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Toshiro Ito

Publications and source records attributed to Toshiro Ito.

At least 19 recordsLinked to original sources
PubMed2006

Chemokine system and tissue infiltration in aggressive NK-cell leukemia.

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.

Chemokines↗
PubMed2006

Adenovirus fulminant hepatic failure: disseminated adenovirus disease after unrelated allogeneic stem cell transplantation for acute lymphoblastic leukemia.

Adenovirus is one of the major causes of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation for hematological malignancy. Fulminant hepatic failure is a rare manifestation of post-transplant complication with adenovirus. Extremely high mortality and aggressiveness of the clinical course have been posing clinical challenges for the diagnosis as well as for the treatment. Here, we report a case with disseminated adenovirus disease presenting with fulminant hepatic failure after bone marrow transplantation for acute lymphoblastic leukemia.

Adenoviridae Infections↗
PubMed2006

A case of acute myelogenous leukemia with MLL-AF10 fusion caused by insertion of 5' MLL into 10p12, with concurrent 3' MLL deletion.

Structural abnormalities involving the mixed-lineage leukemia (MLL) gene on 11q23 have been associated with hematological malignancies. The rearrangement of MLL occurs during translocations and insertions involving a variety of genes on the partner chromosome. We report a rare case of acute myelogenous leukemia (AML-M2) with 11q23 abnormalities. Fluorescence in situ hybridization (FISH) using a commercial dual-color MLL probe detected an atypical signal pattern: one fusion signal, two green signals smaller than those usually detected, and no orange signals. Spectral karyotyping (SKY) analysis indicated that one green signal was detected on the short arm of derivative chromosome 10, and the other green signal on the long arm of a derivative chromosome 11, on which no orange signal was detected. A long-distance inverse polymerase chain reaction (LDI-PCR) identified the fusion partner gene, in which intron 6 of MLL was fused with intron 8 of AF10 on 10p12 in the 5' to 3' direction. Our observations indicated that the MLL-AF10 fusion gene resulted from the insertion of part of the region that included the 5' MLL insertion into 10p12; this was concurrent with the deletion of 3' MLL.

Acute Disease↗
PubMed2006

Intestinal diffuse large B-cell lymphoma associated with celiac disease: a Japanese case.

Intestinal non-Hodgkin's lymphoma (NHL), especially the T-cell type, is well known to be associated with celiac disease (CD), an enteropathic disorder with a propensity for certain racial and genetic backgrounds. CD is typically characterized by gastrointestinal (GI) symptoms, anti-transglutaminase antibodies in the sera, and microscopical findings of the intestinal mucosa, which resolve with a gluten-free diet (GFD). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. We describe a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient's lymphoma has been in a state of complete response, and his GI symptoms have improved with a GFD. This case suggests that the possibility of CD and its association with intestinal NHL should be kept in mind, even in Asian populations.

Aged↗
PubMed2005

Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.

Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4(-/-) but not CD8(-/-) recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28(-/-) and a smaller proportion of CD4(-/-)CD28(-/-) mice with no effect in CD8(-/-)CD28(-/-) recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8(+) T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28(-/-) and CD8(-/-)CD28(-/-) recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-gamma-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.

Animals↗
PubMed2005

CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.

The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.

Acute Disease↗
PubMed2004

The homeotic protein AGAMOUS controls microsporogenesis by regulation of SPOROCYTELESS.

The Arabidopsis homeotic gene AGAMOUS (AG) is necessary for the specification of reproductive organs (stamens and carpels) during the early steps of flower development. AG encodes a transcription factor of the MADS-box family that is expressed in stamen and carpel primordia. At later stages of development, AG is expressed in distinct regions of the reproductive organs. This suggests that AG might function during the maturation of stamens and carpels, as well as in their early development. However, the developmental processes that AG might control during organogenesis and the genes that are regulated by this factor are largely unknown. Here we show that microsporogenesis, the process leading to pollen formation, is induced by AG through activation of the SPOROCYTELESS gene (SPL, also known as NOZZLE,NZZ), a regulator of sporogenesis. Furthermore, we demonstrate that SPL can induce microsporogenesis in the absence of AG function, suggesting that AG controls a specific process during organogenesis by activating another regulator that performs a subset of its functions.

AGAMOUS Protein, Arabidopsis↗
PubMed2004

Floral homeotic genes are targets of gibberellin signaling in flower development.

Gibberellins (GAs) are a class of plant hormones involved in the regulation of flower development in Arabidopsis. The GA-deficient ga1-3 mutant shows retarded growth of all floral organs, especially abortive stamen development that results in complete male sterility. Until now, it has not been clear how GA regulates the late-stage development of floral organs after the establishment of their identities within floral meristems. Various combinations of null mutations of DELLA proteins can gradually rescue floral defects in ga1-3. In particular, the synergistic effect of rga-t2 and rgl2-1 can substantially restore flower development in ga1-3. We find that the transcript levels of floral homeotic genes APETALA3 (AP3), PISTILLATA (PI), and AGAMOUS (AG) are immediately upregulated in young flowers of ga1-3 upon GA treatment. Using a steroid-inducible activation of RGA, we further demonstrated that these floral homeotic genes are transcriptionally repressed by RGA activity in young flowers whereas the expression of LEAFY (LFY) and APETALA1 (AP1) is not substantially affected. In addition, we observed the partial rescue of floral defects in ga1-3 by overexpression of AG. Our results indicate that GA promotes the expression of floral homeotic genes by antagonizing the effects of DELLA proteins, thereby allowing continued flower development.

Arabidopsis↗
PubMed2004

Differential role of CCR2 in islet and heart allograft rejection: tissue specificity of chemokine/chemokine receptor function in vivo.

Chemokines have a pivotal role in the mobilization and activation of specific leukocyte subsets in acute allograft rejection. However, the role of specific chemokines and chemokine receptors in islet allograft rejection has not been fully elucidated. We now show that islet allograft rejection is associated with a steady increase in intragraft expression of the chemokines CCL8 (monocyte chemoattractant protein-2), CCL9 (monocyte chemoattractant protein-5), CCL5 (RANTES), CXCL-10 (IFN-gamma-inducible protein-10), and CXCL9 (monokine induced by IFN-gamma) and their corresponding chemokine receptors CCR2, CCR5, CCR1, and CXCR3. Because CCR2 was found to be highly induced, we tested the specific role of CCR2 in islet allograft rejection by transplanting fully MHC mismatched islets from BALB/c mice into C57BL/6 wild-type (WT) and CCR2-deficient mice (CCR2-/-). A significant prolongation of islet allograft survival was noted in CCR2-/- recipients, with median survival time of 24 and 12 days for CCR2-/- and WT recipients, respectively (p < 0.0001). This was associated with reduction in the generation of CD8+, but not CD4+ effector alloreactive T cells (CD62L(low)CD44(high)) in CCR2-/- compared with WT recipients. In addition, CCR2-/- recipients had a reduced Th1 and increased Th2 alloresponse in the periphery (by ELISPOT analysis) as well as in the grafts (by RT-PCR). However, these changes were only transient in CCR2-/- recipients that ultimately rejected their grafts. Furthermore, in contrast to the islet transplants, CCR2 deficiency offered only marginal prolongation of heart allograft survival. This study demonstrates the important role for CCR2 in early islet allograft rejection and highlights the tissue specificity of the chemokine/chemokine receptor system in vivo in regulating allograft rejection.

Animals↗
PubMed2004

Repression of AGAMOUS-LIKE 24 is a crucial step in promoting flower development.

Flower development begins as floral meristems arise in succession on the flank of the inflorescence meristem. Floral meristem identity genes LEAFY (LFY) and APETALA1 (AP1) promote establishment and maintenance of floral identity in newly formed floral primordia. Without their activity, the floral primordia develop with inflorescence characteristics. The underlying molecular-genetic mechanism is unknown. Here we show that these phenotypes are due in large part to the ectopic expression of AGAMOUS-LIKE 24 (AGL24), a central regulator of floral meristem identity. We present evidence that AGL24 is an early target of transcriptional repression by LFY and AP1. Without such repression, continued AGL24 expression in floral meristems is sufficient to cause floral reversion regardless of the activation of floral organ identity genes. This indicates that LFY and AP1 promote floral development not only by positively regulating genes activated in flower development, but also by repressing AGL24, a promoter of inflorescence fate.

Arabidopsis↗
PubMed2004

Multiple brain tumors of diffuse large B cell lymphoma in a patient with Waldenström's macroglobulinemia/ lymphoplasmacytic lymphoma: PCR and DNA sequence analysis show evidence of differences in clonality of the two B cell malignancies.

Multiple brain tumors of diffuse large B cell lymphoma (DLBL) were observed in a 75-year-old man with Waldenström's macroglobulinemia (WM). Paravertebral and multiple subcutaneous nodules occurred in succession and he died 4 months after onset. We investigated B cell monoclonality by means of polymerase chain reaction (PCR) analysis and sequencing of the immunoglobulin heavy chain of paraffin-embedded sections. The PCR product of the brain tumors showed a different rearrangement pattern from those of the other sections. The co-occurrence of DLBL with WM is rare, and some investigators have examined the clonality of the two malignancies. This case is important because DLBL brain tumors co-occurred with WM, enabling us to prove that DLBL and WM have different clonality.

Aged↗
PubMed2003

Whorl-specific expression of the SUPERMAN gene of Arabidopsis is mediated by cis elements in the transcribed region.

The SUPERMAN (SUP) gene of Arabidopsis is involved in controlling cell proliferation in stamen and carpel primordia and in ovules during flower development. The SUP gene encodes a transcription factor with a C2H2-type zinc finger motif, a serine/proline-rich domain, a basic domain, and a leucine-zipper-like domain and is expressed in a very limited region in stamen primordia and in the developing ovary during flower development. The SUP gene is susceptible to methylation, resulting in epigenetic gene silencing. To understand how the SUP gene is expressed spatially and temporally in its restricted domain, and why methylation of the transcribed region affects early-stage SUP expression, we have identified the SUP cis regulatory elements by characterizing SUP gene fusions. These studies show that the SUP gene has discrete upstream promoter elements required for expression in stamen primordia in early stages and in the ovary in later stages. The promoter activity for stamen primordia is modulated by several positive and negative elements located in the transcribed and translated regions. Several regulatory elements in the transcribed region correlate with the areas of the gene that are heavily methylated in epigenetic alleles; these data provide a possible explanation of how methylation of the transcribed region represses transcription.

Arabidopsis↗
PubMed2003

Myofibrillar responsiveness to cAMP, PKA, and caffeine in an animal model of heart failure.

We investigated whether an alteration of myofilament calcium responsiveness and contractile activation may in part contribute to heart failure. A control group of Broad Breasted White turkey poults was given regular feed without additive, whereas the experimental group was given the control ration with 700 ppm of furazolidone at 1 week of age for 3 weeks (DCM). At 4 weeks of age, left ventricular trabeculae carneae were isolated from hearts and calcium-force relationships studied. No differences in calcium-activation between fibers from control or failing hearts were noted under standard experimental conditions. Also failing hearts demonstrated no significant shift in the population of troponin T isoforms but we did observe a significant 4-fold decrease in TnT content in failing hearts compared to non-failing hearts. Addition of caffeine, however, resulted in a greater leftward shift on the calcium axis in fibers from failing hearts. At pCa 6, caffeine increased force by 26+/-2.1% in control fibers and 44.5+/-8.7% in myopathic fibers. Cyclic AMP resulted in a greater rightward shift on the calcium axis in failing myocardium. In control muscles, the frequency of minimum stiffness (f(min)) was higher than in muscles from failing hearts. cAMP and caffeine both shifted f(min) to higher frequencies in control fibers whereas in fibers from failing hearts both caused a greater shift. These results lead us to conclude that heart failure exerts differential effects on cAMP and caffeine responsiveness. Our data suggest that changes at the level of the thin myofilaments may alter myofilament calcium responsiveness and contribute to the contractile dysfunction seen in heart failure.

Actin Cytoskeleton↗
PubMed2003

Mg-ATPase and Ca+ activated myosin AtPase activity in ventricular myofibrils from non-failing and diseased human hearts--effects of calcium sensitizing agents MCI-154, DPI 201-106, and caffeine.

We investigated the effects of two purported calcium sensitizing agents, MCI-154 and DPI 201-106, and a known calcium sensitizer caffeine on Mg-ATPase (myofibrillar ATPase) and myosin ATPase activity of left ventricular myofibrils isolated from non-failing, idiopathic (IDCM) and ischemic cardiomyopathic (ISCM) human hearts (i.e. failing hearts). The myofibrillar ATPase activity of non-failing myofibrils was higher than that of diseased myofibrils. MCI-154 increased myofibrillar ATPase Ca2+ sensitivity in myofibrils from non-failing and failing human hearts. Effects of caffeine similarly increased Ca2+ sensitivity. Effects of DPI 201-106 were, however, different. Only at the 10(-6) M concentration was a significant increase in myofibrillar ATPase calcium sensitivity seen in myofibrils from non-failing human hearts. In contrast, in myofibrils from failing hearts, DPI 201-106 caused a concentration-dependent increase in myofibrillar ATPase Ca2+ sensitivity. Myosin ATPase activity in failing myocardium was also decreased. In the presence of MCI-154, myosin ATPase activity increased by 11, 19, and 24% for non-failing, IDCM, and ISCM hearts, respectively. DPI 201-106 caused an increase in the enzymatic activity of less than 5% for all preparations, and caffeine induced an increase of 4, 11, and 10% in non-failing, IDCM and ISCM hearts, respectively. The mechanism of restoring the myofibrillar Ca2+ sensitivity and myosin enzymatic activity in diseased human hearts is most likely due to enhancement of the Ca2+ activation of the contractile apparatus induced by these agents. We propose that myosin light chain-related regulation may play a complementary role to the troponin-related regulation of myocardial contractility.

Ca(2+) Mg(2+)-ATPase↗
PubMed2003

Allorecognition and effector pathways of islet allograft rejection in normal versus nonobese diabetic mice.

Islet transplantation is becoming an accepted therapy to cure type I diabetes mellitus. The exact mechanisms of islet allograft rejection remain unclear, however. In vivo CD4(+) and CD8(+) T cell-depleting strategies and genetically altered mice that did not express MHC class I or class II antigens were used to study the allorecognition and effector pathways of islet allograft rejection in different strains of mice, including autoimmunity-prone nonobese diabetic (NOD) mice. In BALB/c mice, islet rejection depended on both CD4(+) and CD8(+) T cells. In C57BL/6 mice, CD8(+) T cells could eventually mediate islet rejection by themselves, but they produced rejection more efficiently with help from CD4(+) T cells stimulated through either the direct or indirect pathway. In C57BL/6 mice, CD4(+) T cells alone caused islet rejection when only the direct pathway was available but not when only the indirect pathway was available. In contrast, in NOD mice, CD4(+) T cells alone, with only the indirect pathway, could mediate islet and cardiac allograft rejection. These findings indicate that different mouse strains can make use of different pathways for T cell-mediated rejection of islet allografts. In addition, they demonstrate that NOD mice, which develop autoimmunity and are known to be resistant to tolerance induction, have an unusually powerful CD4(+) cell indirect mechanism that can cause rejection of both islet and cardiac allografts. These data shed light on the mechanisms of islet allograft rejection in different responder strains, including those with autoimmunity.

Animals↗
PubMed2003

The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity.

Inducible costimulatory molecule (ICOS) plays a pivotal role in T cell activation and Th1/Th2 differentiation. ICOS blockade has disparate effects on immune responses depending on the timing of blockade. Its role in transplantation immunity, however, remains incompletely defined. We used a vascularized mouse cardiac allograft model to explore the role of ICOS signaling at different time points after transplantation, targeting immune initiation (early blockade) or the immune effector phase (delayed blockade). In major histocompatibility-mismatched recipients, ICOS blockade prolonged allograft survival using both protocols but did so more effectively in the delayed-treatment group. By contrast, in minor histocompatibility-mismatched recipients, early blockade accelerated rejection and delayed blockade prolonged graft survival. Alloreactive CD4+ T cell expansion and alloantibody production were suppressed in both treatment groups, whereas only delayed blockade resulted in suppression of effector CD8+ T cell generation. After delayed ICOS blockade, there was a diminished frequency of allospecific IL-10-producing cells and an increased frequency of both IFN-gamma- and IL-4-producing cells. The beneficial effects of ICOS blockade in regulating allograft rejection were seen in the absence of CD28 costimulation but required CD8+ cells, cytotoxic T lymphocyte antigen-4, and an intact signal transducer and activator of transcription-6 pathway. These data define the complex functions of the ICOS-B7h pathway in regulating alloimmune responses in vivo.

Animals↗