Sherin Ahmed, Mohammed A. Satter, Shigeru Yamamoto, Kenichi Maeda, Yasuhiro Minato and Fusao Ota : Further Evidence Regarding the Effect of Dietary Protein on Oral Tolerance against Beta-Lactoglobulin through Th1-mediated Immune Response in Mice, Journal of Nutritional Science and Vitaminology, Vol.49, No.2, 112-119, 2003.
(要約)
Oral tolerance is a potential strategy for preventing or minimizing aberrant immune responses. Although, oral tolerance has been extensively studied, to date the effects of dietary protein on the induction of oral tolerance are poorly understood. We have previously shown that restricted dietary protein induces oral tolerance to ovalbumin. This study was designed to investigate whether or not such tolerance occurs with beta-lactoglobulin (BLG) instead of ovalbumin (OVA) and if the tolerance resulting from this feeding regimen involves Th1-mediated immune response. Female BALB/c mice fed either 20% or 5% dietary protein were given 5 mg BLG or water orally for four consecutive days and then immunized intraperitoneally (ip) twice with BLG at 3-wk intervals. Oral tolerance induction was compared in BLG-fed and water-fed mice by measuring total IgE, BLG-specific antibodies, footpad reactions, splenocyte proliferation, and cytokine production. When mice were given BLG orally before ip immunization, the Th1-mediated immune responses (production of IL-2, IFN-gamma, and IgG2a) were significantly reduced, whereas the Th2-mediated immune responses (production of IL-4 and IgG1) were unchanged. The Th1-mediated immune responses were markedly down-regulated in mice fed 5% protein as compared to those in mice fed 20% protein. Moreover, the production of total IgE, BLG-specific IgE, splenocyte proliferation, and footpad reactions were more reduced in mice fed 5% protein than those in mice fed 20% protein. The present study provides evidence that dietary protein plays an important role in the induction of oral tolerance against BLG as the result of, clear down-regulation of Th1 helper activity accompanied by a reduction in IgE.
Hiroaki Yanagawa, Minoru Shiraga, Youichi Nakamura, Masahiko Azuma, Kazuo Yoneda, Hirohisa Ogawa, Chikato Kitamuro, Kenichi Maeda, Mari Miki, Yuka Matsumori, Akemi Sugita, Sakiko Hashimoto, Chie Hara, Kenji Tani and Saburo Sone : Inhaled steroid therapy and hospitalization for bronchial asthma:trend in Tokushima University Hospital, The Journal of Medical Investigation : JMI, Vol.50, No.1,2, 72-77, 2003.
(要約)
With the recognition that airway inflammation is present even in patients with mild bronchial asthma, therapy with inhaled corticosteroids is now indicated in various stages of patients. In the present article, we retrospectively examined the prescriptions for inhaled corticosteroids and other drugs for the treatment of outpatients with bronchial asthma at Tokushima University Hospital. We also analyzed asthma control in these patients, in terms of the incidence of emergency consultations and hospitalizations due to asthma exacerbations. To analyze the recent trend, the patients observed from 1998 to 2000 (recent years) were included, and for control purpose, those in 1990 and 1991 (earlier years) were also included. The percentage of patients treated with inhaled corticosteroids remarkably increased in recent years (mean; 81.3%) compared to earlier years (mean; 23.5%). In contrast, the usage of oral corticosteroids, oral xanthine derivatives, beta-adrenergic receptor agonists and anti-allergic agents tended to decrease in the 10 years period. After the introduction in 1995, considerable patients up to 25% have been treated with anti-leukotrienes. Emergency consultations decreased in recent years (mean; 0.18/patient/year) compared to earlier years (mean; 0.79/patient/year). Emergency hospitalizations also decreased in recent years (mean; 0.043/patient/year) compared to earlier years (mean; 0.23/patient/ year). In the present study, spread of inhaled corticosteroid therapy and decline in incidence of emergency consultation and hospitalization were simultaneously observed at Tokushima University Hospital, and the former has, at least in part, a contribution to the latter.
Haruko Tanaka, Kenichi Maeda, Yoichi Nakamura, Masahiko Azuma, Hiroaki Yanagawa and Saburo Sone : CD40 and IFN-γ dependent T cell activation by human bronchial epithelial cells, The Journal of Medical Investigation : JMI, Vol.48, No.1, 2, 109-117, 2001.
(要約)
We examined whether freshly isolated human bronchial cells (HBEC) and bronchial epithelial cell line/BEAS-2B cells expressed surface molecules required for APC function. These cells expressed CD40 and ICAM-1, but not B7-1, B7-2 or HLA-DR molecules. Treatment of these cells with IFN-gamma resulted in enhanced expression of CD40 and ICAM-1 as well as induction of HLA-DR expression. Th2 cytokines such as IL-4 and IL-5, proinflammatory cytokine of GM-CSF and nonspecific activator endotoxin had no effect on these phenotypic expressions. Functional examinations showed that allogeneic lymphocytes purified from peripheral blood strongly proliferated in response to BEAS-2B cells cultured with IFN-gamma, but only weakly compared with those without IFN-gamma. When allogeneic lymphocytes were purified to CD4+ cells, the proliferative response against BEAS-2B cells was abolished. Blockade of CD40-CD40L interaction by anti-CD40 antibody also inhibited the proliferation of lymphocytes to BEAS-2B cells, although this treatment showed a minimum effect on the response to allogeneic MNC. Thus, bronchial epithelial cells have the ability to present allogeneic antigens to T cells in both CD40- and IFN-gamma-dependent manners under the presence of third party cells that transduce co-stimulatory signals.
Takahashi Toshiya, Kenichi Maeda, Yoichi Nakamura, Yoshio Okano, N. Ge and Saburo Sone : Interleukin-10 inhibits the production of inflammatory cytokines by antigen-stimulated mononuclear cells from asthmatic patients, Allergology International, Vol.49, No.1, 55-62, 2000.
Mowla Mohammed Golam Chowdhury, Kenichi Maeda, Koji Yasutomo, Yoichi Maekawa, Atsuko Furukawa, Miyuki Azuma, Hideyuki Nagasawa and Kunisuke Himeno : Antigen-specific B cells are required for the secondary response of T cells but not for their priming, European Journal of Immunology, Vol.26, No.7, 1628-1633, 1996.
(要約)
We studied the potential role of B cells in T cell responses using severe-combined immunodeficient (SCID) mice grafted with the thymus from fetal C.B-17 mice (TG mice). These mice developed both CD4+ and CD8+ T cells, but not B cells within 2 months after transplantation. TG mice showed normal delayed-type hypersensitivity responses against the immunizing antigen ovalbumin (OVA). Lymph node (LN) cells of TG mice proliferated well in response to concanavalin A (Con A). Further, Con A stimulation induced the production of interleukin (IL)-2, IL-6 and interferon (IFN)-gamma and the expression of IL-4 mRNA. Thus, TG mice were reconstituted without remarkable immunodeficiency. However, these T cells failed to proliferate to OVA stimulation. Response to OVA was also inhibited in SCID mice grafted with fetal C.B-17 liver cells when B cells were depleted in the proliferation assay. Unresponsiveness against immunizing antigen was restored by the addition of antigen-primed B cells, but not by naive B cells, lipopolysaccharide-activated B cells or B cells primed with sheep red blood cells. Next, we examined whether antigen-primed B cells could induce T cell responses without professional antigen-presenting cells (APC). T and B cells were purified from OVA-immunized mice by cell sorter. These T cells proliferated in response to OVA and produced IFN-gamma in the absence of non-B APC. When anti-CD80 or anti-CD86 was added in the assay, proliferation and IFN-gamma production was inhibited. These results indicate that B cells activated specifically with antigen are required for the secondary response of T cells, but not for their priming.
Atsuko Furukawa, Kenichi Maeda, Masayuki Miyasaka, Susumu Kagawa, Koji Yasutomo, Hajime Hisaeda, HIdeyuki Nagasawa and Kunisuke Himeno : Establishment of a xenogeneic chimera without GVHD in NK cell-depleted SCID mice by grafting rat fetal liver cells, Cellular Immunology, Vol.164, No.2, 176-181, 1995.
(要約)
Rat lymphopoiesis did not develop when naive SCID mice were transplanted with rat fetal liver cells. However, when SCID mice were depleted of NK cells by administration of anti-murine IL-2R beta mAb before transplantation, remarkable reconstitution of both rat T and B cells was observed in these mice without any evidence of graft-versus-host disease macroscopically or histologically. T cells in these reconstituted mice proliferated well in response to Con A and third-party rat and mouse antigens, whereas no response was seen to the stimulation with either donor rat- or host mouse-type cells. When these xenogeneic chimera mice had been immunized with SRBC, these mice exhibited DTH reaction and antibody production against the homologous antigen. These results indicate that rat fetal liver cells can differentiate to functional T and B cells in the xenogeneic microenvironment of SCID mice, if host NK cells are depleted beforehand. These rat-type T cells develop within SCID thymuses and acquire tolerance to either donor F344 rat or host SCID mouse antigens.
Hajime Hisaeda, Hideyuki Nagasawa, Kenichi Maeda, Yoichi Maekawa, Hiroyuki Ishikawa, Yoshihiro Ito, A. Robert Good and Kunisuke Himeno : Gamma delta T cells play an important role in hsp65 expression and in acquiring protective immune responses against infection with Toxoplasma gondii., The Journal of Immunology, No.1, 244-251, 1995.
(要約)
Previously, we reported that the expression of hsp65 within and on host macrophages correlates closely with protection against infection with Toxoplasma gondii in mice. Herein, we propose that gamma delta T cells play a crucial role in the induction of hsp65 and also in the protective immune response to T. gondii. Intraperitoneal inoculation with this protozoan resulted in hsp65 being expressed on and in host peritoneal macrophages and resulted in an increase of T cells bearing the gamma delta receptor with Thy-1+ and Thy-1- phenotypes in the peritoneal cavity and spleen. When mice were depleted of gamma delta T cells by the administration of a mAb, hsp65 expression was markedly decreased. In contrast, the expression of this protein was rather enhanced and gamma delta T cells were prominently expanded in mice depleted of alpha beta T cells. The protection in mice treated with the mAb paralleled the magnitude of hsp65 expression. Mice depleted of gamma delta T cells died most frequently in the early stages of infection, whereas most of those depleted of alpha beta T cells survived the early stages of lethal infection with T. gondii. However, the latter group of mice did not definitely control the T. gondii infection in its late stages. IFN-gamma was not essential for either the expression of hsp65 or the resistance induced by gamma delta T cells, as demonstrated in mice treated with mAb to murine IFN-gamma. These findings indicated that gamma delta T cells having both the Thy-1+ and Thy-1- phenotypes contribute to hsp65 expression within and on macrophages in an IFN-gamma-independent manner. This, in turn, plays a role in the development of protective immunity during the early stage of this parasitic infection.
Koji Yasutomo, Kenichi Maeda, Shigekazu Nagata, Hideyuki Nagasawa, Kaname Okada, A. Robert Good, Yasuhiro Kuroda and Kunisuke Himeno : Defective T cells from gld mice play a pivotal role in development of Thy-1.2+B220+ cells and autoimmunity, The Journal of Immunology, Vol.153, No.12, 5855-5864, 1994.
(要約)
The gld mouse represents a fascinating animal model of autoimmune disease, which is characterized by massive development of Thy-1.2+B220+ CD4-CD8- cells. These cells thus have double positive markers for T and B cells, but are double negative for CD4 and CD8 markers and are thus designated DN cells in the present context. An additional important feature in gld mice is a defect in expression of Fas ligand. To investigate the regulatory role of bone marrow-derived cells for the development of these DN cells and of gld autoimmunity, we constructed chimeric mice transplanted with fetal liver cells or fetal thymus from gld mice into nonirradiated severe combined immunodeficient (SCID) mice. These chimeric mice regenerated, developed both these DN cells and the gld autoimmune syndrome and also generalized lymphoproliferative disorders. However, when fetal liver cells from both gld and non-gld mice (C57BL/10 Thy-1.1 mice) were co-transplanted into SCID mice, the development of DN cells was apparently inhibited. Further, this inhibition was also seen in SCID mice that had been grafted with both gld and non-gld fetal thymus revealing the pivotal role played by T cells in development of DN cells. When B cells purified from non-gld (C3H+/+) mice were transplanted into SCID mice grafted with gld fetal thymus, the development of DN cells was not inhibited. Taken together, these findings indicate that T cells from non-gld mice inhibit the expression of gld features, e.g., lymphoproliferation, immune-based nephritic disease, and autoantibody production. These findings also suggest that the Fas ligand is selectively expressed on T cells.
Kenichi Maeda, Hideyuki Nagasawa, Atsuko Furukawa, Hajime Hisaeda and Kunisuke Himeno : Split tolerance between spleen and lymphnode cells in severe combined immunodeficiency mice grafted with AKR fetal liver cells, International Immunology, Vol.6, No.8, 1213-1219, 1994.
(要約)
Severe combined immunodeficient (SCID) mice defective in stem cells for T and B cells appear to be an ideal host for construction of chimeric mice. When bone marrow cells are used as a source of stem cells, however, host SCID mice do not always show sufficient reconstitution. In this study, fetal liver cells from AKR embryos were transplanted into SCID mice without prior irradiation. This treatment induced full reconstitution of lymphopoiesis as evaluated by flow cytometry analysis and serum Ig production 2 months after transplantation. Thus, fetal liver cells seem to be a better source for reconstitution of SCID mice than bone marrow cells. Lymph node (LN) cells of these mice (FLT mice) had no proliferative or cytotoxic activities against either host-type (C.B-17) or donor-type (AKR) spleen cells. However, spleen cells from FLT mice exhibited marked proliferative and cytotoxic activities against C.B-17 cells, with no activities against AKR cells. Split tolerance against C.B-17 cells in spleen and LN cells was not a transient phenomenon, since similar results were obtained from a cytotoxic T lymphocyte assay 4 months later. In spite of the strong host reactivity in vitro, aberration of clonal deletion or development of a graft-versus-host disease was not seen in FLT mice. As IL-2 induced the host reactivity of LN cells in a mixed lymphocyte reaction, potentially host-reactive T cells were present in LN but were rendered anergic. Tolerance in FLT mice seems to be regulated by a peripheral mechanism. We supposed that the split tolerance in FLT mice was induced by the different antigenicity between the spleen and LN.
Mowla Mohammed Golam Chowdhury, Atsuko Furukawa, Susumu Kagawa, Kenichi Maeda, Koji Yasutomo and Kunisuke Himeno : B cells are required as APC for antigen-specific T cell proliferation but not the differentiation or priming of those T cells, The Tokushima Journal of Experimental Medicine, Vol.41, No.1-2, 1-8, 1994.
(要約)
We studied the influences of B cells on functional differentiation of T cells using SCID mice grafted with fetal thymus of C.B-17 mice (TG mice). T cells were shown to be reconstituted in TG mice without B cell development. These mice showed normal DTH response to SRBC and OVA. LN cells of these mice produced cytokines including IL-2, IL-4, IL-6 and IFN-gamma according to Con A stimulation. Thus, majority of T cell functions seem to differentiate in the absence of B cells. However, T cells of TG mice failed to proliferate in response to immunizing antigens in vitro, although they responded well to stimulation with Con A. This unresponsiveness of T cells in TG mice to these antigens was restored when antigen-primed B cells were added to the proliferation assay. Such an inability of T cells in antigen-specific proliferation was not seen in SCID mice grafted with C.B-17 fetal liver cells, in which B cells as well as T cells were efficiently reconstituted (FLT mice). T cell proliferation to immunizing antigen was also abrogated in FLT mice when B cells were depleted from lymphoid population. These results indicate that T cells can functionally differentiate and be primed in the absence of B cells, but they require B cells to proliferate in response to foreign antigens.
Kenichi Maeda, Hideyuki Nagasawa, Atsuko Furukawa, Hajime Hisaeda, Yoichi Maekawa, Tetsuya Manabe, Eiji Kudo, A. Robert Good and Kunisuke Himeno : Development of T cells in SCID mice grafted with fetal thymus from AKR mice or F344 rats, European Journal of Immunology, Vol.23, No.12, 3151-3157, 1993.
(要約)
To examine the development of T cells within an allogeneic or xenogeneic environment, we engrafted the fetal thymus from AKR mice or F344 rats under the kidney capsule of SCID mice (mTG and rTG mice). T lymphopoiesis developed in SCID mice 2 months after transplantation, although the ratio of CD4/CD8 in both experimental groups was different from that of normal control. T cells in mTG mice did not show in vitro proliferation or cytotoxicity against either host-type C.B-17 (H-2d) or donor-type AKR (H-2k) cells, while they exerted potent activities against third-party B10 (H-2b) cells. In contrast, T cells in rTG mice exhibited proliferation against both host-type C.B-17 and donor-type F344 rat cells. Consistently, graft-vs.-host disease symptoms developed in these mice and histological examination showed impressive infiltration of lymphocytes into the skin or into the mucosal layers of the stomach. Activated state of T cells in rTG mice was also evidence by the positive expression of interleukin-2 receptor. Taken together, fetal thymus appears to contain progenitor cells which are sufficient for in vivo reconstitution of T lymphopoiesis, but species-specific environment is important for the induction of tolerance. In mTG mice, V beta 6+ T cells reactive to donor Mlsa determinants and V beta 3+ T cells reactive to host Mlsc determinants were deleted, suggesting that tolerance was regulated mainly by clonal deletion. By contrast, V beta 11+ T cells reactive to Mlsf determinants were not deleted possibly due to the lack of their ligands.
Satoru Moriguchi, Hitomi Miwa, Mariko Okamura, Keisei Maekawa, Kishino Yasuo and Kenichi Maeda : Vitamine E is an important factor in T cell differentiation in thymus of F344 rats, Journal of Nutritional Science and Vitaminology, Vol.39, No.5, 451-463, 1993.
(要約)
The effect of vitamin E (dl-alpha-tocopheryl acetate) on T cell differentiation in thymus of F344 rats was examined in this study. The rats were divided into three groups: vitamin E-free, regular and high vitamin E groups and fed a diet containing various levels of vitamin E (0, 50, and 585 mg/kg diet) for 7 weeks. The number of thymocytes was significantly lower in the vitamin E-free group relative to the regular group. Although the proportions of both CD4+CD8- and CD4-CD8+ T cells in thymocytes were significantly greater in the high vitamin E group, the proportion of CD4+CD8- T cells inversely decreased in vitamin E-free group compared to that of the regular group. The ratio of CD4+CD8-/CD4-CD8+ T cells increased in the high vitamin E group (p < 0.01) and significantly decreased in the vitamin E-free group (p < 0.001) compared to that of the regular group. Although the marked changes of T cell subsets were not seen in peripheral blood lymphocytes (PBL), the ratio of CD4+CD8-/CD4-CD8+ T cells was significantly lower in the vitamin E-free group and significantly greater in the high vitamin E group compared to that of the regular group. Production of interleukin (IL) 2 by thymocytes following the stimulation with Con A for 48 h increased about threefold in the high vitamin E group compared to the regular group. Conversely, thymocytes from rats fed the vitamin E-free diet showed a significant decrease of IL2 production compared to that of the regular group. Prostaglandin E2 (PGE2) production from thymocytes was significantly lower in the high vitamin E group compared to that of the regular group, whereas thymocytes of rats fed the vitamin E-free diet showed a significant increase of PGE2 production compared to that of rats fed the regular diet. Furthermore, in vitro addition of indomethacin provided a restoration of IL2 production from thymocytes of rats fed the vitamin E-free diet to the level of rats fed the regular diet. These results suggest that vitamin E plays an important role in T cell differentiation in thymus, which may be related to the action of vitamin E as antioxidant.
Hideyuki Nagasawa, Mikio Oka, Kenichi Maeda, Chai Jian-Guo, Hajime Hisaeda, Yoshihiro Ito, Robert A Good and Kunishuke Himeno : Induction of heat shock protein closely correlates with protection against Toxoplasma gondii infection, Proceedings of the National Academy of Sciences of the United States of America, Vol.89, No.7, 3155-3158, 1992.
(要約)
Heat shock proteins (HSPs) are evolutionarily highly conserved polypeptides that appear to be produced by many cells to preserve cellular functions under a variety of conditions of stress, including infections. We report that a 65-kDa HSP is present in mouse peritoneal cells that have been infected with a low-virulence (Beverley) strain of Toxoplasma gondii, as determined by electroblot assay using a monoclonal antibody specific for microbial HSP65. This HSP is, however, not expressed when infection occurs with the high-virulence RH strain of T. gondii. Furthermore, HSP was demonstrable in mice that acquired resistance against infection with a lethal dose of bradyzoites of the Beverley strain or even of an inoculum of a highly virulent strain of T. gondii (RH). From these results, it can be suggested that HSPs play an important role in developing effective defenses that include effective immune responses against infection with Toxoplasma parasites in vivo.
Jian-Guo Chai, Takashi Bando, Satoshi Kobashi, Mikio Oka, Hideyuki Nagasawa, Shoji Nakai, Kenichi Maeda, Kunisuke Himeno, Mitsunobu Sato and Shinya Ohkubo : An extract of seeds from Aeginetia indica L., a parasitic plant, induces potent antigen-specific antitumor immunity in Meth A-bearing BALB/c mice, Cancer Immunology, Immunotherapy, Vol.35, No.3, 181-185, 1992.
(要約)
The antitumor activity of an extract of seeds from Aeginetia indica L., a parasitic plant, was investigated. BALB/c mice, inoculated i.p. 1 x 10(5) syngeneic Meth A tumor cells, were administered 2.5 mg/kg A. indica extract i.p. every 2 days from day 0. The untreated mice died of an ascitic form of tumor growth within 21 days, whereas all the treated mice completely recovered from tumor challenge without any side-effects. The extract did not exert direct cytotoxic activity against Meth A in vitro. Mice that survived after the first challenge as a result of A. indica treatment overcame the rechallenge with homologous Meth A without additional administration of the extract. On the other hand, those mice could not survive after rechallenge with Meth 1 tumor cells, which were also established in BALB/c mice but were different in antigenicity from Meth A, suggesting the development of antigen-specific concomitant immunity in the A. indica-cured mice. In the induction phase of antitumor resistance in this system, CD4+ T cells appeared to be the main contributors, since in vivo administration of anti-CD4 mAb completely abolished such resistance. In contrast, anti-CD8 mAb administration did not influence the effect of A. indica. The importance of CD4+ T cells in antitumor immunity was again clarified by Winn assay; that is, spleen and lymph node cells depleted of CD4+ T cells in vitro prior to assay abolished antitumor activity on co-grafted Meth A tumor cells in vivo.
Kenichi Maeda, Saburo Sone, Yasukazu moto Oh and Takeshi Ogura : A novel differentiation antigen on human monocytes that is specifically induced by granulocyte-macrophage colony-stimulating factor or IL-3, The Journal of Immunology, Vol.146, No.11, 3779-3784, 1991.
(要約)
A mouse mAb (TOMS-1) was generated against human blood monocytes that had been cultured for 4 days in medium with recombinant human granulocyte-macrophage CSF (GM-CSF). TOMS-1 (IgG1) detected a unique cell surface Ag with a molecular mass of about 43 kDa under both reducing and nonreducing conditions. TOMS-1Ag was expressed on monocytes treated with GM-CSF, but not on fresh or untreated monocytes. This Ag was induced dose dependently during culture of monocytes with GM-CSF for more than 24 h, reaching a maximum level in 3 or 4 days. Treatment of monocytes with cycloheximide in the presence of GM-CSF blocked TOMS-1Ag induction completely, indicating that de novo protein synthesis was required for its expression. TOMS-1Ag was also induced by treatment of monocytes with IL-3, but not with other cytokines such as macrophage-CSF, IL-4, and IFN-gamma or stimulators including LPS, desmethyl muramyl dipeptide, and PMA. TOMS-1Ag expression induced by GM-CSF was up-regulated by IL-4, but down-regulated by IFN-gamma. TOMS-1Ag was not induced on lymphocytes, granulocytes, or AM by GM-CSF or appropriate stimuli. TOMS-1Ag was also not expressed on any cell lines of human leukemias or solid tumors examined. Thus, TOMS-1Ag is a monocyte-specific differentiation Ag induced by GM-CSF or IL-3. These results suggest that TOMS-1 should be useful for monitoring the process of monocyte differentiation by GM-CSF or IL-3.
Saburo Sone, Eiji Kunishige, Farid Fawzy, Hiroaki Yanagawa, Akihiko Nii, Kenichi Maeda, Shinji Atagi, Yuji Heike, Yasuhiko Nishioka, Kazuhito Mizuno and Takeshi Ogura : Interleukin-2-inducible killer activity and its regulation by blood monocyte from autologous lymphocytes of lung cancer patigents, Japanese Journal of Cancer Research, Vol.82, No.6, 716-723, 1991.
(要約)
The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by 51Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.
Mmanabu Nakashima, Keiko Mori, Kenichi Maeda, Horoyuki Kishi, Kazuho Hiratao, Masaru Kawabuchi and Takeshi Watanabe : Selective elimination of double-positive immature thymocytes by a thymic epithelial cell line, European Journal of Immunology, Vol.20, No.1, 47-53, 1990.
(要約)
A cloned epithelial cell line, TEL-2, has been established from the stroma tissues of normal mouse thymus. Incubation of mouse thymocytes on TEL-2 cells resulted in the selective elimination of double-positive (CD4+CD8+) cells from the culture, whereas single-positive (CD4+CD8- or CD4-CD8+) thymocytes remaining in the culture were concentrated in non-integrated cell population. The CD3- or CD3 low-positive thymocytes were also eliminated by the TEL-2 cells from the culture, followed by the concentration of CD3 high-positive cells in the culture. Only intact viable thymocytes were integrated into TEL-2 cells. Electron microscopic examination showed that the integrated cells into TEL-2 cytoplasm were gradually degenerated. Mature single-positive T cells, mature B cells or double-negative thymocytes were not integrated into TEL-2 cells. The TEL-2 cell may provide information on the mechanism of selective disappearance of double-positive immature cells from the thymus.
Hiroaki Yanagawa, Saburo Sone, Akihiko Nii, Katsuyuki Fukuta, Mie Nakanishi, Kenichi Maeda, Mitsuo Honda and Takeshi Ogura : Lymphokine-activated killer induction and its regulation by macrophages in malignant pleural effuusion, Japanese Journal of Cancer Research, Vol.80, No.12, 1220-1227, 1989.
(要約)
Mononuclear cells (MNC) from pleural effusions and peripheral blood of 18 patients with primary lung cancer with malignant pleural effusion were studied. Pleural and blood MNC generated lymphokine-activated killer (LAK) activity similarly when cultured for 4 days with an optimal concentration of interleukin 2 (IL-2). Highly purified lymphocytes (greater than 98%) and monocyte-macrophages (greater than 90%) were isolated by discontinuous Percoll gradient centrifugation from pleural and blood MNC. Pleural macrophages, as well as blood monocytes, showed significant augmenting effects on in vitro LAK cell induction from pleural and blood lymphocytes by IL-2. During daily intrapleural administration of IL-2, significant induction of LAK activity in vivo was observed after 3 days, but then this LAK activity in pleural MNC decreased almost to zero by day 15. Daily injections of IL-2 resulted in reduction in the up-regulation of LAK induction by pleural macrophages and also in increases in the levels of soluble IL-2 receptors in pleural effusions. These findings indicate that in vivo LAK induction of lymphocytes in malignant effusions by IL-2 may be regulated by macrophages in the effusions.
Kenichi Maeda, Manabu Nakashima, Sinji Komori and Takeshi Watanabe : Trans-acting regulatory factors for T cell antigen receptor α- and γ-chain gene expression, The Journal of Immunology, Vol.140, No.8, 2796-2801, 1988.
(要約)
BALB/c mouse thymoma-derived T cell line, CAK4.4 (Thy-1+, L3T4-, Lyt-2-), produced a large amount of TCR-gamma mRNA, a trace amount of TCR-beta mRNA but no detectable level of TCR-alpha mRNA. Another BALB/c mouse thymoma-derived T cell line, CAK1.3 (Thy-1+, L3T4+, Lyt-2+), synthesized a high level of TCR-alpha as well as TCR-beta mRNA but did not produce any amount of TCR-gamma mRNA. HAT-sensitive clones were established from the two T cell lines. Azaguanine-resistant, HPRT- CAK4.4 cells and bromodeoxyuridine-resistant, TK- CAK1.3 cells were fused by electrofusion method and the resultant hybrids were analyzed for expression of TCR genes as well as the changes of their cell surface phenotypes. Transcription of TCR-gamma gene was completely suppressed in all hybrids tested, although Southern blot analysis showed that the hybrids maintained TCR-gamma chain genes derived from both parental cells. TCR-alpha gene transcription occurred normally in one hybrid. In two other hybrids, TCR-alpha gene transcription was strongly suppressed. Treatment of the hybrid cells with 12-O-tetradecanoyl phorbol-13-acetate reversed the suppression of TCR-alpha gene transcription, but TCR-gamma gene transcription was not recovered by the same treatment. However, transcription level of TCR-beta gene was not changed in all hybrids. Our results suggested that the different trans-acting regulatory mechanisms control the transcription levels of TCR-alpha and TCR-gamma genes and that such a transcriptional control may play a crucial role in the determination of orderly appearance of TCR-gamma and TCR-alpha gene products during T cell ontogeny in the thymus.
NK cells / Bone marrow transplantation / SCID mouse
2.
小倉 剛, 前田 健一, 曽根 三郎 : 免疫学的治療 a) LAK, Medical Immunology, Vol.18, No.6, 885-889, 1989年12月.
国際会議:
1.
Momoyo Azuma, Takada Shinsuke, Sato Seidai, Hisatsugu Goto, Hiroaki Yanagawa, Yasuhiko Nishioka, Kenichi Maeda, Shin-ichi Akiyama and Saburo Sone : Investigation of complementary and alternative medicine in lung cancer patients in Tokushima Univerity Hospital., 第9回アジア臨床腫瘍学会学術集会, Gifu, Aug. 2010.
2.
Mohammed A. Satter, Sherin Ahmed, Mohammad Alizadeh, Kenichi Maeda, Yosihiro Minato and Fusao Ota : Low protein diet inducing oral tolerance to Th1 & Th2 dietary antigens and its control mechanisms, Nutrition and Immunology in the 21st Century, New Delhi, Feb. 2003.