PubMed Health⌕ Search

Biomedical subjects

H Hisaeda

Publications and source records attributed to H Hisaeda.

At least 37 records · Page 2Linked to original sources
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

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

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↗
PubMed1997

Heat shock protein 65 induced by gammadelta T cells prevents apoptosis of macrophages and contributes to host defense in mice infected with Toxoplasma gondii.

We previously reported that gammadelta T cells mediate the expression of endogenous heat shock protein 65 (HSP65) in macrophages of mice with acquired resistance against infection with Toxoplasma gondii. We show here that HSP65 contributes to protective immunity by preventing apoptosis of infected macrophages. Macrophages of BALB/c mice, which readily acquired resistance to T. gondii infection with the low virulence Beverley strain, strongly expressed HSP65, and only a few of these macrophages underwent apoptosis. On the other hand, the BALB/c mice were susceptible to the infection with the high virulence RH strain of T. gondii; their macrophages did not express HSP65 and did undergo apoptosis. Mice depleted of gammadelta T cells using a mAb specific for TCR-gammadelta became highly susceptible to infection even with the Beverley strain. In these mice, HSP65 expression was markedly suppressed, and their infected macrophages died via apoptosis. Apoptosis was induced in cultured macrophages or macrophage cell lines after infection in vitro with the RH strain, whereas apoptosis was prevented when HSP65 was induced in these cells, before infection, by activation with IFN-gamma and TNF-alpha. However, apoptosis associated with infection by T. gondii RH strain was not prevented when HSP65 synthesis was inhibited by introducing an antisense oligonucleotide for this protein into the cells before activation with IFN-gamma plus TNF-alpha. Thus, HSP65 appears to contribute to immunity by preventing the apoptosis of infected macrophages, and the high virulence Toxoplasma appears to have mechanisms that allow these organisms to evade the host defense system by interfering with HSP65 expression.

Animals↗
PubMed1997

The Fas-deficient SCID mouse exhibits the development of T cells in the thymus.

The Fas Ag is a cell surface protein that mediates apoptosis and is highly expressed on thymocytes. However, the role of the Fas system in the thymus is unclear. To study the role of the Fas system in the thymus, we established a novel SCID mouse bearing the lpr (lymphoproliferation) mutation. Thymocytes from these mice differentiated into CD4+ CD8+ T cells and then underwent further differentiation into CD4+ CD8- or CD4- CD8+ single-positive T cells with a low surface expression of CD3, whereas B cell development remained unrescued. These TCR-positive T cells can proliferate in response to stimulation with PMA plus ionomycin, but not with third-party spleen cells. Furthermore, thymocytes from scid/lpr mice had a great variety of TCR Vbeta repertoires. These results suggest that the Fas system plays an essential role in regulating the development of intrathymic T cells as well as peripheral T cells.

Animals↗
PubMed1997

Acetaminophen absorption test as a marker of small bowel transplant rejection.

We recently evaluated the acetaminophen absorption test as a marker of graft rejection for small bowel transplantation(SBTX). Randomly bred male Wistar rats were used as recipients and donors. Rats (n=45) received heterotopic small intestinal transplants and were divided into three groups (n=15 for each group). In group A, a 10-cm segment of jejunum of was exteriorized as a Thiry-Vella loop. In group B, immunosuppression was not given after SBTX. In group C, rats were treated with FK506 after SBTX (0.3 mg/kg body weight, 0-6 postoperative days). Serum acetaminophen concentrations were measured 15 min after instillation of 0.15 g/kg acetaminophen into the intestinal loop on postoperative days 1, 3, and 7 (n=5 for each group). Blood flow and histology of the graft were also evaluated. In the SBTX group only, the grafts showed the histological change after acute rejection. On day 3, plasma acetaminophen concentrations in this group showed a significant decrease, which correlated with the mild histological changes of graft rejection. Graft blood flow of the SBTX group decreased significantly on day 7, following the severe graft destruction of advanced rejection. No remarkable changes were observed in the other two groups. The acetaminophen absorption test appears to be useful for the early detection of SBTX graft rejection.

Absorption↗
PubMed1997

The role of host-derived heat-shock protein in immunity against Toxoplasma gondii infection.

Heat-shock proteins (HSPs) are evolutionarily highly conserved polypeptides synthesized by cells to preserve cellular functions under a variety of stressful conditions, including infections. In infections, both host cells and pathogens express HSPs, although the role of these molecules in the host-pathogen relationship is elusive. Here, Hajime Hisaeda and Kunisuke Himeno show that a correlation exists between the 65 kDa HSP molecule (HSP65) and protection against Toxoplasma gondii infection, suggesting that this protein contributes to the host defense system. These findings may help in the understanding of the complicated host-parasite relationship.

Journal Article↗
PubMed1996

Fas system-mediated apoptosis suppresses lymphopoiesis.

The lymphoproliferation (lpr) mutation causes the defective expression of Fas Ag, which normally transduces an apoptotic signal into cells. T cells from mice homozygous for this mutation overexpress the counter-receptor, Fas ligand. In this study, we investigated the effects and regulatory influences attributable to Fas ligand overexpression on lymphocyte development to clarify the role of Fas system-mediated apoptosis in lymphopoiesis in vivo. Nonirradiated severe combined immunodeficient (SCID) mice grafted with a fetal thymus (FT) plus fetal liver cells (FLC) from MRL-lpr/lpr mice (Fas Ag-defective mice), or with FT from C3H-gld/gld mice (Fas ligand-defective mice) plus FLC from C3H +/+ mice, developed FLC-derived T and B cells. In contrast, SCID mice grafted with FT from MRL-lpr/lpr Thy-1.1 mice plus FLC from MRL +/+ Thy-1.2 mice (chimera 1) developed few FLC-derived T and B cells in the spleen, and the thymus of the recipients also contained few FLC-derived T cells. In addition, when SCID mice grafted with FT from MRL-lpr/lpr Thy-1.2 mice (H-2k) were co-transplanted with FLC from C57BL/10 Thy-1.1 mice (H-2b) (chimera 2), FLC-derived T and B cells developed normally. Thy-1.1 + cells from chimera 1 expressed Fas ligand mRNA about threefold higher than those from chimera 2, and seven- to eightfold higher than Thy-1.2+ cells from SCID mice grafted with FT from MRL +/+ Thy-1.2 mice by Northern blot analysis. These findings indicate that overexpression of Fas ligand on T cells significantly impairs both T and B cell development. Furthermore, the Fas ligand overexpression sufficient to impair lymphopoiesis appears to require MHC-restricted T cell activation. These results suggest that the Fas system suppresses lymphopoiesis in vivo.

Animals↗
PubMed1996

Human V delta 2+ gamma delta T-cell tolerance to foreign antigens of Toxoplasma gondii.

Little is known about the mechanisms involved in human gammadelta T-cell tolerance to self or to foreign antigens. Patients with congenital toxoplasmosis offer a unique opportunity to examine Vdelta2+ gammadelta T-cell tolerance. Analysis of gammadelta T cells in patients with congenital toxoplasmosis revealed evidence for anergy of these cells with or without clonal Vdelta2+ gammadelta T-cell expansion in the acute phase of the Toxoplasma infection. T cells in general were unresponsive and did not proliferate upon exposure to mitogens or to Toxoplasma lysate antigens or in response to live Toxoplasma-infected cells when the congenitally infected infants were 1 month of age, and they exhibited selective anergy to Toxoplasma lysate antigens and live Toxoplasma-infected cells when the infants were aged 5 months. During the chronic phase of congenital toxoplasmosis in the patients who were more than I year of age, the repertoires of the gammadelta T-cell receptors were found to be within normal ranges. In addition, in the chronic phase, the gammadelta T cells proliferated and secreted gamma-interferon in response to exposure to live Toxoplasmia-infected cells. By contrast, alphabeta T cells remained anergic. Vdelta2+ gammadelta T cells have been considered to undergo extrathymic maturation and thus to be subject to development of peripheral tolerance. Our findings indicate that Vdelta2+ gammadelta T-cell tolerance was lost in these infected infants earlier than alphabeta T-cell tolerance. These findings suggest that gammadelta T cells play a role in protection against Toxoplasma gondii in the chronic phase when congenitally infected children are more than 1 year of age, especially in those in whom alphabeta T cells continue to exhibit deficits in specific immune responses to Toxoplasma antigens.

Acute Disease↗
PubMed1996

The novel regulatory mechanism of Fas system-mediated apoptosis in mesangial cells: implication to mesangial proliferative glomerulonephritis.

Fas Ag is a cell surface molecule that transduces the signal for apoptosis. Since mesangial cells (MC) play important roles in regulating glomerulonephritis, we investigated regulatory mechanisms of Fas system in MC. Fas Ag was expressed on MC from normal mice. This Fas Ag expression was down-regulated by inducing proliferation with platelet-derived growth factor or 18% fetal bovine serum, but was reversed when cycloheximide was added to the culture. Anti-Fas Ab alone did not induce apoptosis in MC, but MC became susceptible to apoptosis induced by anti-Fas Ab is actinomycin D or cycloheximide was added. Noteworthy findings are that mRNA of Fas ligand was expressed in MC. Taken together, MC appears to control the proliferation by regulating Fas system-mediated apoptosis, at least in part, through an autoregulatory mechanism with Fas Ag Fas ligand expressed on their own MC.

Animals↗
PubMed1996

Contribution of 65-kDa heat shock protein induced by gamma and delta T cells to protection against Toxoplasma gondii infection.

Heat shock proteins (HSPs) are evolutionarily highly conserved polypeptides synthesized by many cells to preserve cellular functions under a variety of stressful conditions including infections. We have investigated the involvement of 65-kDa HSP (HSP65) in host protection against an intracellular protozoan parasite, Toxoplasma gondii, in mice. Experiments using low and highly virulent strains of Tox. gondii revealed that induction of murine HSP65 on macrophages closely correlates with protection against infection with this protozoan. Furthermore, we clarified that T cells, especially gamma delta T cells, are indispensable for HSP65 expression. A similar relationship between the expression of HSP65 on host macrophages and protective immunity was observed in mice infected with Leishmania major and Trypanosoma cruzi, both of which are obligate intracellular protozoa as is Tox. gondii.

Animals↗
PubMed1996

Contribution of extrathymic gamma delta T cells to the expression of heat-shock protein and to protective immunity in mice infected with Toxoplasma gondii.

We demonstrated that gamma delta T cells contribute to protective immunity against Toxoplasma gondii by inducing the expression of a 65,000 MW heat-shock protein (hsp 65) in host macrophages. Here we examined the role of extrathymic and intrathymic gamma delta T cells in protective immunity and hsp 65 expression in mice infected with T. gondii. Intrathymic gamma delta T cells were obtained from severe combined immunodeficiency (SCID) mice grafted with syngeneic fetal thymus (TG-SCID), in which only T cells derived from the donor thymus developed, whereas extrathymic gamma delta T cells were obtained from nude mice that lack thymus. Extrathymic gamma delta T cells from T. gondii-infected nude mice differed from intrathymic gamma delta T cells of infected TG-SCID mice, in terms of Thy1.2 expression and V-region gene usage of T-cell receptor (TCR) gamma delta. Extrathymic gamma delta T cells expressed extremely high levels of Thy1.2, and had V gamma 7 repertoire but lacked V gamma 5,6 and V delta 1,5. On the other hand, intrathymic gamma delta T cells express intermediate and low levels of Thy1,2. These cells possessed V gamma 5,6 and V delta 1,5 but failed to rearrange the V gamma 7 gene. Peritoneal macrophages from infected nude mice contained hsp 65, whereas this protein was scarcely expressed in those of infected TG-SCID mice. Transfer of extrathymic, but not of intrathymic gamma delta T cells to SCID mice enabled their macrophages to express hsp 65. Athymic nude mice were significantly resistant to the infection compared with SCID mice which lack gamma delta T as well as alpha beta T cells. The resistance was dependent upon extrathymic gamma delta T cells, since nude mice depleted of gamma delta T cells using a corresponding monoclonal antibody became extremely susceptible. These results indicated that extrathymic rather than intrathymic gamma delta T cells play some crucial roles in protection against T. gondii and in hsp 65 expression.

Animals↗
PubMed1996

Influence of two different modes of resistance training in female subjects.

In resistance training, it has been empirically accepted that muscle hypertrophy is developed by low intensity and high volume training, while muscle strength and power are developed by high intensity and low volume training. The purpose of the present study was to investigate the influence of two different modes of resistance training on isokinetic strength and muscle cross-sectional area (CSA) in females. Eleven females, who had no experience in resistance training, participated in this study and were randomly divided into two groups. The former consisted of 4-5 sets of 15-20 RM (repetition maximum) with sufficient rest between sets (Group H), while the latter consisted of 8-9 sets of 4-6R M with 90 s of rest between sets (Group S). The former was assumed to be appropriate for muscle hypertrophy and the latter muscle strength, respectively. All subjects completed isotonic knee extension exercise three times a week for 8 weeks. Measurements were made on quadriceps muscle cross-sectional area (CSA) and isokinetic torques at 0, 60, 180, and approximately 300 degrees before training, at the fifth week and the end of training period. Muscle CSA was defined as the sum of CSA measured at 30, 50 and 70% of femur length. After training, muscle CSA had significantly increased in both groups: 3.3 +/- 0.7% (p < .05) for group H and 3.6 +/- 1.1% (p < .05) for group S, respectively. While the changes in isokinetic torque were 43.4 +/- 47.5% (p < .05) for group H and 27.4 +/- 31.3% (p < .05) for group S, respectively. In both groups the percentage changes of the isokinetic strength were significantly higher than those of the CSA. No significant difference in these variables were found between the two groups. These results suggest that during the early phase of resistance training two different modes of resistance training may have similar effects on muscle CSA and isokinetic strength in untrained females.

Adult↗
PubMed1996

Development of functional rat-derived T cells in SCID mice engrafted with the fetal thymus of LEC rats which are defective in CD4+ T cells.

We reported that LEC rats are genetically deficient in the development of thymic CD4+8- cells and that this defect is caused by bone marrow (BM)-derived stem cells. To determine which BM-derived cells are responsible for the arrest of T-cell development in LEC rats, fetal thymuses of LEC rats, or LEA rats which bear the same major histocompatibility complex (MHC) as LEC rats but are immunologically normal, were engrafted under the kidney capsule of severe combined immunodeficiency (SCID) mice (LEC-TG and LEA-TG mice, respectively). We than examined the differentiation of T cells and their immunological functions in the SCID mice. A large number of rat-derived CD4+ T cells appeared in the peripheral blood, lymph nodes (LN) and spleens in LEC-TG mice. Furthermore, the peripheral LN cells in LEC-TG mice appeared to be functional. These cells produced IL-2 upon Con A stimulation, whereas LN cells from LEC rats produced no IL-2 in the same conditions. Thymopoiesis was observed at 3 weeks in LEC-TG as well as LEA-TG mice. The distribution of thymocyte subsets with respect to CD4 and CD8 expression in LEC-TG mice closely resembled that of LEA rat thymus and that in LEA-TG mice, suggesting that normal T-cell differentiation occurred in LEC-TG mice. The results indicated that BM-derived progenitor T cells of LEC rats could differentiate to functional CD4+ T cells.

Animals↗