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Biomedical subjects

K Himeno

Publications and source records attributed to K Himeno.

At least 37 records · Page 2Linked to original sources
PubMed2000

Lysosomal cathepsin B plays an important role in antigen processing, while cathepsin D is involved in degradation of the invariant chain inovalbumin-immunized mice.

We previously reported that CA074, a specific inhibitor of cathepsin B, modulates specific immune responses from the T helper 2 (Th2) type to Th1 type in BALB/c mice infected with Leishmania major. In the present study, we found that a similar type of immune deviation was also induced in mice immunized with ovalbumin (OVA). However, treatment of mice with pepstatin A, a specific cathepsin D inhibitor, suppressed the OVA-specific proliferation of lymphocytes and blocked the development of both Th1 and Th2 cellular responses. These inhibitors did not appear to have any direct influence in vitro on functions of naive lymphocytes. OVA antigen (47 000 MW) was digested mainly into 40 000 MW protein in vitro by lysosomal proteases from naive BALB/c mice, and its digestion was markedly inhibited by the addition of CA074, but not by addition of pepstatin A, during incubation. However, pepstatin A strongly suppressed the degradation of the major histocompatibility complex class II-associated invariant chain (Ii) molecule in vivo and in vitro. Thus, cathepsin B appears to process antigens directed to preferential activation of Th2 cells, while cathepsin D may be responsible for the degradation of Ii, the processing of which is essential in initiating the antigen-specific activation of Th1 and Th2 CD4+ T cells. These lysosomal proteases may have different functions in regulating immune responses.

Animals↗
PubMed2000

Gene gun-mediated delivery of an interleukin-12 expression plasmid protects against infections with the intracellular protozoan parasites Leishmania major and Trypanosoma cruzi in mice.

An interleukin-12 (IL-12) expression plasmid was transferred, using a gene gun, to mice infected with Leishmania major or Trypanosoma cruzi. Transfer of the IL-12 gene to susceptible BALB/c mice resulted in regression of lesion size and reduced the number of parasites in draining lymph nodes (LN) at the site of L. major infection. Coincident with these protective effects, the T-helper type (Th) response shifted towards Th1, as evaluated by cytokine production in vitro and L. major-specific antibody responses. Protective effects of the IL-12 gene were also observed in T. cruzi infection. Treatment of BALB/c mice infected with T. cruzi enhanced the production of interferon-gamma (IFN-gamma) by spleen cells, while suppressed production of interleukin-10 (IL-10) compared with control mice. Administration of anti-CD4 or anti-CD8 monoclonal antibody (mAb) abolished the protective immunity against T. cruzi infection, and treatment with the IL-12 gene could not restore the resistance in these mice. Mice depleted of natural killer (NK) cells with anti-asialo GM1 also became susceptible to infection, while the resistance was restored when these mice were treated with the IL-12 gene. Thus, target cells for the treatment appear to be CD4+ and CD8+ T cells, which are ordinarily activated by NK cells. These results suggest that the transfer of cytokine genes using a gene gun is an effective method for investigating the roles of cytokines and gene therapy in infectious diseases.

Animals↗
PubMed2000

Cytokine gene therapy for cancer with naked DNA.

Plasmid DNA vectors (naked DNA) can easily be purified and transferred in vivo by intramuscular or intradermal injection. Naked DNA is stable in vivo, and long-term expression of the encoded protein is seen without chromosomal integration. Gene gun-mediated delivery of an expression plasmid is slightly more complicated but more efficient. These techniques have been applied to DNA vaccination or cytokine gene therapy for various diseases, including infections, autoimmune disorders, and cancer. We review cytokine gene therapy for cancer with naked DNA in animal models and present our preliminary data on gene gun-mediated in vivo transfection with the interleukin-12 gene in a murine renal cancer model. Because of its safety, simplicity, and low cost, cytokine gene therapy with naked DNA may become an important cancer treatment.

Animals↗
PubMed2000

Schistosoma mansoni infection cancels the susceptibility to Plasmodium chabaudi through induction of type 1 immune responses in A/J mice.

Susceptibility to Plasmodium chabaudi depends on the relative dominance of T(h)1/T(h)2 responses in host mice. A T(h)2-dominant response during the early phase of infection in susceptible A/J mice causes a fatal disease course due to severe malaria. Schistosoma mansoni is a potent inducer of a T(h)2-dominant response not only to the parasite antigens, but also to other antigens concurrently existing in the host animals. In spite of S. mansoni infection, these A/J mice escape death from malaria and showed accompanied enhanced production of IFN-gamma to malaria antigens. Treatment with anti-IFN-gamma mAb in S. mansoni-infected A/J mice abolished the resistance to malaria, indicating that IFN-gamma was responsible for the resistance to P. chabaudi in S. mansoni-infected A/J mice. Results in this study show that under certain circumstances, S. mansoni infection can promote type 1 immune responses in A/J mice that normally develop T(h)2 responses.

Animals↗
PubMed2000

CD4(+) v(alpha)14 NKT cells play a crucial role in an early stage of protective immunity against infection with Leishmania major.

The roles of gamma delta T, NK and NKT cells in an early stage of protective immunity against infection with Leishmania major were investigated. Further, the contribution of these innate cells to the expression of 65 kDa heat shock protein (HSP65) in host macrophages was examined, since we found previously that this expression prevents apoptotic death of infected macrophages and is a crucial step in the acquisition of protective immunity against infection with various obligate intracellular protozoa including L. major. C57BL/6 and DBA/2 mice were found to be resistant against the infection on the basis of the parasite burden in their regional lymph nodes, and to strongly express HSP65 in their macrophages, whereas BALB/c mice were susceptible and barely expressed the HSP65. In those resistant mice, CD4(+) NKT cells prominently increased in their regional lymph node and were the main effector cells at least for an early stage of the protective immunity and for the HSP65 expression, whereas this subset did not increase in susceptible BALB/c mice. Further, neither gamma delta T nor NK cells in resistant mice contributed to those protective immune responses. The NKT cell subset bore CD3, CD4, TCR alpha beta, IL-2R beta and NK1.1 but scarcely asialo-GM(1). Moreover, this effector subset was confirmed to be V(alpha)14 NKT cells by using J(alpha)281(-/-) mice.

Animals↗
PubMed2000

Changes in gamma-aminobutyric acid content during beni-koji making.

The changes in the gamma-aminobutyric acid (GABA) content during the making of beni-koji prepared with Monascus pilosus IFO 4520 vs. the difference in the rate of tomo koji (10%, 30%, and 50%) were examined. The increased proportion of tomo koji would increase the GABA production and the productions of GABA peaked on the fifth day and thereafter declined. The glutamate decarboxylase activity during beni-koji making with 50% tomo koji steadily increased after the start of the koji making, reaching its peak on the fifth day. The succinic acid content increased after the sixth day. The mycelial growth was in the stationary phase after the sixth day. Therefore, the GABA content increases with an increase in the proportion of tomo koji. It is presumed that the maximum amount of GABA reached on the fifth day was the cause of the increasing amount of conversion of GABA into succinic acid, in addition to the decline in the GAD activity after the fifth day of koji making.

Ascomycota↗
PubMed1999

Expression and role of heat-shock protein 65 (HSP65) in macrophages during Trypanosoma cruzi infection: involvement of HSP65 in prevention of apoptosis of macrophages.

The 65-kDa heat-shock protein (HSP65) is thought to play a role in host defense against infections with various microbial pathogens and in autoimmune inflammatory disorders. We investigated the biological function and expression mechanism of HSP65 in macrophages of mice infected with Trypanosoma cruzi. BALB/c mice, which are susceptible to T. cruzi, showed high levels of parasitemia, and 80% of these mice died within 42 days after the infection, whereas resistant C57BL/6 or DBA/2 mice showed low levels of transient parasitemia and all survived. HSP65 expression was correlated with resistance to T. cruzi infection; HSP65 was more strongly expressed in macrophages of resistant C57BL/6 and DBA/2 mice than in macrophages of susceptible BALB/c mice. Immunodeficient BALB/c-nu/nu (nude) and C.B-17 scid/scid (SCID) mice were shown to be highly susceptible to this infection, and they did not express detectable levels of HSP65, suggesting that T cells play essential roles in the expression of HSP65 as well as in protective immunity against the infection. CD4(+) T cells, but not CD8(+) T cells or gammadelta T cells, were the cell population responsible for the induction of HSP65 expression in macrophages. Furthermore, depletion of asialo GM-1(+) NK cells made resistant C57BL/6 mice more susceptible to the infection, and HSP65 expression in their macrophages was abolished. Semiquantitative reverse transcription PCR analyses showed that both interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) mRNA levels in CD4(+) T cells became low when resistant C57BL/6 mice were depleted of NK cells, suggesting that NK cells contribute to functional differentiation of CD4(+) T cells and thereby affect the induction of HSP65 expression. To determine the function of HSP65, macrophages were treated in vitro with antisense oligonucleotide for HSP65 prior to inducing HSP65 with IFN-gamma plus TNF-alpha or T. cruzi infection. This treatment did not affect the production of nitric oxide following activation, but the treated macrophages became susceptible to apoptosis. These results indicate that HSP65 plays a role in preventing the apoptosis of macrophages and thereby contributes to host resistance against T. cruzi infection.

Animals↗
PubMed1999

DNA immunization with Plasmodium falciparum serine repeat antigen: regulation of humoral immune response by coinoculation of cytokine expression plasmid.

We immunized mice with plasmid expressing the 47-kDa amino-terminal domain of the Plasmodium falciparum serine repeat antigen (SERA) using gene gun and investigated humoral immune response to SERA antigen. Significant SERA-specific IgG was observed in BALB/c mice after immunization three times with SERA expression plasmid. Furthermore, these levels were increased by the coinoculation of cytokine (IFN-gamma, IL-4, GM-CSF, or IL-12) expression plasmid. In respect to the SERA-specific Ig subclasses, coinoculation of IFN-gamma, GM-CSF, or IL-12 expression plasmid increased the levels of SERA-specific IgG2a, and these were much higher than that in mice immunized with SERA expression plasmid alone. In contrast to the SERA-specific IgG2a, coinoculation of any cytokine expression plasmid did not change the levels of SERA-specific IgG1. These results indicate that cytokine expression plasmid enhances and regulates humoral immune response elicited by SERA DNA immunization.

Animals↗
PubMed1999

Macrophages expressing heat-shock protein 65 play an essential role in protection of mice infected with Plasmodium yoelii.

C57BL/6 (B6) mice are resistant to infection with the non-lethal (NL) strain of Plasmodium yoelii 17X, while being susceptible to that with the lethal (L) strain. The 65 000 MW heat-shock protein (hsp 65) was strongly expressed in splenic adherent cells of B6 mice 10 days after infection with the NL strain of P. yoelii but only slightly in those from mice infected with the L strain. Mice which had survived infection with the NL strain were resistant to challenge with the L strain and hsp 65 was strongly expressed in splenic adherent cells of these mice. Severe combined immunodeficient mice and nude mice were susceptible to malaria infection even with the NL strain and did not express hsp 65 after infection, suggesting that T cells are required for the expression of hsp 65 as well as for protective immunity. B6 mice treated intraperitoneally with carrageenan, which impairs the macrophage function, became susceptible to NL strain infection, indicating that macrophages play an important role as the final effectors in protective immunity. These results demonstrate that the hsp 65 expressed by macrophages correlates closely with protection against P. yoelii infection.

Animals↗
PubMed1999

Antimicrobial activity of Monascus pilosus IFO 4520 against contaminant of Koji.

Antimicrobial activity of Monascus pilosus IFO 4520 was examined to prevent contamination during beni-koji making in the open air. The antibacterial effect of the beni-koji prepared with this strain occured with 30 mg/ml of beni-koji extract in combination with 0.5% lactic acid against two contaminants of koji, Micrococcus varians and Bacillus subtilis. There were two compounds, antibacterial and antiyeast substances, in the beni-koji extract. These results suggest a possibility of inhibiting the growths of contaminants during beni-koji making using beni-koji extract and lactic acid.

Anti-Bacterial Agents↗
PubMed1999

Hypothalamic neuronal histamine as a target of leptin in feeding behavior.

Leptin, an ob gene product, has been shown to suppress food intake by regulating hypothalamic neuromodulators. The present study was designed to examine the involvement of brain histamine in leptin-induced feeding suppression. A bolus infusion of 1.0 microg leptin into the rat third cerebroventricle (i3vt) elevated the turnover rate of hypothalamic neuronal histamine (P < 0.05) as assessed by pargyline-induced accumulation of tele-methylhistamine (t-MH), a major metabolite of histamine. No remarkable change in the mRNA expression of histidine decarboxylase (HDC), a histamine-synthesizing enzyme, was observed in the hypothalamus after i3vt infusion of leptin. These results indicate that leptin increases histamine turnover by affecting the posttranscriptional process of HDC formation or histamine release per se. As expected, concomitant suppression in 24-h cumulative food intake was also observed after infusion of leptin. Systemic depletion of brain histamine levels by pretreatment with an intraperitoneal injection of 224 micromol/kg alpha-fluoromethylhistidine (FMH), a suicide inhibitor of HDC, attenuated the leptin-induced feeding suppression by 50.7% (P < 0.05). This attenuation of feeding suppression was mimicked by the i3vt infusion of 2.24 micromol/kg FMH before leptin treatment (P < 0.05). In addition, concentrations of hypothalamic histamine and t-MH were lowered in diabetic (db/db) mice, which are known to be deficient in leptin receptors (P < 0.05 vs. lean littermates for each amine), although the amine levels were higher in diet-induced obese rats (P < 0.05 for each amine). Leptin-deficient obese mice (ob/ob) showed lower histamine turnover (P < 0.05 vs. lean littermates), which recovered after leptin infusion. Thus, a growing body of results points to an important role for the hypothalamic histamine neurons in the central regulation of feeding behavior controlled by leptin.

Animals↗
PubMed1999

Investigation of the mechanism of lymphocyte injection therapy in treatment of lymphedema with special emphasis on cell adhesion molecule (L-selectin).

We previously employed intraarterial lymphocyte injection therapy in conjunction with standard non-operative treatment of peripheral lymphedema of various etiologies. In this study, we further evaluated the clinical outcome of this therapy in 46 patients with unilateral lymphedema of the extremities. The results showed combined therapy (lymphocyte injection with compression) was effective in 74% (34 of 46 patients) with dramatic reduction in lymphedema in 37% (17 of 46 patients). In the most recent 5 patients treated, we examined the expression of cell adhesion molecule of the lymphocytes (L-selectin) before, during and after lymphocyte injection therapy to study the putative pathomechanism of this treatment method. The expression of L-selectin, a lymphocyte-specific adhesion molecule, increased in the autologous lymphocytes obtained by a blood cell separator and in the lymphocytes from the peripheral blood after injection. Moreover, the lymphocyte fraction, which was positive for L-selectin and negative for CD3, a T-cell marker, decreased after lymphocyte injection. We postulate that the lymphocytes of L-selectin (+) and CD (-) remain in the affected swollen limb and play a role in an ill-defined immunologic responsiveness that potentiates reduction in edema.

Adult↗
PubMed1998

Switch of CD4+ T cell differentiation from Th2 to Th1 by treatment with cathepsin B inhibitor in experimental leishmaniasis.

When activated, CD4+ T helper cells differentiate functionally into one of two subsets, Th1 or Th2. Before the Th differentiation, Ags must be processed into peptide epitopes and presented to CD4+ T cells in association with MHC class II molecules. However, the proteases responsible for this Ag processing have not been well defined. When BALB/c mice susceptible to infection with Leishmania major were treated with a specific inhibitor (CA074) of cathepsin B, a lysosomal cysteine protease that digests exogenous antigenic proteins, those mice acquired resistance against infection with L. major and showed the shift of immune responses from Th2 to Th1; that is, they produced specific IgG2a Ab and generated IFN-gamma in contrast to untreated and infected mice that produced IgG1 and IgE and generated IL-4. CA074 interfered with the digestion of L. major Ags with lysosomal enzymes in vivo as well as in vitro. However, this inhibitor did not show any direct influence on the growth of L. major and the functions of T cells stimulated with anti-CD3 Ab. These findings indicate that cathepsin B inhibitor could switch CD4+ T cell differentiation from Th2 to Th1, suggesting that the alteration in Ag processing modulates the polarity of Th differentiation.

Animals↗
PubMed1998

Effect of donor-specific splenocytes via portal vein and FK506 in rat small bowel transplantation.

BACKGROUND: To investigate the role of the liver in immune responses after small bowel transplantation, donor-specific splenocytes were infused perioperatively, via the portal vein, in a rat heterotopic small bowel transplant model. METHODS: Heterotopic small bowel transplantation between the fully allogenic Brown Norway (BN) (RT1n) and Lewis (RT1[1]) strain rats were performed. We prepared donor splenocytes from BN or third-party WKA (RT1k) rat spleens for Lewis hosts and injected the splenocytes perioperatively via the host portal vein or the systemic vein. The hosts were treated with a short course of the immunosuppressive agent, FK506 (0.5 mg/kg, 0-3 days postoperatively), following the experimental protocols. RESULTS: Untreated Lewis hosts rejected BN small bowel grafts at 5.4+/-0.9 days (n=8). BN splenocytes given alone caused fatal graft-versus-host disease in six of eight animals, and two others died from graft rejection. FK506 alone did not significantly prolong graft survival (6.3+/-1.0 days, n=10). However, BN splenocytes injected via the portal vein, combined with FK506, prolonged graft survival to 12.7+/-2.1 days (n=12, P < 0.01) and 10 of 12 rats survived more than 70 days. This was donor antigen specific. BN splenocytes administered systemically caused fatal graft-versus-host disease in all recipients, and FK506 did not ameliorate this. Histologic findings of graft rejection were remarkably mild in the recipients of the combined therapy, compared with the recipients that were given FK506 alone. Down-regulation of one-way mixed lymphocyte reaction to BN splenocytes was observed in the splenocytes of the tolerant hosts. CONCLUSIONS: Combined administration of donor splenocytes and FK506 reduced allograft rejection and prolonged survival in this rat model of small bowel transplantation.

Animals↗
PubMed1998

Combined treatments with Ninjin-youei-to (Ren-shen-yang-rong-tang) plus a suboptimal dose of prednisolone on autoimmune nephritis in MRL/lpr mice.

MRL/lpr mice suffer from a systemic lupus erythematosus-like autoimmune disease. We studied the effects of oral treatments with Ninjin-youei-to (NYT, Ren-shen-yang-rong-tang, 1000 mg/kg/day), a suboptimal dose (2 mg/kg/day) of prednisolone(PSL) and their combination on nephritis in MRL/lpr mice. Treatments with NYT or PSL alone inhibited the development of proteinuria and prolonged survival. The combined treatment reduced the incidence of proteinuria and prolonged survival. In histological analysis, NYT treatments decreased the degree of mesangial proliferative glomerulonephritis and infiltration of mononuclear cells in the kidneys. PSL treatment was effective in reducing periglomerular nephritis and vasculitis in addition to such effects as NYT and NYT plus PSL treatment was more effective than PSL alone. The active form of TGF-beta was reduced in NYT and PSL-treated mouse serum, and the combined treatments further suppressed it. However, the treatment with NYT alone did not induce a decrease in the latent form of TGF-beta. The effect of NYT can be assumed to be different from an immunosuppressive effect of PSL. Therefore, the combined treatment with NYT and PSL can be expected to be more useful for the therapy of autoimmune disease such as nephritis, compared with NYT or PSL alone treatments.

Animals↗
PubMed1998

Unresponsiveness of CD4-8+/- thymocytes to lectin stimulation in LEC mutant rats.

A mutant strain of rat, LEC, shows a novel arrest of T-cell maturation from CD4+8+ to CD4+8-, but not to CD4-8+ cells in the thymus. The responsible mutant locus is designated the thid, which was acted upon in a recessive manner of inheritance. We found that LEC rat thymocytes failed to respond to interleukin (IL)-1, IL-6 and IL-7 in the presence of the mitogenic lectins, Allo A or concanavalin A (Con A). The unresponsiveness appeared to be due to unresponsiveness to the lectin stimulation rather than because of cytokine stimulation. Normal rat CD4-8+/- (consisting of CD4-8+ and CD4-8- thymocytes), CD4+/-8- (consisting of CD4+8- and CD4-8- thymocytes), and CD4-8- thymocyte subsets normally responded to mitogenic stimulation, while CD4+8+ thymocytes did not. In contrast, all LEC rat CD4-8+/-, CD4+/-8-, CD4-8- and CD4-8+ thymocytes did not respond to the mitogenic stimulation, suggesting that the unresponsiveness of the CD4-8+/- thymocytes seems to be responsible for the unresponsiveness of whole thymocytes in LEC rats. LEC rat CD4-8+/- thymocytes normally expressed Con A receptor (R), lymphocyte function-associated antigen-1 (LFA-1), and CD45, which are thought to be important molecules for lectin stimulation. When backcross rats from (F344xLEC)F1xLEC were examined, the phenotype for the thid mutation correlated with the [3H]thymidine deoxyribose (TdR) incorporation level in response to Con A stimulation; thymocytes from backcross rats showing +/thid phenotype responded to Con A stimulation normally, whereas thymocytes from backcross rats showing thid/thid phenotype showed significantly lower responsiveness compared with +/thid rats. However, in WKAH.C-thid congenic rat thymocytes that carry the thid mutation, the responsiveness to mitogenic stimulation was comparable to that of normal rat thymocytes. These results suggest that a defect in responsiveness to mitogenic stimulation in LEC rat thymocytes is controlled by multiple genetic loci and the thid locus is one of the important loci for the development of this abnormal phenotype.

Animals↗