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Toru Higuchi

Publications and source records attributed to Toru Higuchi.

8 recordsLinked to original sources
PubMed2005

Induction of obliterative airway disease in murine tracheal allografts by CD8+ CTLs recognizing a single minor histocompatibility antigen.

The role of minor histocompatibility Ag (mHAg)-specific CD8+ CTLs in the pathogenesis of chronic lung allograft rejection (bronchiolitis obliterans syndrome) remains to be elucidated. Thus, the goal of this study was to define the role of a single mHAg mismatch at the polymorphic H13 allele in the development of obliterative airway disease (OAD) after murine heterotopic tracheal transplantation. The H13a and H13b alleles encode for the SSVVGVWYL (SVL9) and SSVIGVWYL (SIL9) mHAgs, respectively, presented in the context of the H2Db MHC class I molecule. Toward this, C56BL/10SnJ (H13a) tracheal allografts were transplanted into congenic B10.CE-H13b Aw(30NX)/Sn (H13b) recipients. The allografts were harvested at 30, 60, and 90 days after transplantation, and OAD lesions (epithelial damage, cellular infiltration, and luminal fibrosis) were confirmed histologically. Selected groups of mice were immunized (s.c.) or tolerized (i.v.) with the SVL9 peptide before transplantation. This single mHAg mismatch induced the development of OAD within 90 days. SVL9 immunization significantly accelerated the kinetics of the OAD lesions. In contrast, SVL9 tolerization completely abrogated the development of OAD. This was correlated with a complete abrogation of H13a-specific CD8+ CTL responses with a significant reduction in the frequency of IFN-gamma-producing CTLs and the activation of TGF-beta-producing CD8+ T cells. In conclusion, a single mHAg mismatch can induce the development of OAD. These data also suggest that mHAg-reactive CD8+ CTLs may play an important role in the pathogenesis of chronic lung allograft rejection in humans.

Animals↗
PubMed2005

Stabilization of microtubule dynamics at anaphase onset promotes chromosome segregation.

Microtubules of the mitotic spindle form the structural basis for chromosome segregation. In metaphase, microtubules show high dynamic instability, which is thought to aid the 'search and capture' of chromosomes for bipolar alignment on the spindle. Microtubules suddenly become more stable at the onset of anaphase, but how this change in microtubule behaviour is regulated and how important it is for the ensuing chromosome segregation are unknown. Here we show that in the budding yeast Saccharomyces cerevisiae, activation of the phosphatase Cdc14 at anaphase onset is both necessary and sufficient for silencing microtubule dynamics. Cdc14 is activated by separase, the protease that triggers sister chromatid separation, linking the onset of anaphase to microtubule stabilization. If sister chromatids separate in the absence of Cdc14 activity, microtubules maintain high dynamic instability; this correlates with defects in both the movement of chromosomes to the spindle poles (anaphase A) and the elongation of the anaphase spindle (anaphase B). Cdc14 promotes localization of microtubule-stabilizing proteins to the anaphase spindle, and dephosphorylation of the kinetochore component Ask1 contributes to both the silencing of microtubule turnover and successful anaphase A.

Anaphase↗
PubMed2005

Induction of obliterative airway disease by anti-HLA class I antibodies.

Anti-HLA class I Abs are associated with the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. BOS is characterized histologically by fibrosis and airway epithelial cell apoptosis. We have previously shown that anti-HLA class I Abs induce proliferation, growth factor production and apoptosis in airway epithelial cells in vitro. Thus, this study was designed to determine whether anti-HLA class I Abs alone could induce obliterative airway disease (OAD) in heterotopic murine tracheal allografts. Toward this, HLA-A*0201-transgenic tracheal allografts were transplanted into Rag1-deficient mice treated with the W6/32 anti-HLA class I mAb. Allografts were harvested at days +30, +45, +60 and +90. Allografts displayed epithelial metaplasia by day +45, epithelial destruction and mild cellular infiltration by day +60 and complete lumen obliteration and moderate cellular infiltration by day +90. Anti-HLA class I Abs induced the production of several growth factors and growth factor receptors and apoptosis of parenchymal cells in the allograft. In addition, anti-HLA class I Abs induced macrophages and granulocytes infiltration. The results from this study demonstrate that anti-HLA class I Abs play an important role in the pathogenesis of OAD by inducing growth factor production, apoptosis and chemotaxis of inflammatory cells.

Animals↗
PubMed2005

[Rapid diagnosis of donor infection and renal allograft contamination using a polymerase chain reaction technique and rapid shaking culture].

Post transplant infection is one of the serious complications of the organ recipients. We detected the donor infections and allograft contaminations in a limited period of time by polymerase chain reaction (PCR) and rapid shaking culture (RSC). The pre-procurement blood from 86 possible renal donors as well as the preservation solution (PS) and renal pelvic urine (PU) from 158 grafts were examined in order to detect highly virulent organisms such as methicillin resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and fungi. The average age of donors was 48.8 years old. The average period between the admission and brain death was 4.9 days, and the average period between the brain death and cardiac arrest was 3.6 days. The inflammatory indices such as body temperature, white blood cell count and C-reactive protein increased to 37.9 +/- 1.1 degree C, 12,600 +/- 6300/microl, and 20.2 +/- 11.6 mg/dl, respectively. Following PCR and RSC, procurement operations of the three possible donors were cancelled because of systemic bacterial infections by MRSA or Bacteroides fragilis. Six out of 158 grafts were discarded due to the diagnoses of MRSA or Candida albicans in PS and/or PU. All the other 148 grafts were transplanted. Following transplant, no single infectious complication transmitted by the graft was noted. We conclude that PCR combined with RSC is very accurate and useful for detecting donor infections and allograft contaminations, which may cause severe complications in the recipients.

Bacteria↗
PubMed2004

Cdc14 phosphatase induces rDNA condensation and resolves cohesin-independent cohesion during budding yeast anaphase.

At anaphase onset, the protease separase triggers chromosome segregation by cleaving the chromosomal cohesin complex. Here, we show that cohesin destruction in metaphase is sufficient for segregation of much of the budding yeast genome, but not of the long arm of chromosome XII that contains the rDNA repeats. rDNA in metaphase, unlike most other sequences, remains in an undercondensed and topologically entangled state. Separase, concomitantly with cleaving cohesin, activates the phosphatase Cdc14. We find that Cdc14 exerts two effects on rDNA, both mediated by the condensin complex. Lengthwise condensation of rDNA shortens the chromosome XII arm sufficiently for segregation. This condensation depends on the aurora B kinase complex. Independently of condensation, Cdc14 induces condensin-dependent resolution of cohesin-independent rDNA linkage. Cdc14-dependent sister chromatid resolution at the rDNA could introduce a temporal order to chromosome segregation.

Adenosine Triphosphatases↗
PubMed2002

Different kinetics of obliterative airway disease development in heterotopic murine tracheal allografts induced by CD4+ and CD8+ T cells.

BACKGROUND: Both T and B cells have been shown to be implicated in the pathogenesis of bronchiolitis obliterans syndrome, which is considered to represent chronic lung allograft rejection. However, the relative contributions of T cells and alloantibodies in the pathogenesis of the disease are still unknown. In this study, we used an heterotopic murine tracheal transplantation model to determine the contribution of these components of the immune system in the pathogenesis of posttransplant obliterative airway disease (OAD). METHODS: Tracheal allografts from BALB/c and HLA-A2-transgenic (HLA-A2+) mice were heterotopically transplanted into C57BL/6, CD4-knockout (KO), CD8-KO, Ig-KO, and Rag1-KO mice. In additional experiments, recipient mice were pretreated with depleting antibodies against CD4+, CD8+, and NK1.1+ cells. Development of OAD was determined by histopathology at days 10, 30, 60, 90, and 180 after transplantation. RESULTS: HLA-A2+ allografts transplanted into C57BL/6, CD8-KO, and Ig-KO mice demonstrated OAD lesions by day 30. In contrast, allografts transplanted into CD4-KO mice showed no OAD lesions at day 30, partial OAD development by days 60 and 90, and complete OAD development by day 180. No OAD development was observed in allografts transplanted into Rag1-KO mice. Treatment with anti-NK1.1 antibody did not show any effect on posttransplant OAD development. In contrast, anti-CD4+ or anti-CD8+ antibody treatments partially reduced the OAD histopathology and combined anti-CD4/CD8 antibody treatment further abrogated the histopathology of the disease. CONCLUSION: These results show that both CD4+ and CD8+ T cells have a role in the pathogenesis of OAD and that natural killer cells and alloantibodies are not necessary for the development of this disease.

Animals↗
PubMed2002

Protein kinase A regulates sexual development and gluconeogenesis through phosphorylation of the Zn finger transcriptional activator Rst2p in fission yeast.

Protein kinase A (PKAi a cyclic AMP-dependent protein kinase) negatively regulates sexual development and gluconeogenesis in fission yeast by suppressing the transcription of ste11 required for the former and the transcription of fbp1 required for the latter. Here we show that Rst2p, a zinc finger protein that can bind to the upstream region of ste11 and fbp1 via the STREP motif, mediates the activity of PKA to transcription of these genes. A simple reporter system confirmed that PKA could cause its negative effect on transcription through the combination of Rst2p and STREP. Rst2p was phosphorylated by PKA in vitro at two consensus sequences on it. Substitution of the target threonine residues by alanine made the protein active even in the presence of high PKA activity. Rst2p underwent hyperphosphorylation in the medium lacking glucose, and PKA inhibited this hyperphosphorylation. Rst2p was mainly cytoplasmic under high PKA activity but was concentrated in the nucleus when this activity was lowered, suggesting that PKA might regulate ste11 and fbp1 negatively by excluding Rst2p from the nucleus. However, the shift of Rst2p localization was not perfect under physiological conditions, leaving the possibility that PKA inhibits Rst2p function in another way as well. Although the PKA-Rst2p-STREP pathway is apparently central to the regulation of ste11 and fbp1 transcription in accordance with nutritional conditions, some additional paths are likely to connect nitrogen to repression of ste11 and glucose to repression of fbp1. These paths may ensure the specificity between the type of nutrients in shortage and the type of genes to be expressed.

Cyclic AMP-Dependent Protein Kinases↗