Biomedical subjects

Toru Abo

Publications and source records attributed to Toru Abo.

At least 19 recordsLinked to original sources

PubMed2006

Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma.

BACKGROUND/AIMS: The immune response to tumor-specific antigens is typically unable to control the growth and spread of malignant cells. Accumulating evidence indicates that the suppressive effects of CD4+ CD25+ regulatory T-cells are at least partially responsible for the failure of immune-mediated elimination of tumor cells. METHODS: We have studied 25 patients with hepatocellular carcinoma (HCC). The liver tissues with HCC were separated into the marginal region of tumor (peri-tumor region) and the non-tumor region distant from the tumor. CD4+ CD25+ T-cells were quantified in the blood and the liver by flow cytometry and immunohistochemistry, and their effect on T-cell proliferation and activation was determined. RESULTS: We found a significant increase in both the proportion and absolute numbers of CD4+ CD25+ T-cells in the peri-tumor regions, but not in unaffected areas (9.5 +/- 4.5 vs. 4.6 +/- 2.8%, P = 0.011). CD4+ CD25+ T-cells isolated from peri-tumor regions displayed phenotype markers characteristic of regulatory T-cells, and expressed Foxp3 mRNA. CD8+ T-cells in peri-tumor regions were inversely proportional to CD4+ CD25+ T-cells in the same region (P < 0.001). Moreover, isolated CD4+ CD25+ T-cells inhibited autologous CD8+ T-cell proliferation. CONCLUSIONS: Our results suggest that CD4+ CD25+ T-cells in the marginal region of HCC may play a critical role in controlling CD8+ cytotoxic T-cell activity and, thereby, contribute to the progression of HCC.

Adult↗

PubMed2006

Reasons why DBA/2 mice are resistant to malarial infection: expansion of CD3int B220+ gammadelta T cells with double-negative CD4- CD8- phenotype in the liver.

DBA/2 (H-2(d)) mice are known to be more resistant than C57BL/6 (B6, H-2(b)) mice to the non-lethal 17XNL strain of Plasmodium yoelii. This is a very strange phenomenon because the functions of conventional T cells, especially CD8(+) T cells, are known to be somewhat lower in DBA/2 mice than in other strains of mice. We examined herein how immune responses differed between DBA/2 mice and B6 mice during malarial infection. DBA/2 mice and (DBA/2 x B6)F(1) (BDF(1), H-2(b/d)) mice were found to have milder parasitaemia and to recover more quickly from malarial infection than B6 mice. These DBA/2 and BDF(1) mice were also found to experience a marked expansion of interleukin (IL)-2Rbeta(+) CD3(int) cells and gammadelta T cells in the liver, especially in the recovery phase. The expansion of unconventional T cells (i.e. B220(+) T cells) was also marked in DBA/2 and BDF(1) mice. The majority of B220(+) T cells were gammadelta T cells and these T cells were double-negative CD4(-) CD8(-). More importantly, the production of immunoglobulin M (IgM)-type anti-DNA autoantibody was also higher in DBA/2 and BDF(1) mice than in B6 mice. In conjunction with data on cytokine production, these results indicate that primitive T and B cells, namely autoreactive extrathymic T cells and autoantibody-producing B cells, may be much more activated in DBA/2 mice and therefore resistant to the non-lethal 17XNL strain of P. yoelii.

Animals↗

PubMed2006

Protection against malaria due to innate immunity enhanced by low-protein diet.

Mice were fed ad libitum with a normal diet (25% protein) or low-protein diets (0-12.5% protein) for a wk and then infected with a nonlethal or lethal strain of Plasmodium yoelii, that is, blood stage infection. The same diet was continued until recovery. Mice fed with a normal diet showed severe parasitemia during nonlethal infection, but survived the infection. They died within 2 wk in the case of lethal infection. However, all mice fed with low-protein diets survived without apparent parasitemia (there were small peaks of parasitemia) in cases of both nonlethal and lethal strains. These surviving mice were found to have acquired potent innate immunity, showing the expansion of NK1.1 -TCRint cells and the production of autoantibodies during malarial infection. Severe combined immunodeficiency (scid) mice, which lack TCRint cells as well as TCRhigh cells, did not survive after malarial infection of lethal strain of P. yoelii, even when low-protein diets were given. These results suggest that low-protein diets enhanced innate immunity and inversely decreased conventional immunity, and that these immunological deviations rendered mice resistant against malaria. The present outcome also reminds us of our experience in the field study of malaria, in which some inhabitants eventually avoided contracting malaria even after apparent malarial infection.

Animals↗

PubMed2005

Activation of CD1d-independent NK1.1+ T cells in the large intestine by Lactobacilli.

Among digestive organs, the liver and the large intestine are abundant in T cells expressing NK1.1. NK1.1+ T cells in the liver are mostly CD1d-dependent whereas those in the large intestine are CD1d-independent. In this study, we investigated the effects of Lactobacilli on NK1.1+ T cells in the digestive organs of mice. C57BL/6 mice were orally given a dietary supplement prepared from mixed cultures of eight strains of Lactobacilli. Oral administration of Lactobacilli to mice resulted in the selective expansion of NK1.1+ T cells in the large intestine. These colon NK1.1+ T cells activated by Lactobacilli were found to express IFN-gamma mRNA. The level of IFN-gamma in the serum was also elevated by the administration of Lactobacilli. Our results suggest that Lactobacilli selectively activate CD1d-independent NK1.1+ T cells in the large intestine to produce IFN-gamma and therefore modulate Th1 immune responses.

Animals↗

PubMed2005

Immunopotentiation of NKT cells by low-protein diet and the suppressive effect on tumor metastasis.

Mice were fed with a 5% low-protein diet for two weeks, at which point tumor inoculation was conducted. Following this inoculation, the 5% low-protein diet was continued. On the other hand, control mice were fed with a normal diet (25% protein) and such diet was continued after tumor inoculation. In comparison with control mice, mice fed with the 5% low-protein diet showed a prominent prolongation of survival rate when injected with both EL4 and 3LL tumors. Interestingly, CD1d(-/-) mice, which primarily lack natural killer T (NKT) cells, did not show the prolongation of survival rate even when they received a 5% low-protein diet. The most striking phenomenon seen in tumor-bearing mice fed with the 5% low-protein diet was the suppression of tumor metastasis to the liver and lung. Such suppression was not seen in CD1d(-/-) mice who were fed with a 5% low-protein diet. Phenotypic study revealed that the proportion of NKT cells after tumor inoculation decreased in the mice fed with a normal diet. However, such decrease did not occur in mice fed with the 5% low-protein diet. Reflecting the activation of NKT cells by feeding, tumor cytotoxicity and cytokine production were also augmented by the 5% low-protein diet. These results suggest that a low-protein diet has the potential to augment the innate immunity against tumors, especially mediated by the activation of NKT cells.

Animals↗

PubMed2005

Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells.

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic bone marrow transplantation, which is caused by donor T cells specific for host alloantigens. In a murine model, we found that donor T cells expressed a natural killer cell inhibitory receptor, CD94/NKG2A, during the course of aGVHD. Administration of an anti-NKG2A mAb markedly inhibited the expansion of donor T cells and ameliorated the aGVHD pathologies. These results suggested that the CD94/NKG2A inhibitory receptor expressed on host-reactive donor T cells can be a novel target for the amelioration of aGVHD.

Acute Disease↗

PubMed2005

Association of NKT cells and granulocytes with liver injury after reperfusion of the portal vein.

Reperfusion of the liver was conducted by clamping the portal vein for 30 min in mice, followed by unclamping. Unique variation in the number of lymphocytes was induced and liver injury occurred thereafter. The major expander cells in the liver were estimated to be natural killer T cells (i.e., NKT cells), whereas conventional T cells and NK cells increased only slightly or somewhat decreased in number and proportion at that time. Reflecting the expansion of NKT cells in the liver, a Th0-type of cytokine profile was detected in sera, and cytotoxic activity was enhanced in liver lymphocytes. In NKT cell-deficient mice including CD1d (-/-) mice and athymic nude mice, the magnitude of liver injury decreased up to 50% of that of control mice. It was also suspected that accumulating granulocytes which produce superoxides might be associated with liver injury after reperfusion. This might be due to stress-associated production of catecholamines. It is known that granulocytes bear surface adrenergic receptors and that they are activated by sympathetic nerve stimulation after stress. The present results therefore suggest that liver injury after reperfusion may be mainly caused by the activation of NKT cells and granulocytes, possibly by their cytotoxicity and superoxide production, respectively.

Animals↗

PubMed2005

No mixing of granulocytes and other lymphocytes in the inflamed joints of parabiosis mice with collagen-induced arthritis: possible in situ generation.

Collagen-induced arthritis was evoked by an injection of lipopolysaccharide and anti-type II collagen antibody in mice. In parallel with the onset of arthritis, granulocytes with large light scatter and a Mac-1(+) Gr-1(+) phenotype expanded in the joints of these mice. Lymphocytes with a CD3(-) B220(+) phenotype (i.e. B220(+) B cells) were the major population among lymphocyte subsets in the joints, irrespective of disease. To determine the origin of these leucocyte populations in the joints and other organs, parabiotic experiments using CBF(1)Ly5.1 and CBF(1)Ly5.2 mice were conducted in mice with and without collagen-induced arthritis. As expected, leucocyte populations in the liver and spleen became a half-and-half mixture of their own cells and partner cells (e.g. approximately 45% of Ly5.1(+) cells in Ly5.2(+) partner mice). However, such a mixture was extremely delayed in the joints and bone marrow, even in mice with arthritis. These results suggest that, because circulatory blood is not exchanged in the joints, granulocytes and other lymphocytes are generated in situ in the inflamed joints of mice with collagen-induced arthritis or are possibly supplied by the bone marrow. It is of interest that granulocytes in the joints expanded, even without a supply from another site, namely, the synovium.

Animals↗

PubMed2005

Multipotential acceptance of Peyer's patches in the intestine for both thymus-derived T cells and extrathymic T cells in mice.

Peyer's patches (PP) are important inductive sites for the mucosal immune response. It is well known that lymphocytes that migrate into PP are mainly of T-cell lineage from thymus-derived cells (i.e. alphabetaTCR(high) cells). In this study, we further characterized the properties of PP lymphocytes in mice using a mouse model of colitis induced by dextran sulphate sodium (DSS). Although the major site of the inflammation induced by DSS is known to be the large intestine, the small intestine was also damaged. When mice developed DSS-induced colitis, CD3+CD8+B220+ gammadelta T cells increased in PP in the small intestine. These gammadelta T cells, which are not seen in the PP of normal mice, resembled intraepithelial lymphocytes (IEL) in the small intestine in terms of their expression of CD5, CD103 and Thy1.2. In addition, the Vgamma/delta repertoire of these gammadelta T cells was similar to that of gammadelta IEL. When DSS-treated mice were injected with IEL isolated from normal mice, IEL including gammadelta T cells preferentially migrated to PP, raising the possibility that B220+ T cells seen in PP of diseased mice may derive from IEL in the small intestine. Our present study suggests that PP might be able to accept T-cell lineages from intestinal IEL as well as from thymus-derived T cells.

Animals↗

PubMed2005

Protection against malaria by anti-erythropoietin antibody due to suppression of erythropoiesis in the liver and at other sites.

We have previously reported that erythropoiesis commences in the liver and spleen after malarial infection, and that newly generated erythrocytes in the liver are essential for infection of malarial parasites as well as continuation of infection. At this time, erythropoietin (EPO) is elevated in the serum. In the present study, we administered EPO or anti-EPO antibody into C57BL/6 (B6) mice to modulate the serum level of EPO. When mice were infected with a non-lethal strain (17NXL) of Plasmodium yoelii (blood-stage infection of 10(4) parasitized erythrocytes per mouse), parasitemia continued for 1 month, showing a peak at day 17. Daily injection of EPO (200 IU/day per mouse) from day five to day 14 prolonged parasitemia, whereas injection of anti-EPO antibody (1.5 mg/day per mouse) every second day from day five to day 28 decreased it. Erythropoiesis was confirmed in the liver, spleen and bone marrow by the appearance of nucleated erythrocytes (TER119+). When anti-EPO antibody was injected by the same protocol into mice infected with a lethal strain (17XL) of P. yoelii, all mice showed decreased parasitemia and recovered from the infection. These results suggest that the use of anti-EPO antibody after malarial infection may be of therapeutic value in severe cases of malaria.

Animals↗

PubMed2005

Hepatic natural killer and natural killer T cells markedly decreased in two cases of drug-induced fulminant hepatic failure rescued by living donor liver transplantation.

The human liver contains significant numbers of innate immune cells, such as natural killer (NK) cells and natural killer T (NKT) cells, which express both T-cell receptors and NK-cell receptors simultaneously. It has been suggested that the innate immune system plays a crucial role in the liver. In this report, the distribution of NK and NKT cells in the liver and peripheral blood of two patients with drug-induced fulminant hepatic failure (FHF) who had undergone living donor liver transplantation was examined. In both the liver and peripheral blood, the proportions of NK and NKT cells markedly decreased compared with those in healthy donors. It was also revealed that, unlike murine NKT cells, human CD56(+) T cells and CD57(+) T cells did not constitutively express CD28, which is one of the important costimulatory molecules on T cells. Additionally, the residual CD56(+) T cells and CD57(+) T cells in the patients expressed more CD28 than in controls. This result suggests that NKT cells might be more activated in FHF. Although the accumulation of further cases is required, it is suggested that both NK and NKT cells might be involved in hepatic injury in FHF.

Adult↗

PubMed2005

Distinguishing between proliferating nodal lymphoid blasts in chronic myelogenous leukemia and non-Hodgkin lymphoma: report of three cases and detection of a bcr/abl fusion signal by single-cell analysis.

Lymph node biopsies were analyzed from three patients with chronic myelogenous leukemia (CML) showing nodal blast proliferation. Immunohistochemically, the blasts from all three patients had an immature marker profile with a T-blast population (cCD3+, CD4-, CD7+, CD8-, CD99+, terminal deoxynucleotidyl transferase +) and a hematopoietic progenitor cell marker (CD34). In two patients, the blasts also expressed myeloid lineage specificity (naphthol AS-D chloroacetate esterase activity and myeloperoxidase positivity). However, it was difficult to distinguish between blast proliferation in CML and non-Hodgkin lymphoma from these immunohistopathological findings alone. Subsequently, bcr gene rearrangement and bcr/abl mRNA expression were detected by Southern blot and reverse transcription-polymerase chain reaction analysis of the lymph nodes. Fluorescence in situ hybridization (FISH) analysis of lymph node touch smears also disclosed bcr/abl gene fusion signals in the blasts of all patients, confirming that the blasts were derived from Philadelphia chromosome-positive CML. Accurate discrimination between the proliferating nodal blasts of CML and non-Hodgkin lymphoma is essential for determining subsequent therapy. FISH analysis of bcr/abl in single-cell blast preparations is an efficient tool that allows rapid, accurate cytopathological diagnosis of extramedullary blast-phase CML and its discrimination from non-Hodgkin lymphoma.

12E7 Antigen↗

PubMed2005

Immunologic states of autoimmune diseases.

The etiology and immunologic states of autoimmune diseases have mainly been discussed without consideration of extrathymic T cells, which exist in the liver, intestine, and excretion glands. Because extrathymic T cells are autoreactive and are often simultaneously activated along with autoantibody-producing B-1 cells, these extrathymic T cells and B-1 cells should be introduced when considering the immunologic states of autoimmune diseases. The immunologic states of autoimmune diseases resemble those of aging, chronic GVH disease, and malarial infection. Namely, under all these conditions, conventional T and B cells are rather suppressed concomitant with thymic atrophy or involution. In contrast, extrathymic T cells and B-1 cells are inversely activated at this time. These facts suggest that the immunologic states of autoimmune diseases should be reevaluated by introducing the concept of extrathymic T cells and autoantibody-producing B-1 cells, which might be primordial lymphocytes in phylogeny.

Animals↗

PubMed2004

Increase in hepatic NKT cells in leukocyte cell-derived chemotaxin 2-deficient mice contributes to severe concanavalin A-induced hepatitis.

Leukocyte cell-derived chemotaxin 2 (LECT2) was originally identified for its possible chemotactic activity against human neutrophils in vitro. It is a 16-kDa protein that is preferentially expressed in the liver. Its homologues have been widely identified in many vertebrates. Current evidence suggests that LECT2 may be a multifunctional protein like cytokines. However, the function of LECT2 in vivo remains unclear. To elucidate the role of this protein in vivo, we have generated LECT2-deficient (LECT2(-/-)) mice. We found that the proportion of NKT cells in the liver increased significantly in LECT2(-/-) mice, although those of conventional T cells, NK cells, and other cell types were comparable with those in wild-type mice. Consistent with increased hepatic NKT cell number, the production of IL-4 and IFN-gamma was augmented in LECT2(-/-) mice upon stimulation with alpha-galactosylceramide, which specifically activates Valpha14 NKT cells. In addition, NKT cell-mediated cytotoxic activity against syngeneic thymocytes increased in hepatic mononuclear cells obtained from LECT2(-/-) mice in vitro. Interestingly, the hepatic injury was exacerbated in LECT2(-/-) mice upon treatment with Con A, possibly because of the significantly higher expression of IL-4 and Fas ligand. These results suggest that LECT2 might regulate the homeostasis of NKT cells in the liver and might be involved in the pathogenesis of hepatitis.

Animals↗

PubMed2004

Fc receptor-mediated accumulation of macrophages in crescentic glomerulonephritis induced by anti-glomerular basement membrane antibody administration in WKY rats.

Anti-glomerular basement membrane (GBM) glomerulonephritis induced in WKY rats is characterized by glomerular accumulation of CD8(+) T cells and monocytes/macrophages, followed by crescent formation. The mechanism of leukocyte accumulation after antibody binding to GBM is still unclear. To unveil an involvement of Fcgamma receptors (FcgammaR) in leukocytes recruitment we examined the expression of FcgammaR in glomeruli and the effects of the administration of F(ab')(2) fragment of anti-GBM antibody or FcgammaR blocking on the initiation and progression of this model. A gradual increase of FcgammaR mRNA expression in glomeruli during the time course of disease suggested their significance in the development of glomerulonephritis. Glomerular lesions and proteinuria were induced only in rats injected with intact IgG of anti-GBM antibody, but not with the F(ab')(2) fragment. In vivo blocking of FcgammaR by administering heat-aggregated IgG led to the decrease of mRNA expression for all types of FcgammaR (types 1, 2 and 3) and a significant amelioration of glomerulonephritis manifestations. By flow cytometry and immunohistochemistry FcgammaR2-expressing cells in glomeruli were identified as macrophages, but not CD8(+) T cells. The expression of FcgammaR1 and 3 was significantly decreased, and that of FcgammaR2 became undetectable in CD8(+) T cell-depleted rats. Thus, CD8(+) T cells may stimulate FcgammaR expression on macrophages, contributing to their glomerular accumulation and injury. These studies provide direct evidence for a crucial involvement of IgG Fc-FcgammaR interaction in glomerular recruitment of macrophages and following induction of anti-GBM glomerulonephritis in WKY rats.

Animals↗

PubMed2004

Changes in extrathymic T cells in the liver and intestinal intraepithelium in mice with obstructive jaundice.

Recently, T cells were classified into two categories: intrathymic T cells (ITCs; thymus-derived T cells) and extrathymic T cells (ETCs). ETC, localized in the liver and intestinal intraepithelium (IE), play an important immunologic role in the suppressed condition of T-cell development in the thymus. Given the fact that complications of surgery in patients with obstructive jaundice are often related to immunosuppression in the gut-liver circulation, we attempted to investigate the changes in the proportion of ETCs in mice with obstructive jaundice. Three mice models were prepared ( n = 10 per group): sham group with simple laparotomy; ligation group with common bile duct ligation; deoxycholic acid (DCA) group with an oral intake of DCA as a model of the presence of bile salts in the gut lumen. In each model, total mononuclear cells (MNCs), ITCs in the thymus, and ETCs in the liver and IE were counted using monoclonal antibodies in conjunction with a two-color immunofluorescence test by flow cytometry. In the ligation group the number of MNCs was reduced in the thymus and IE, and only those in the IE recovered after oral intake of DCA. A decrease of ITCs in the thymus and the increase in ETCs in the liver and IE occurred simultaneously during the early phase of biliary obstruction. At day 7 after biliary obstruction, ETCs in the livers of the DCA and ligation groups decreased to nearly the level in the sham group. However, on day 7 the ETCs in the IE remained significantly higher in the DCA group than in the ligation group. These results suggested that ETCs can act in place of ITCs at an early phase of obstructive jaundice, and the presence of bile in the gut lumen may be associated with the consumption of ETCs in the IE, a reaction that may bring about improved immunoreactivity.

Animals↗

PubMed2004

Involvement of natural killer T cells and granulocytes in the inflammation induced by partial hepatectomy.

BACKGROUND/AIMS: Natural killer T (NKT) cells are present in the liver of mice. We examined whether NKT cells and other leukocytes were associated with hepatic inflammation after partial hepatectomy. METHODS: Approximately 70% of the liver was removed from mice using the method described by Higgins and Anderson. RESULTS: Partial hepatectomy induced the expansion of NKT cells in the liver and the elevation of transaminase. These responses were completely suppressed by the administration of tacrolimus. NKT cell-deficient mice showed a decreased level of transaminase after partial hepatectomy. Perforin (-/-) mice showed an elevation of transaminase while B6-gld/gld mice (Fas ligand-) showed a decreased elevation of transaminase. In TAP-1(-/-) mice which lacked CD8+ cytotoxic T cells, inflammation remained at a normal level after partial hepatectomy. Since NKT cell-deficient mice showed up to 50% decrease in the level of inflammation, we examined the association of other leukocytes with the remaining inflammation. The number and proportion of granulocytes were increased by partial hepatectomy. CONCLUSIONS: Both NKT cells and granulocytes participated in the hepatic inflammation after partial hepatectomy. The function of NKT cells, but not of granulocytes, was found to be sensitive to the immunosuppressive effect of tacrolimus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially natural killer T cells, double-positive CD4+ CD8+ cells and B220+ T cells, in mice.

The age-dependent variation in the proportion and number of lymphocyte subsets was examined at various extrathymic sites, including the liver, small intestine, colon and appendix in mice. In comparison with young mice (4 weeks of age), the number of total lymphocytes yielded by all tested organs was greater in adult (9 weeks) and old (40 weeks) mice. The major lymphocyte subset that expanded with age was interleukin-2 receptor (IL-2R) beta+ CD3int cells (50% of them expressed NK1.1) in the liver, whereas it was CD3+ IL-2Rbeta- NK1.1- cells at all intraepithelial sites in the intestine. Although NK1.1+ CD3+ cells were present at intraepithelial sites in the intestine, the proportion of this subset was rather low. The ratio of CD4 to CD8 tended to decrease among natural killer T (NKT) cells and T cells at all intraepithelial sites in the intestine with age. A unique population of double-positive CD4+ CD8+ cells in the small intestine increased in old mice. B220+ T cells were found mainly in the appendix and colon, and the proportion of these T cells decreased in old mice. Conventional NKT cells were very few in Jalpha281-/- and CD1d-/- mice in the liver, while NKT cells which existed in the appendix remained unchanged even in these mice. This was because unconventional CD8+ NKT cells were present in the intestine. The present results suggest that despite the fact that both the liver and intraepithelial sites in the intestine carry many extrathymic T cells, the distribution of lymphocyte subsets and their age-associated variation are site-specific.

Aging↗