Biomedical subjects

K Nomoto

Publications and source records attributed to K Nomoto.

At least 289 records · Page 16Linked to original sources

PubMed1994

The difference in gp160 and gp120 of HIV type 1 in the induction of CD4 downregulation preceding single-cell killing.

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is synthesized as a precursor glycoprotein, gp160, and is then processed into gp120 and gp41. In the present study, CD4+ cell clones expressing either gp160 or gp120 of HIV-1 under the transcriptional control of an inducible promoter were made in order to examine the effect of these env products on the downregulation of surface CD4 and cell injury. A complete disappearance of surface CD4 preceding single-cell death occurred in the cell clones expressing gp160, in which a complex between CD4 and gp160 was formed and then accumulated intracellularly. In contrast to this, the cell clones expressing gp120 neither exhibited any such depletion of surface CD4 nor showed any apparent cytopathic effect. Therefore, it is thought that gp160 but not gp120 plays a crucial role in both the downregulation of surface CD4 and the resultant cell death in the cells infected with HIV-1.

Base Sequence↗

PubMed1994

Calcium reduces the increased fecal 1,2-sn-diacylglycerol content in intestinal bypass patients: a possible mechanism for altering colonic hyperproliferation.

Diacylglycerol (DAG) is a second messenger for protein kinase C, an enzyme with a key role in cellular signal transduction and growth control. In previous studies, it was demonstrated that DAG is produced by intestinal microflora. Bacterial DAG production is increased by bile acids and phospholipids, both of which may be precipitated by calcium. We have demonstrated that fecal total lipids, bile acids, and rectal epithelial proliferation are increased in intestinal bypass (IB) patients. Calcium was shown to alter fecal lipid composition and to reduce cell proliferation. In the present study, fecal DAG content and 14C-labeled DAG, 14C-phosphatidylcholine, and 14C-phosphatidylinositol metabolism were measured in 24-h stool collections in 15 stable IB patients before and after 3-month therapy with oral elemental calcium, 2.4 or 3.6 g/day. Fecal DAG concentration and output in IB patients were > 25- and > 200-fold greater than in normal controls. Oral calcium markedly reduced fecal DAG concentration and output and increased DAG, phosphatidylcholine, and phosphatidylinositol metabolism without enhancing DAG production. We conclude that fecal DAG content is markedly elevated post-IB and that calcium supplementation in these patients reduces fecal DAG and accelerates bacterial metabolism of DAG and its precursors. In separate studies, we have found that calcium supplementation also decreases rectal hyperproliferation in IB patients. Taken together, these findings suggest that a high luminal level of DAG enhances colonic cell proliferation and that calcium reduces cell proliferation in part by decreasing the level of DAG.

Calcium↗

PubMed1994

Annetocin: an oxytocin-related peptide isolated from the earthworm, Eisenia foetida.

An oxytocin-vasopressin-related peptide, Cys-Phe-Val-Arg-Asn-Cys-Pro-Thr-Gly-NH2, was isolated from the lumbricid earthworm, Eisenia foetida and termed annectocin. Annetocin potentiated not only spontaneous contractions of the gut but also pulsatory contractions and bladder-shaking movement of the nephridia. Annetocin may be involved in osmoregulation of the animal through nephridial function.

Amino Acid Sequence↗

PubMed1994

Prognostic significance of the overexpression of c-erbB-2 protein in adenocarcinoma of the uterine cervix.

BACKGROUND: The overexpression of c-erbB-2 protein is a prognostic marker in patients with breast cancer. Alteration of the c-erbB-2 oncogene in development of adenocarcinoma of the uterine cervix, an unfavorable gynecologic neoplasm, is unknown. METHODS: To clarify the role of the c-erbB-2 oncogene in adenocarcinoma of the uterine cervix, formalin-fixed, paraffin-embedded tissue sections from 44 cases of cervical adenocarcinoma were immunohistochemically examined for expression of c-erbB-2 protein and for c-erbB-2 gene amplification in DNA by slot blot-hybridization analysis. RESULTS: The expression of c-erbB-2 protein was detected in 34 cases (77%). Strong expression on cell membranes was detected in 11 cases (25%). Most cases with strong membrane expression of c-erbB-2 protein also showed amplification of the c-erbB-2 gene by slot blot-hybridization. Expression of the protein on cell membranes was more often seen at clinical Stage II or III (9 of 23 [39%]) than at Stage 0 or 1 (2 of 21 [9%]) (P < 0.05, Fisher's exact test). Expression of the c-erbB-2 protein was also associated with poorer prognosis of patients with cervical adenocarcinoma by comparison of survival curves (P < 0.005) and by the Cox regression model analysis. CONCLUSIONS: Overexpression of c-erbB-2 protein is associated with amplification of c-erbB-2 gene and frequently occurred in cervical adenocarcinomas of the patients with poor prognoses.

Adenocarcinoma↗

PubMed1994

Exacerbation of established collagen-induced arthritis in mice treated with an anti-T cell receptor antibody.

OBJECTIVE: To investigate the effect of T cell depletion on established collagen-induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor alpha/beta (TCR alpha/beta). In addition, experiments using anti-CD3 MAb were performed for comparison. METHODS: CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti-CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence-activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells. RESULTS: When anti-TCR alpha/beta MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti-CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti-CII antibody titers were not affected. The addition of anti-TCR gamma/delta MAb had no effect on the augmented arthritis. T cell depletion by anti-CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti-CD3 MAb paralleled the early recovery of alpha/beta T cells in the periphery. CONCLUSION: The present results support the concept that alpha/beta T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell-targeted therapy in patients with rheumatoid arthritis.

Animals↗

PubMed1994

CD3-CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL.

Present evidence suggests that a majority of murine CD3+ intraepithelial intestinal lymphocytes (IEL) are extrathymically derived T cells and that these extrathymically derived IEL phenotypically express the CD8 homodimer (CD8 alpha alpha). Recently, CD3- IEL have been reported to express the recombination activating gene (RAG-1), suggesting that precursors to extrathymically derived CD3+CD8+ alpha alpha IEL exist on the intestinal epithelium. To study in detail whether these CD3-IEL can develop into CD3+CD8+ alpha alpha IEL, we analyzed the CD3-IEL subset and found that it can be separated into two subsets, namely CD3-CD8- and CD3-CD8+ IEL. We show that (1) CD3-CD8- IEL are mostly small, non-granular and phenotypically Pgp-1+ IL-2R+ B220-, while CD3-CD8+ IEL are mostly large, granular and phenotypically Pgp-1- IL-2R+ B220+, (2) CD(3-)-CD8+ IEL express the RAG-1 gene, and (3) CD3-CD8-, CD3-CD8+ and CD3+CD8+ alpha alpha IEL, respectively, appear sequentially in normal ontogeny and in bone marrow-reconstituted thymectomized radiation chimeras. In the latter, virtually all CD3+CD8+ alpha alpha IEL expressed the gamma delta T cell receptor (TCR), but not the alpha beta TCR. From this and what is presently known about T cell development, we propose that CD3-CD8+ IEL are an intermediate in extrathymic IEL development and that the development of extrathymically derived IEL occurs at the intestinal epithelium from CD3-CD8- to CD3-CD8+ to CD3+(gamma delta TCR)CD8+ alpha alpha.

Animals↗

PubMed1994

Progenies of fetal thymocytes are the major source of CD4-CD8+ alpha alpha intestinal intraepithelial lymphocytes early in ontogeny.

Present literature supports the view of an extrathymic origin for the subset of intestinal intraepithelial lymphocytes (IEL) that express the CD4-CD8+ alpha alpha phenotype. This subset would include virtually all T cell receptor (TCR) gamma delta IEL and a portion of TCR alpha beta IEL. However, these reports do not exclude the possibility that some CD4-CD8+ alpha alpha IEL are actually thymically derived. To clarify this issue, we examined the IEL day 3 neonatally thymectomized (NTX) mice. NTX resulted in as much as 80% reduction in total TCR gamma delta IEL and in a nearly complete elimination of TCR alpha beta CD4-CD8+ alpha alpha IEL early in ontogeny (3- to 5-week-old mice). The thymus dependency of TCR gamma delta IEL and TCR alpha beta CD4-CD8+ IEL was less prominent in older mice (7- to 10-week-old mice), as the total number of these IEL increased in NTX mice, but still remained severalfold less than that in euthymic mice. Furthermore, we demonstrate, by grafting the fetal thymus of CBF1 (H-2b/d) mice under the kidney capsule of congenitally nude athymic mice of BALB/c background (H-2d), that a substantial number of TCR gamma delta IEL and TCR alpha beta CD4-CD8+ alpha alpha IEL can be thymically derived (H-2b+). In contrast, but consistent with our NTX data, grafting of adult thymi into nude mice generated virtually no TCR gamma delta IEL and relatively less TCR alpha beta CD4-CD8+ alpha alpha IEL than did the grafting of fetal thymi. These results suggest that the thymus is the major source of TCR gamma delta and TCR alpha beta CD4-CD8+ alpha alpha IEL early in ontogeny, but that the extrathymic pathway is probably the major source of these IEL later in ontogeny. A reassessment of the theory that most CD4-CD8 IEL are extrathymically derived is needed.

Animals↗

PubMed1994

Characteristics of fetal thymus-derived T cell receptor gamma delta intestinal intraepithelial lymphocytes.

We have previously demonstrated that grafting of CBF1 (H-2b/d) fetal thymus (FTG) under the kidney capsule of congenitally athymic nude mice of BALB/c background (H-2d) generates a substantial number of T cell receptor (TCR) gamma delta intestinal intraepithelial lymphocytes (IEL) that were of FTG origin (H-2b+) (see accompanying report). Here we investigated the characteristics of these FTG-derived TCR gamma delta IEL and compared them to the extrathymically derived TCR gamma delta IEL found in nude mice. Phenotypically, FTG-derived TCR gamma delta IEL were similar to their extrathymically derived counterparts in that most were Thy-1-, CD5- and CD8 alpha alpha (homodimer). V gamma and V delta gene usage in thymus-derived and extrathymically derived TCR gamma delta IEL were found to be virtually the same. Functionally, FTG-derived TCR gamma delta IEL were similar to the TCR gamma delta IEL found in euthymic mice as both were relatively anergic to TCR cross-linking in vitro. However, FTG-derived TCR gamma delta IEL differed slightly from extrathymically derived TCR gamma delta IEL, which were completely nonresponsive to the same in vitro stimulation. Overall, these findings support the view that FTG-derived and extrathymically derived TCR gamma delta IEL are almost indistinguishable. Lastly, we demonstrate that despite their thymic origin, development of FTG-derived TCR gamma delta IEL partially takes place extrathymically; that is positive selection of FTG-derived V delta 4 IEL occurs extrathymically. In addition, we demonstrate that the CD8 molecule is not necessary for development and homing of FTG-derived TCR gamma delta IEL. This later finding suggests that the CD8 alpha alpha molecule develops extrathymically for FTG-derived CD8 alpha alpha TCR gamma delta IEL.

Animals↗

PubMed1994

Increased Fas antigen expression in murine retrovirus-induced immunodeficiency syndrome, MAIDS.

The Fas antigen (Fas), which is a cell surface protein belonging to the tumor necrosis factor receptor family, mediates apoptosis. To assess the contribution of Fas to the pathogenesis of retrovirus-induced immunodeficiency, we examined the kinetics of Fas expression on the lymphocytes during the course of murine acquired immunodeficiency syndrome (MAIDS) induced by a defective LP-BM5 murine leukemia virus. The Fas-positive cells were increased in proportion both in alpha beta T cells and B cells with the progression of MAIDS. The appearance of Fas-positive cells in alpha beta T cells preceded those in B cells during the course of MAIDS. Among alpha beta T cells, about half of the Thy1.2+ alpha beta T cells were positive for Fas, while almost all of Thy1.2- CD4+ alpha beta T cells were of the Fas-positive phenotype. The Fas-positive cells in MAIDS mice, especially unique Thy1.2-CD4+ alpha beta T cells, were easily rendered apoptotic by stimulation via Fas, indicating that Fas expressed on the lymphocytes is functional. Furthermore, concomitant infection with Mycobacterium avium in MAIDS mice caused a marked increase in Fas-positive cells accompanied by a severely impaired T cell reactivity to polyclonal stimuli. Taken together, these results suggest that possible participation of the Fas system in the pathogenesis of retrovirus-induced immunodeficiency.

Animals↗

PubMed1994

The effects of bile acids on phospholipase C activity in extracts of normal human colon mucosa and primary colon tumors.

Phospholipase C (PLC) activity and its response to stimulation by bile acids was assayed in cellular extracts from 16 primary human colon tumors of various Duke's stages and paired adjacent normal mucosal samples. In the absence of bile acid, there was negligible degradation of phosphatidylinositol (PI) 1-stearoyl-2-[14C]-arachiodonoyl by tumor or normal tissue, but the addition of deoxycholic acid (DCA) or taurocholic acid (TCA) resulted in concentration-dependent and time-dependent stimulation of diacylglycerol (DAG) formation at optimal concentrations of 2 mM DCA and 4 mM TCA. Triton X-100 (0.125-1.0%) inhibited rather than enhanced the PI-degrading activity of these extracts, indicating that the stimulatory effects of DCA and TCA were not simply due to a detergent effect. Under the same assay conditions there was only a small amount of labeled monoacylglycerol or free arachidonic acid produced by extracts incubated in the absence or presence of DCA or TCA. No major differences in DAG production from PI were seen between paired samples of normal colon mucosa and primary colon tumors, in assays done in the presence of 2 mM TCA. Extracts from tumors in the distal part of the colon had higher activity than those from the proximal colon. This was also true for the extent of release of free arachidonic acid from labeled PI. Under the same conditions, labeled phosphatidylcholine or phosphatidylethanolamine did not serve as substrates for the colon mucosa or tumor extracts. Nor was there significant hydrolysis of the labeled DAG (1-stearoyl-2-14C-arachidonoylglycerol) by normal colon mucosa or tumor extracts, in the absence or presence of DCA or TCA. On the other hand, a low level of DAG lipase activity was detected in the presence of Triton X-100. These findings provide the first evidence that normal human colon mucosa and primary colon tumors contain a PI-specific PLC activity that is markedly stimulated by bile acids. Our results also suggest that bile acids may enhance colon carcinogenesis by acting on this enzyme system, thereby influencing signal transduction pathways in the target cells.

Aged↗

PubMed1994

Appearance of extrathymic early differentiated CD4-CD8- T cells with T cell receptor gamma/delta or alpha/beta after thymus grafting to nude mice: influence of thymus on extrathymic T cell differentiation.

Fetal thymus grafting into athymic nude mice has been used as an experimental model of T cell development. To understand the early events of T cell development, we have examined the sequence of appearance of T cell subsets in lymph nodes (LN) of BALB/c nu/nu mice after grafting with syngeneic fetal thymus. T cells expressing T cell receptor (TCR) alpha/beta or gamma/delta increased in LN from 1 week after grafting, although no host-derived CD3+ T cells were detected in the grafted thymus and no donor thymus-derived T cells were detected in the LN. The early appearing T cells of both TCR alpha/beta and TCR gamma/delta showed a CD4-CD8- phenotype. V region usage analysis of the early appearing TCR alpha/beta T cells revealed that they contained cells bearing V beta 3 or V beta 11, which are potentially reactive to self-superantigen Mls-2a or Dvb11, respectively, and are deleted in the course of T cell development in the thymus of euthymic BALB/c mice. The early appearing T cells showed neither mixed lymphocyte reaction nor cytotoxic T cell activity against allogeneic cells. In contrast, lymphokine-activated killer cells from early appearing T cells, which contained high percentages of TCR gamma/delta T cells, exhibited higher cytotoxic activity against P815 mastocytoma than those from euthymic mice or untreated nude mice. All these results suggest that the early appearing T cells are developed extrathymically. We propose that the thymus may induce extrathymic T cell development without direct cell-to-cell interaction. It seems likely that the extrathymically developed T cells, especially TCR gamma/delta T cells, induced by the thymus have some role in the defense mechanism in the absence of conventional thymus-derived T cells.

Animals↗

PubMed1994

The role of B cells in in vitro induction of IFN-gamma-producing CD4+ T cells specific to Listeria monocytogens: positive and IL-10-mediated negative regulation.

We have reported that Listeria monocytogenes-specific IFN-gamma-producing CD4+ T cells are induced by in vitro 5-day culture of naive spleen cells with viable L. monocytogenes (VLM), but not induced by culture with heat-killed L. monocytogenes (HKLM). In the present study, the role of B cells in the regulation of induction of IFN-gamma-producing CD4+ T cells in the in vitro system was investigated. We found that L. monocytogenes-specific IFN-gamma-producing CD4+ T cells were not generated when B cells were depleted from spleen cells before culture with VLM although Ag-specific proliferative response was retained. IFN-gamma production by CD4+ T cells was restored by addition of B cells cultured with VLM to the culture of B cell-depleted spleen cells and VLM. In contrast, B cells cultured with HKLM could not restore the induction of IFN-gamma production when added in culture of B cell-depleted spleen cells and VLM. Analysis of cytokine gene expression by reverse transcription-polymerase chain reaction method revealed that expression of interleukin-10 (IL-10) was higher but TNF-alpha was lower in B cells cultured with HKLM when compared with that in B cells cultured with VLM. Furthermore, addition of neutralizing anti-IL-10 mAb into culture of naive spleen cells with HKLM resulted in appearance of IFN-gamma-producing cells. These results suggest that B cells have positive and negative roles in the induction of IFN-gamma-producing CD4+ T cells. The inhibition of induction of IFN-gamma-producing CD4+ T cells may depend on B cell-derived IL-10.

Animals↗

PubMed1994

Generation of tumor-specific cytotoxic T lymphocytes in vivo by combined treatment with inactivated tumor cells and recombinant interleukin-2.

In order to search for a new therapy that would maximize the effect of interleukin-2 (IL-2) in evoking antitumor immunity in vivo, the therapeutic effect of a combination of mitomycin-C(MMC)-treated tumor cells and recombinant IL-2 was examined for its induction of antitumor activity against established melanoma metastasis. In C57BL/6 mice intravenously (i.v.) injected with B16 melanoma cells on day 0, the combined treatment with an intraperitoneal (i.p.) injection of MMC-treated melanoma cells on day 6 and 2500 U rIL-2 (twice daily) on days 7 and 8 markedly reduced the number of pulmonary metastases. This antitumor activity was more effective than that in untreated controls and mice that were injected with MMC-treated melanoma cells alone or rIL-2 alone. When the i.p. injection of MMC-treated tumor cells was replaced by other syngeneic tumor cells, antitumor activity against metastatic melanoma was not induced. The antitumor activity induced by this treatment increased in parallel with an increase in the dose of rIL-2 injected. In contrast, an i.p. injection of soluble tumor-specific antigens alone could induce only a marginal level of antitumor activity, and this activity was not augmented by subsequent i.p. injections of rIL-2. In vivo treatment with anti-CD8 monoclonal antibody (mAb), but not with anti-CD4 mAb or anti-asialo-GM1 antibody, abrogated the antitumor activity induced by this combined therapy. This suggests that the antitumor effect was dependent on CD8+ T cells. Lung-infiltrating lymphocytes from mice that had been i.v. injected with melanoma cells 11 days before and were treated with this combined therapy, showed melanoma-specific cytolytic activity. This combined therapy also showed significant antitumor activity against subcutaneously inoculated melanoma cells. These results demonstrate that the combined therapy of an i.p. injection of MMC-treated tumor cells and subsequent and consecutive i.p. administration of rIL-2 increases antitumor activity against established metastatic melanoma by generating tumor-specific CD8+ CTL in vivo.

Animals↗

PubMed1994

Analysis of effector T cells against the murine syngeneic tumor MethA in mice orally administered antitumor polysaccharide SPR-901.

The growth of MethA tumor was significantly inhibited by oral administration of the alpha-glucan SPR-901 in BALB/c (+/+) mice but not in nude mice. Mice treated orally with SPR-901 exhibited an augmentation of antigen-specific resistance against rechallenge with the tumor cells. The tumor-neutralizing activity of regional lymph node cells from MethA-bearing mice against the tumor was augmented by oral administration of SPR-901. The tumor-neutralizing activity of lymph node cells from SPR-901-treated mice mainly appeared in Lyt2+ cells. Furthermore, lymphokine-activated killer activity of these cells was enhanced by administration of SPR-901. The antitumor effect of SPR-901 was abrogated in mice depleted of either L3T4+ or Lyt2+ cells, and in cyclosporin-A-treated mice. These results suggest that Lyt2+ cells are important effector cells in MethA-bearing mice orally administered SPR-901 and that functional exertion of both Lyt2+ and L3T4+ T cells is necessary for the antitumor effect of orally administered SPR-901 in vivo.

Adjuvants, Immunologic↗

PubMed1994

Th1 type CD4+ T cells may be a potent effector against poorly immunogenic syngeneic tumors.

We examined the possibility that Th1 type CD4+ T cells may be an effector against three kinds of syngeneic tumors such as highly immunogenic B16 melanoma (B16) and two poorly immunogenic lines of MCA fibrosarcoma (MCA) and 3LL carcinoma (3LL). In a proliferation assay, the Th1 type CD4+ T cell clone (MH2) recognized the purified protein derivatives (PPD) derived from Mycobacterium tuberculosis. In a tumor-neutralizing assay, MH2 showed anti-tumor activity against both B16 and MCA. In a model of pulmonary metastasis, MH2 also showed anti-tumor activity against both B16 and 3LL. In an assay of cytolysis, MH2 showed a moderate level of tumor necrosis factor-dependent cytolytic activity only against MCA. In a cytostasis assay, MH2 showed a high level of interferon gamma-dependent cytostatic activity against the three tumors in the presence of macrophages. The anti-tumor activity of MH2 against B16 and 3LL was suggested to be, at least in part, attributable to the augmented natural killer activity. Taken together, these findings suggest that we may potentially be able to utilize Th1 type CD4+ T cells as an effector for immunotherapy against poorly immunogenic tumors.

Animals↗

PubMed1994

Increased heparin-releasable platelet factor 4 and D dimer in patients one month after the onset of acute myocardial infarction: persistent activation of platelets and the coagulation/fibrinolytic system.

To evaluate the activity of platelets and the coagulation/fibrinolytic system 1 month after the onset of acute myocardial infarction, we measured the plasma levels of molecular markers, i.e. beta-thromboglobulin, platelet factor 4, thrombin-antithrombin III complex and D dimer, in 16 patients with acute myocardial infarction and in 11 normal subjects. Blood was drawn through a catheter placed in the pulmonary artery before heparin injection. The heparin-releasable platelet factor 4 was calculated by subtracting the level before the injection of 5000 U of heparin, from the level 5 min after injection. The plasma beta-thromboglobulin, thrombin-antithrombin III complex and the D dimer levels in the acute phase of myocardial infarction were 134.9 +/- 121.2, 11.2 +/- 7.1 and 164.4 +/- 115.3 ng/ml, respectively. These values were significantly higher than those in the normal subjects. The plasma levels of beta-thromboglobulin and thrombin-antithrombin III complex, 1 month after the onset (36.6 +/- 16.4 and 4.6 +/- 2.3 ng/ml, respectively) were not significantly different from those of the normal subjects. In contrast, D dimer and heparin-releasable platelet factor 4 were 216.9 +/- 176.9 and 80.5 +/- 29.3 ng/ml, respectively, and significantly higher than in the normal subjects. These findings suggest a latent but persistent activation of the platelets and the coagulation/fibrinolytic system 1 month after the onset of acute myocardial infarction.

Adult↗

PubMed1994

Combined treatment of autoimmune MRL/MP-lpr/lpr mice with a herbal medicine, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to) plus suboptimal dosage of prednisolone.

Therapeutic effects of combined treatment with a Chinese medicine prescription, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT) and suboptimal doses of prednisolone (PSL) on pathological findings of autoimmune-prone MRL/lpr mice were examined. Six-week-old MRL/lpr mice were treated orally with 1000 mg/kg of NYT, 0.5 or 2 mg/kg of PSL, 1000 mg/kg of NYT plus 0.5 or 2 mg/kg of PSL (combined treatment) or solvent only (control) six times per week. The rates of signs and symptoms of autoimmune disease (lymphadenopathy, proteinuria, dermatitis, loss of hair) were suppressed significantly in groups given PSL (2 mg/kg) alone, NYT alone and combined treatment with PSL (2 mg/kg) plus NYT (1000 mg/kg) compared with control, respectively, whereas treatment with PSL (0.5 mg/kg) alone did not inhibit their occurrence. ConA response and IL-2 production were also improved significantly in lymphocytes of mice given the combined treatment. Interestingly, treatment with NYT alone enhanced further the augmented IFN-gamma production in MRL/lpr mice but the combined treatment suppressed such an augmented production. The combined treatment dramatically reduced the level of anti-DNA antibodies in serum of MRL/lpr mice. By contrast, NYT alone treatment had no effect on autoantibodies production. These results suggest that combined treatment with NYT plus a suboptimal dose of PSL could be effective for systemic lupus erythematosus without severe side-effects.

Animals↗

PubMed1994

Effect of antitumor polysaccharide SPR-901 on antitumor activity in combination with 5-FU.

We have examined the effects of the antitumor polysaccharide SPR-901 in combination with 5-fluorouracil (5-FU) on the antitumor activities against mouse syngeneic tumors. SPR-901 was administered p.o. from day 1 to day 10 at the dose rate of 30 mg/kg, and 5-FU was injected i.p. from day 1 to day 5 at the dose rate of 20 mg/kg after BALB/c mice were injected s.c. with 6 x 10(4) cells/mouse of Meth A on day 0. Tumor sizes of mice treated with both SPR-901 and 5-FU were significantly smaller than those from the untreated control group on days 10, 15 and 20. LAK activity of spleen cells from mice treated with both SPR-901 and 5-FU was higher than that from the untreated control group and either the SPR-901 or 5-FU treated group. Flow cytometrical analysis revealed that spleen cells from mice treated with both SPR-901 and 5-FU were much more abundant in both T-cell receptor alpha/beta+ and IL-2 receptor alpha+ T-cells. Furthermore, spleen cells from both the SPR-901- and 5-FU-treated groups exhibited higher growth responses to IL-2 than that from the untreated control group and either of the SPR-901- or 5-FU-treated groups. Therefore, the effects of the antitumor polysaccharide SPR-901 used in combination with 5-FU were augmented as compared with single drug use.

Animals↗