criteria for Adverse Events version 3.0 greater than grade 3) were observed. After the first and the second administration of alpha-GalCer-pulsed APCs, an increased number of NKT cells was observed in four patients and enhanced natural killer activity was detected in the peripheral blood of eight patients. Conclusion The administration of alpha-GalCer-pulsed APCs into the nasal submucosa was found to be safe and induce anti-tumor activity in some patients.

Purpose: The Wnt and epidermal growth factor receptor (EGFR) signaling pathways play crucial roles in the pathogenesis of a variety of malignant tumors. Although the details of each cascade are understood, very little is known about their collective effects in non -small cell lung cancer (NSCLC). Experimental Design: A total of 238 NSCLC samples were examined for methylation of Wnt antagonists [secreted frizzled-related protein (sFRP)-1, sFRP-2, sFRP-5,Wnt inhibitory factor-1, and Dickkopf-3] and for EGFR and KRAS mutations. Protein expression levels of P-catenin were assayed in 91 of the 238 NSCLCs. Results: We found that (a) aberrant methylation of Wnt antagonists is common in NSCLCs; (b) methylation of sFRP-2 is more prevalent in females, nonsmokers, and adenocarcinoma cases; (c) Dickkopf-3 methylation is significantly associated with a poor prognosis in adenocarcinomas; (d) there is a positive correlation between activated EGFR mutation and nuclear accumulation of beta-catenin; (e) KRAS mutation and aberrant methylation of Wnt antagonists are positively correlated; and (f) EGFR mutation is significantly associated with a good prognosis in tumors lacking methylated Wnt antagonist genes. Conclusions: These results contribute to a better understanding of the cross-talk between the Wnt and EGFR signaling pathways and help foster development of chemotherapeutic treatments in NSCLCs.

Purpose: Human V alpha 24 natural killer T (V alpha 24 NKT) cells bearing an invariant V alpha 24J alpha Q antigen receptor are activated by a glicolipid ligand a-galactosylceramide (alpha GalCer; KRN7000) in a CD1d-dependent manner. The human V alpha 24 NKTcells activated with alpha GalCer and interleukin-2 have been shown to produce large amounts of cytokines, such as IFN-gamma, and also exerting a potent killing activity against various tumor cell lines. We did a phase I study with autologous activated V alpha 24 NKT cell therapy. Experimental Design: Patients with advanced or recurrent non-small cell lung cancer received i.v. injections of activated V alpha 24 NKTcells (level 1: 1 x 10(7)/m(2) and level 2: 5 x 107/m(2)) to test the safety, feasibility, and clinical response of this therapeutic strategy. Immunomonitoring was also done in all cases. Results: Six patients were enrolled in this study. No severe adverse events were observed during this study in any patients. After the first and second injection of activated V alpha 24 NKTcells, an increased number of peripheral blood V alpha 24 NKTcells was observed in two of three cases receiving a level 2 dose of activated V alpha 24 NKTcells. The number of IFN-gamma-producing cells in peripheral blood mononuclear cells increased after the administration of activated V alpha 24 NKT cells in all three cases receiving the level 2 dose. No patient was found to meet the criteria for either a partial or a complete response. Conclusions: The clinical trial with activated V alpha 24 NKT cell administration was well tolerated and carried out safely with minor adverse events even in patients with advanced diseases.

A unique lymphocyte population, CD1d-restricted NKT cells, has been revealed to be a key player in both the innate and acquired immune responses, including antitumor effects. Recent studies revealed that at least two subsets of CD1d-restricted NKT cells exist: type I, having invariant V alpha 14 receptor; and type II, having heterogeneous non-V alpha 14 receptor. The specific glycolipid ligand, alpha-GalCer, effectively stimulates mouse and human type I NKT cells. The activation of type I NKT cells substantially influences function of other various cell types, particularly DC, NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells, all contributing to the antitumor immune responses. Recent studies also indicated that, unlike type I NKT cells, type II NKT cells have a potential to repress antitumor immune responses. In this review, we summarize the characteristics of the antitumor immune responses mediated by both mouse and human CD1d-restricted NKT cells and discuss their potential in clinical applications against cancer.

We report on a case of a complete resection for bronchogenic carcinoma necessitating right upper sleeve lobectomy with prosthetic replacement of right pulmonary artery (PA) and superior vena cava (SVC). A 74-year-old male with squamous cell carcinoma had a tumor which extended to the right main bronchus, right PA and SVC. After reconstruction of the SVC with a ringed polytetrafluoroethylene (PTFE) graft between the left brachiocephalic vein (BCV) and right atrial auricle, the tumor was completely resected en bloc. Bronchial anastomosis followed by the prosthetic reconstructions of PA and SVC between the right BCV and the origin of SVC were performed. Pathological staging was t4n2m0 (stage IIIB). The postoperative course was uneventful and the patient discharged from the hospital on the 29th postoperative day. He has been doing well without recurrence and keeping a good graft patency for more than 3 years.

Background. Treatment of pulmonary metastases from colorectal cancer by excision has increased rapidly, but reports on indications and prognostic factors are inconsistent. We sought to identify poor prognostic factors preoperatively and to retrospectively evaluate preoperative clinical indications for surgery. Methods. A total of 75 patients with colorectal cancer had pulmonary metastases excised from 1986 to 2003. Tumor size, number, laterality, hilar or mediastinal lymphadenopathy, and carcinoembryonic antigen level were possible risk factors for metastatic tumors, with primary site of colorectal tumor, disease-free interval, and hepatectomy for liver metastasis possible risk factors for primary tumors. Prognostic factors in univariate and multivariate analyses also included age and sex. Results. Five-year survival rates were 41.3% after pulmonary excision and 73.1% after primary colorectal resection. Three factors identified as significant by univariate log-rank test for overall survival after pulmonary resection were carcinoembryonic antigen (p < 0.0001), tumor laterality (p = 0.0205), and number of pulmonary metastases (p = 0.0028). Multivariate analysis found that carcinoembryonic antigen, tumor number, tumor size, and patient's age were also independent prognostic factors. In contrast, carcinoembryonic antigen, number of metastases, and disease-free interval predicted prognosis after primary colorectal resection. Prior hepatectomy for metastases did not influence prognosis after pulmonary metastasectomy. Conclusions. Elevated carcinoembryonic antigen level and multiple metastases are preoperative predictors of poor prognosis after resection of pulmonary metastases from colorectal cancer. Survival rate is sufficient to justify pulmonary metastasectomy if there is no local or distant metastatic lesion other than in the liver; if needed, sequential pulmonary and hepatic metastasectomy can be performed.

Human invariant V alpha 24(+) natural killer T (NKT) cells display potent antitumor activity upon stimulation. Activation of endogenous V alpha 24(+) NKT cells would be one strategy for the treatment of cancer patients. For example, dendritic cells (DCs) loaded with a glycolipid NKT cell ligand, alpha-galactosylceramide (alpha GalCer, KRN7000), are a possible tool for the activation and expansion of functional V alpha 24(+) NKT cells in vivo. In this report, we demonstrate that the levels of expansion and the ability to produce IFN-gamma of V alpha 24(+) NKT cells induced by alpha GalCer-loaded whole PBMCs cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs) were superior to those of cells induced by monocyte-derived CD11c(+) DCs (moDCs) developed with IL-4 and GM-CSF. Interestingly, CD11c(+) cells in the IL-2/GM-CSF-cultured PBMCs showed a mature phenotype without further stimulation and exerted potent stimulatory activity on V alpha 24(+) NKT cells to enable them to produce IFN-gamma preferentially at an extent equivalent to mature moDCs induced by stimulation with LPS or a cytokine cocktail. Cocultivation with CD11c(-) cells in the IL-2/GM-CSF-cultured PBMCs induced maturation of moDCs. In particular, CD11c(-)CD3(+) T cells appeared to play important roles in DC maturation. In addition, TNF-alpha was preferentially produced by CD11c(-)CD3(+) T cells in IL-2/GM-CSF-cultured PBMCs and was involved in the maturation of moDCs. Thus, the maturation of DCs induced by CD11c(-) T cells through TNF-alpha production appears to result in the efficient expansion and activation of V alpha 24(+) NKT cells to produce IFN-gamma preferentially. (c) 2005 Wiley-Liss, Inc.

In 1999, the World Health Organization introduced a new classification of a rare thymic cancer called papillary adenocarcinoma of the thymus gland. In this study we report on a case of papillary thymic carcinoma in a 29-year-old woman. Histologically, the tumor consisted of a papillary component admixed with a solid component, a component that is commonly found in type A thymoma.

A unique lymphocyte population, V alpha 14 NKT cells, has recently been revealed to be a key player in the immune responses against tumors. Activation of V alpha 14 NKT cells affects various cell types, particularly dendritic cells (DCs), NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells in the innate and acquired immune systems, eventually resulting in the enhanced activation of NKT cell-mediated cellular cascade in the anti-tumor responses. The specific ligand, alpha-galactosylceramide (alpha-GalCer), effectively stimulates mouse and human NKT cells, making NKT cells an ideal target for the development of cancer immunotherapy. Clinical trials using alpha-GalCer have actually started in several centers in the world. In this review, we summarize the Va14 NKT cell-mediated cellular cascade in the anti-tumor response in mice and discuss potential clinical applications of alpha-GalCer-pulsed DC therapy.

Neurogenic benign tumors arising from the trachea and bronchus are relatively rare. We experienced three cases of neurofibroma of the bronchus which were successfully treated by transbronchial electrical snaring and Nd-YAG laser abrasion. The first was a 67-year-old man with right lung cancer, who was pointed out to have a neurofibroma in the left main bronchus. The second was a 34-year-old man with an obstruction in the right main bronchus due to neurofibroma. The third was a 66-year-old woman with a complete obstruction in the left main bronchus due to schwannoma. All patients were successfully treated to remove the tumors and obtain a patency of the bronchus by transbronchial electrical snaring and Nd-YAG laser abrasion. We also review 23 reported cases of endobronchial neurogenic tumors and discuss the efficacy of endoscopic treatments for endobronchial neurogenic tumors.

Papillary thyroid carcinoma with massive invasion into the great veins of the neck and mediastinum has rarely been reported and is thought to have a poor prognosis. Here we report successful management of a case of papillary thyroid carcinoma with extensive invasion into the left internal jugular vein, left brachiocephalic vein, and superior vena cava, followed by reconstruction of the superior vena cava using an artificial graft. The operation was conducted to prevent sudden death due to complete obstruction of venous flow, improve the patient's quality of life, and prolong survival. The patient has survived for more than two years after surgery, with good general condition.

Interleukin 6 (IL-6) facilitates the differentiation of B cells to immunoglobulin-secreting cells and is reported to be a proliferative factor in some tumors. In this study, we examined IL-6 production in non-small cell lung carcinoma (NSCLC) and the proliferation of tumor cells following IL-6 treatment in vitro and in vivo. We analyzed the expression of IL-6 mRNA and protein in a series of 15 human lung cancer cell lines (four adenocarcinomas, five squamous cell carcinomas, two large cell carcinomas, and four small cell carcinomas) by reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). We established an IL-6-producing cell line (ABC-1#IL-6) by transfecting a human IL-6 cDNA into a human non-IL-6-producing NSCLC cell line (ABC-1). These two cell lines were used to determine tumor cell proliferation both in vivo and in vitro in order to clarify the effect of IL-6 on tumor growth and metastasis. Athymic nude mice, SCID mice, and BALB/c mice were subcutaneously inoculated with these two cell lines, and body weight, tumor growth, and tumor doubling time were measured. The presence of IL-6 and tumor-infiltrating lymphocytes (TILs) within tumor tissues was examined by immunohistochemical staining. Results: Eight of 15 (53%) lung cancer cell lines expressed both IL-6 mRNA and protein. Tumor lesions of both cell lines developed in nude and SCID mice, although no such lesions of either cell lines developed in BALB/c mice. The tumor doubling time in nude and SCID mice was 2.97+/-1.22 days and 2.45+/-1.32 days, respectively, in mice inoculated with the cell line ABC-1#IL-6. These doubling times were statistically significantly shorter than those evident in mice inoculated with the control original ABC-1 cell line (nude, p=0.0337; SCID, p=0.0119; unpaired t-test). The rates of cell proliferation in vitro of the ABC-1#IL-6 and original ABC-1 cells lines were comparable (p=0.1441, unpaired t-test). Immunohistochemical staining revealed strong IL-6 expression in tumors derived from the IL-6-producing cell line but not in tumors derived from the original ABC-1 cell line (both in nude and SCID mice). Conclusion: 53% of lung cancer cell lines produce IL-6 mRNA and protein. Although IL-6 itself does not influence tumor cell proliferation in vitro, an association between IL-6 expression and tumor proliferation was found in vivo in nude and SCID mice. An anti-IL-6 reagent could provide a novel therapeutic strategy in patients with IL-6-producing lung tumors.

Sarcoidosis is a systemic disorder associated with granuloma characterized by an abnormal T(h)1-type cytokine production and accumulation of T(h)1 CD4 T cells in the granuloma lesions, suggesting an importance of T(h)1 responses in sarcoidosis. However, the pathogenesis of sarcoidosis remains to be solved. Here, we investigated the nature of V(alpha)24 NKT cells with immunoregulatory functions in sarcoidosis. Patients with non-remitting sarcoidosis displayed a decrease in the number of V(alpha)24 NKT cells in peripheral blood, but an accumulation of these cells in granulomatous lesions. When stimulated with the specific glycolipid ligand, alpha-galactosylceramide, peripheral blood V(alpha)24 NKT cells from patients with non-remitting disease produced significantly less IFN-gamma than those from healthy volunteers, but normal levels of IL-4. The reduced IFN-gamma production was observed only in V(alpha)24 NKT cells and not conventional CD4 T cells, but was normal in patients with remitting disease, suggesting that non-remitting sarcoidosis involves an insufficient IFN-gamma production of V(alpha)24 NKT cells which is well correlated with disease activity. Thus, these results suggest that V(alpha)24 NKT cells play a crucial role in the disease status of sarcoidosis.